Diagnosis and Treatment of Non-Muscle Invasive Bladder Cancer: AUA/SUO Guidelines

This is a talk that gives you I think highlights regarding the guidelines that we have for non-muscle invasive bladder cancer that was a joint product of both the AUA and the SUO, and through the talk I’m going to give you highlights of points that I think are important and that were different from the previous guidelines. So, these guidelines came out less than a year ago, were published actually approximately six months ago, and it’s an attempt to I think integrate some of the newer knowledge that we’ve gained over the time period from the previous guidelines, which was back in 2007.

The purpose of the guidelines, as with most guidelines, is an attempt to give the clinical practicing urologist a framework, an idea of how to evaluate patients, how to treat patients, and how to follow up patients. And this was an attempt for the first time to move away from our index patients, which some of the guidelines have used, and take into account a risk stratification screen, and that is an attempt to basically understand that individual patients represent a very heterogeneous group, and to evaluate each one at a different point in time helps determine their best treatment. And so, we went through a review of I guess 150 different studies focused on randomized clinical trials, and focused on the data that hopefully was of the highest quality, and we were assisted by AHRQ, and the focus was on non-muscle invasive bladder cancer, focusing specifically on TA disease, CIS, and T1 disease. The focus as well was taking into account the most recent grading system, taking into account low-grade disease, papilloma, as well as non-muscle invasive low-grade and high-grade disease.

In understanding the importance of bladder cancer treatment there’s obviously the issue of recurrence as well as looking at prognosis and the issue regarding progression. And so, this is an attempt in this guideline to risk stratify these patients as opposed to the one size fits all. And what we actually did for the first time was come up with a stratification table. Now, this table looked at and identified in buckets low-risk patients, intermediate-risk patients, and high-risk patients. And as one would assume the low-risk bucket clearly low risk. These are small tumors, individual or PUNLMP tumors. The high-risk tumors were those that have higher pathologic concerns, but also actually for the first time we included response to therapy, and I’ll talk a little bit about that as we go through.

The most difficult group was the intermediate-risk group. I mean honestly some of the intermediate-risk group patients act more like low risk, for instance a solitary low-grade larger tumor probably acts more like a low-risk tumor as opposed to a high-risk tumor. But this was an attempt to give some stratification in terms of how these patients have in terms of recurrence as well as progression.

In looking at a diagnosis we went through diagnosis, evaluation, treatment, and follow up, and as we went through the data one thing that was very clear was the lack of standards in terms of describing what is done at the time of TURBT. So, for the first time we actually laid out that in documentation there was debate whether or not we should use maps, verbalization, a combination of both, but an idea of basically giving an idea for that practicing clinician, and anybody else who may be treating that patient, what a tumor looks like, where it’s located, how many tumors there were, and the actual quality and nature of the tumor itself. And part of that was we understood that many times complete visual resection is the goal for the clinician, and that we also understand that many times we are missing tumors, we are not going a good enough job in terms of evaluating them upfront, and actually up to 45% of patients with tumors seen at follow up may be tumors that were missed at the initial TURBT.

Some basic clinical principles that aren’t much different, the importance of performing an upper urinary tract study, as well as the fact that if you have that tricky patient with what appears to be a normal cystoscopy with abnormal urine study, specifically an abnormal cytology, a clinician should consider certain things to do; one would include biopsies of the prostatic urethra, as well as upper tract evaluation and imaging, as well as the use of enhanced cystoscopic techniques, and/or random bladder biopsies. And so, this is actually a new addition to the guidelines from 2007 as well.

Risk stratification; what we did was actually take a combination of the previously well-done models put out by EORTC and CUETO looking at okay these are patients who are more likely to recur, who are more likely to progress, or both. And there were specific factors that came into play for them, including tumor size, tumor focality, the grade, stage, recurrence pattern, and the number of tumors. Well, to this risk panel and stratification we added certain histopathologic variance, specifically lymphovascular invasion, the presence of prostatic urethral involvement, variant histology, and actually poor response to BCG or other intravesical therapy. So, in our risk table we take into account the fact how patients actually responded to a previous treatment, in other words, a patient that came back with a smaller tumor if they’d had previous treatment already they’re put into a higher risk category as opposed to someone who came in de novo. And so, this was actually a big, we think, a big leap forward in terms of determining how patients are likely to do. And we’ll go through the algorithm at the end of this talk.

Again, a new addition was actually the variant histology recognition. These variant histologies have been around forever, and going back and looking at pathology specimens from years ago these are not new pathologies, but these are actually a recognition of pathologic patterns that bring about actually significant concern. Some of these include micropapillary, neuroendocrine, sarcomatoid, plasmacytoid. Really those types of pathologies are one where we’ve actually recommended that an experienced GU pathologist should review this. Now, this brought about some concerns about how do you describe or define an experienced GU pathologist? We left it in this way because not everyone can send a pathology slide to Mayo, to Johns Hopkins, to wherever for a secondary review, but it was an attempt to understand that if there’s concern that this variant histology exists we need another set of eyes that looks at a lot of these to help determine whether or not this is actually happening because due to the high rate of upstaging currently with this disease process we say upfront that we should actually initially consider radical cystectomy, which is a significant leap forward compared to the other bladder cancer types within the guidelines.

Biomarkers; I think Dr. Black is going to speak about biomarkers and an update regarding this, but what we found was that there are a lot of biomarkers out there but perhaps not as good as we would like them, and we say that upfront that they should not replace cystoscopy. This is a partial list of the biomarkers that are out there. They’re helpful in certain instances but they are not good enough in any way to replace cystoscopy. And specifically, the use of cytology we actually brought into account and for low-risk cancer in a normal cystoscopy, and we say that actually cytology should not be used as a normal routine kneejerk biomarker, and part of that is the data that clearly shows that the use of cytology is not only insensitive but can also have areas of concern and are unlikely to be helpful in these patients with a low risk of progression. Now, for patients that actually have higher risk disease, CIS, who have been treated with BCG, we do think that certainly the biomarkers may be helpful to help determine how patients are likely doing or responding to therapy.

A second point that has been reemphasized by these guidelines were the importance of a repeat resection or a repeat TURBT. Upfront we say that if there’s any question that there’s an incomplete initial resection then further resection should be done. A change here that I’ve outlined in red is for those patients with T1 disease. In the previous guidelines we talked about if there is no muscle present that a T1 patient or that pathology should undergo a repeat resection. This has actually been modified or strengthened to basically say if there is any patient with high-grade T1 disease that a repeat TURBT should be performed if there is any thought to go ahead and try to save this patient’s bladder, and not proceed to cystectomy. So, this is a real change. Part of that is understanding along those lines that intravesical therapy tends to be helpful with certain disease parameters as opposed to others, and we understand that for this group of patients we are not as strongly an advocate in terms of giving everyone perioperative chemotherapy, but an understanding that it is an option.

In a low-risk patient we say clearly they should not administer actually perioperative chemotherapy. For intermediate and higher risk patients intravesical immunotherapy or chemotherapy is reasonable for an intermediate risk, but for the high-risk patient we do recommend BCG as the treatment of choice, and specifically we actually modify a little bit in terms of recommendations regarding BCG. There’s no particular strain that we’ve recommended in the guidelines. We don’t talk about a particular strength, and right now there is not enough data to say a combination of immunotherapy with chemotherapy is any way better.

This is a bit of a modification from the SWOG outline protocol regarding BCG maintenance therapy, and for intermediate risk patients we say that upfront that our recommendation is to consider maintenance for at least a year, whereas for the high-risk patient we do recommend continued up to three years, taking into account the impact of possible side effects associated with it. Now, part of this was based upon a European trial which was not powered to overall outcomes, actually was looking at complications and side effects, and what was basically found was that, let me go back, was that for patients with intermediate risk disease if you had a combination of either one-third strength or one year, one-third strength or three years there was really no difference in terms of outcomes or side effects, but there seemed to be an advantage for high-risk patients for a full dose and for three years of therapy, for the full three years, and as a result, for the high-risk patients we do recommend that. For the intermediate-risk patient we say at least a year and if it’s well tolerated continue to attempt to try to complete the full three years.

Relapse regimen; still importantly for those patients that have high-grade T1 disease after single dose of intravesical BCG if there is still disease present the recommendation is still to offer radical cystectomy. In addition, we’ve made it clear that those patients that have BCG and it’s not well tolerated and/or unfit for cystectomy we need to consider after two induction courses of BCG another therapy. Any more BCG after that has really little, if any, response and probably if anything a negative response. And so, we recommend that if they’re not fit for cystectomy or unwilling to consider at least a clinical trial, and/or a different type of intravesical regimen. That intravesical-specific regimen was not outlined specifically. Options are given within the actual document.

Cystectomy; this was actually a statement that we made upfront, which we didn’t previously in the guidelines, is for patients with actually low-risk disease, lower intermediate-risk disease, an attempt should be made to have some type of bladder sparing treatment done. Large-volume tumors can be treated adequately with resection and intravesical therapy, and upfront this should be attempted before moving to cystectomy. In addition, for high-grade disease, and those that have varying histologies initial radical cystectomy is an option. So, understanding the importance of those patients with perhaps a higher volume T1 disease or multiple locations, and/or those with varying histologies upfront cystectomy is definitely something that can be considered and should be offered. And in those patients who have continued disease and/or recurrence soon after their intravesical immunotherapy the radical cystectomy should be offered.

We have a separate section for the first time to talk about enhanced cystoscopy techniques, understanding that not everyone has these available. We basically say that if available we should offer blue-light cystoscopy to increase detection and decrease recurrence rates. In addition, they may consider the use of NBI for those patients also to increase detection and to decrease recurrence rates.

In 2007, we had nothing about follow-up. Our one statement was that these patients should undergo follow up and routine surveillance. So, an attempt to try to address that need unfortunately there was no evidence that says this is the best policy or this is the best practice that we should advocate. So, these are our recommendations; for low-risk patients at their first surveillance cystoscopy if that is negative the next surveillance should be done six to nine months later. So, the habit of every three months for the first couple of years is something that we’ve actually pushed off, and to try to decrease the morbidity and also decrease the rigor for these low-risk patients. In an asymptomatic patient with a history of low-risk disease routine upper tract surveillance, so the CT scan or the retrograde pyelograms, or the yearly renal ultrasounds are actually not necessary and should not be performed. And for low-grade disease if there’s anything smaller, for the first time we did support the use of in-office fulguration for those patients who have previous pathologically documented low-risk disease.

For those patients with intermediate-risk disease we actually accelerated or made more rigorous the surveillance protocol, and allowed some flexibility of every 3 to 6 months and then every 6 to 12 months. But for high-risk patients we did maintain the rigor of every three to four months for the first couple of years to do evaluation cystoscopy. And for these higher risk or intermediate risk patients that upper tract surveillance was something that should be considered, and one- to two-year intervals we thought was reasonable.

We have a whole section, as do most guidelines, regarding ongoing research, and this is just a partial list of what’s going on with non-muscle invasive disease. And this is our algorithm. So, this is a complicated but one-page, that was the goal of both the AUA and the SUO was to try to get on one page an outline of the algorithm. And this I can tell you at our residents’ clinic, at our VA, this is the one page that the residents have. This is the one page my partners have on the wall to basically help go over kind of all right, I’ve got this patient, what do we do? Now, the nice thing about this if we look at low risk is we’ve got the consideration of post-operative chemotherapy. If there’s a complete response surveillance, if there’s recurrence or if there’s partial no response this patient actually gets moved into the intermediate risk patient. He’s not always a low-risk patient. It takes into account response and how they do. And how you’ve got the intermediate-risk group and the high-risk group, and you’ve got these dotted lines that tell you hey you can consider upfront cystectomy for the high-risk patients. For those patients who actually failed chemotherapy, failed BCG they move straight to cystectomy. And so, you’ve got this basically variation where patients can actually change risk groups based upon their recurrence and their progression rates, and also take into account variability and flexibility.

I’ve gone through this multiple times with different types of scenarios and so far it seems to be okay. If anybody finds any issues or concerns this is something that we’ll continue to update and evaluate.

What’s next? Well, actually this coming May for the first time actually multiple organizations are going to come together for the muscle invasive guidelines. So, there has been a memorandum of understanding and an agreement between the AUA, ASTRO, ASCO, and the SUO, and there’s a guidelines committee specifically for muscle invasive bladder cancer. And some of the panel members include actually some, actually some of the folks here as well, and this takes into account a multidisciplinary group of urologists, of medical oncologists, of radiation oncologists, of patient advocates, all in an attempt to actually provide guidelines for muscle invasive disease. And this is the first time that actually like I said all of the different organizations that actually treat muscle invasive bladder cancer have come together, and that presentation will be actually done by the vice chair, Jeff Holzbeierlein, and that will be presented actually at the AUA meeting in Boston.

Some concepts, a brief preview, there will be some focus on neoadjuvant chemotherapy taking into account the important data that actually Dr. Crawford mentioned that still has not, or is starting to gain traction but an attempt for the first time to actually put that into guidelines. Actually, the role of multimodality preserving, bladder preserving therapy and the importance of surveillance and how that should be done for muscle invasive disease for patients who actually have had their bladders removed or have had some type of bladder preserving modality. So, that should be, so far it’s on timeline and should be done, and definitely should be presented by the AUA this spring.

This is the last slide, this is actually the guideline’s panel from the AUA and SUO guidelines. The vast majority of work was clearly done by all of the panel members here who completed those guidelines in actually less than a year, which is actually the quickest that AUA has ever done a guideline. So, I thank you for your attention.

Update on Radiopharmaceuticals: Choosing a Companion Drug to Radium-223

I’m going to give you an update on radiopharmaceuticals, choosing a companion drug for Radium-223. So first I’d like to review some of the data with radium. These are my disclosures.

So we know that for bone targeted therapy there are a variety of different agents that are bone specific. We have beta emitters, which are strontium and samarium. As well know, these drugs do not improve survival, but they do palliate pain. The alpha emitters, radium-223. And then there are the osteoclast targeted agents, zoledronic acid and denosumab. But of course, we also have other agents as well that effect different portions of prostate cancer. The big difference, of course, with alpha and beta emitters has to do with DNA damage. As we know, an alpha particle consists of a helium nucleus. It does not penetrate a sheet of paper. It kills about 1 to 10 cells predominately by inhibiting double-stranded DNA breaks. The beta particles, it requires more energy to cause DNA hits. And it causes predominantly single-stranded DNA breaks. And so this is the reason why we think there’s such a difference in the activity. And, of course, there’s a difference in the radius of activity as well, which has implication for side effects.

So this is a cartoon that depicts bone marrow with a tumor that’s present. And, of course, there’s marrow and stroma that’s around that tumor. A beta particle ranges this area. It’s about 1 to 1,000 cell diameters, the activity of the radiation. And then the alpha particle is a much, much smaller area of activity, it’s about 2 to 10 cell diameters overall; and thus, normal marrow is not affected to the same degree as it would a beta particle.

The trial that led to the approval of radium-223 for prostate cancer was ALSYMPCA. As we know, this was a trial that had two different components, both docetaxel ineligible or refusal, patients as well as docetaxel experienced patients. Patients had to have symptomatic bone metastases, more than two lesions, no evidence of visceral metastases, and as I mentioned before, they had to be either post-docetaxel or unfit for docetaxel. They were stratified based upon alkaline phosphatase, bisphosphatase use and prior docetaxel, and then randomized to a maximum of 6 cycles of radium-223, plus best supportive care, versus best supportive care alone.

Now, it’s important to note that this best supportive care included adding bicalutamide, included adding estrogens, included external beam radiation therapy to hot spots which made them painful. So this is just not really pure radium arm, but would normally what somebody would do in the standard of care. It did not include the newer generation drugs such as abiraterone or enzalutamide, which we’ll talk about a little bit later.

This trial was what one would expect with randomization, very, very equally balanced. Median age was about 70. About half of patients had more than 20 lesions on bone scan, predominately ECOG 1 or better for the performance status. If you look at the hemoglobins, these are not terribly advanced. Hemoglobin median of 12.2. This is a known poor prognostic factor, LDH of 315, median PSA between 146 and 170. And about half of the patient were on bisphosphonates. About half of patients also had prior docetaxel treatment.

This is the combined survival curve for both the post-docetaxel and the docetaxel ineligible patients. The hazard ratio is 0.65, and the median survival was 14.9 months versus 11.3 months overall. If we break this up based upon prior chemotherapy, median survival of 4.64, the docetaxel naïve patients, and 3.1 for those patients who were docetaxel experienced. Not unexpected.

Now, if we start looking at skeletal-related events, as defined by Fred Sodd’s [phonetic] trial, we see that there’s a delay in the time to the first SRE. This giving radium compared to the placebo, it’s about a 6 month delay. And we start looking at the individual skeletal event related components the one that always strikes out is spinal cord compression, which to my knowledge is the only trial that shows a difference in, or improvement in rates of spinal cord compression. It makes, of course, since this a bone targeted agent.

A very well-tolerated drug. If we start looking at grade 3 and grade 4 adverse events, slightly higher in the placebo. That’s predominately due to pain events. Discontinuation due to adverse events only 17% of patients, and death due to AEs, 16% of patients.

The majority of patients did get all 6 injections, 63% of all patients, and 47% received all 6 placebo injections. Adverse events, these are, of course, related to hematologic events predominately. We do see grade 3 and grade 4 neutropenia, thrombocytopenia, but not anywhere near what you would expect samarium or strontium.

When we look at the prognostic subgroups that were looked at in this trial, alkaline phosphatase, use of bisphosphonates, docetaxel, ECOG performance test, all these, it’s shifted toward the left, towards radium.

So we’ve had many questions about whether you can safely give chemotherapy, and this has a lot, of course, important implications for therapeutic layering and how we sequence our drugs. And from ALSYMPCA is there any evidence that chemotherapy treatment is compromised by giving radium-223 upfront. And there was a subgroup analysis, or retrospective analysis looking at those patients who received radium. And of those patients, 90 of the 615 patients in the radium group were evaluated, and 54 of the 307 in the placebo group, and the most common chemo therapeutic agents that were administered were docetaxel, of course, mitoxantrone and cyclophosphamide. Very well balanced for age and also the different characteristics as far as overall extent of disease is concerned. Similar rates of bisphosphonate use, and also similar rates of median numbers of injections of study drug.

If we look at the platelets and the hemoglobin they seem to cross for those patients who were on the placebo arm and received chemotherapy, or those patients who received radium-223. It does seem to be a difference in the neutrophil counts, but there is no difference in febrile neutropenia between the two different arms. So I think that when we’re looking at therapeutic layering and sequencing it’s not really going to make a difference whether you give the radium before or afterwards. And, of course, there’s been no trial that’s been done looking at cabazitaxel in this situation.

So we talked regular skeletal-related events according to the Sodd definition. What about systematic skeletal-related events, which I think are a little bit more clinically significant. Oliver Sartaor went back and he looked at the data from ALSYMPCA and looked at rates of symptomatic skeletal events. About a third of the patients treated with radium-223 versus 38% of the placebo group had an event, but the time to the first event was longer in those patients who received radium by about 6 months overall. When you start looking at the components that he looked at of the symptomatic events, the reduction was seen and the need for radiation therapy as well as we pointed out before, the incidence of spinal cord compression, but there was no difference in pathological fractures or tumor-related orthopedic surgical events.

And then Dr. Nilsson has actually looked back at the data 1.5 years after treatment to see if there had been any of types of long-term side effects seen with radium. And I think the most important one, the one that we get most concerned about is the fact that these patients are exposed to an isotope, do they develop leukemia? There weren’t any reports of that, or mild dysplastic syndrome, or primary bone tumors. So again, I think that the long-term safety is being defined.

So what have we learned from ALSYMPCA? What haven’t we learned? Well, we’re improving survival, we’re improving symptomatic skeletal-related events or delaying it. We also have been able to give bisphosphates, external beam radiation therapy, and as mentioned before, the first generation hormonal agents with radium, but we didn’t look at abiraterone, we didn’t look at enzalutamide. Denosumab was not included in the entry criteria. And this has been I think a real frustration for a lot of clinician, the dose of radium is limited to 6 cycles by the FDA approval, so we really can’t give more than 6 cycles at this particular point. So can we give more than that? And I think I’m going to ask that question.

So, protocol 16506, I borrowed these slides from Oliver Sartor, looked at radium in patients who have had 6 cycles and then progressed, and were strictly eligible by homologic criteria. They were eligible to receive 6 more cycles of radium, and what they concluded was that radium could safely be given for another 6 cycles after the first 6 cycles.

What I think is very, very interesting is the pattern of progressions. And this actually leads us to think of how we can partner radium with other drugs. So this is the progression in bone. As one would expect, the progression in bone is not particularly, not at a high rate. More than 90% of patients did not progress in bone after the 6 cycles of radium, not surprising. Now, think back to ALSYMPCA as well, unfortunately, that trial did not do scans mid and after the third cycle. So again, this is sort of new territory. But what was very, very interesting was the progression of disease was dominant in soft tissue, which again leads us to think that we’d like to combine radium with drugs that target agents in soft tissue, such as hormonal agent, or potentially chemotherapeutic agents.

So this is modified from our friend Ken Pienta, looking at the way that we can think about prostate cancer. As we know, radium hits three different portions of the bone equilibrium with the tumor cell and the stroma. It affects the stroma, it affects the extracellular matrix, as well as the osteoblasts, and then, of course, it directly causes cytotoxicity of the tumor cells. This also lets antigens out, it could affect the immune system. And there are studies, which we’ll talk about later, which combine radium along with immune agents. And then, of course, we have agents that effect osteoclasts, such as bisphosphates and denosumab. And then our other targeted therapies, cytotoxic and androgen directed therapies, these all can be used to help improve overall response rates. Remember, as we’ve often pointed out at this meeting, Hodgkin’s disease is cured by four drugs, one approach, it’s very, very unlikely that one approach is going to cure prostate cancer. So that’s why we’ve got to look at this in terms of multiple areas of target.

So, we know that in patients who undergo bisphosphate treatment there can be an upregulation or a flare effect after giving bisphosphonates. And we again also see this with chemotherapy, we see this with abiraterone, we see this with enzalutamide. So, since we’re increasing the bone activity would it make sense to give radium in this particularly situation? That’s the interesting question. So if we look at the data from ALSYMPCA and look at bisphosphonates in terms of is an increased effect on survival in those patients who receive bisphosphonates versus those patients who didn’t, there isn’t any effect. But there is an effect on skeletal-related events. When you look at the data from the expanded access trial you see a very, very different pattern when you combine radium with denosumab. Those patients who received denosumab have a better survival than those patients who just simply received radium alone. So it’s radium plus denosumab versus radium. There does seem to be a better survival. Be careful, of course, this is only hypothesis generating. It’s not a randomized study.

The same thing is seen when you combine radium-223 with abiraterone. You see the same effect. There’s a better survival in those patients with have abiraterone plus radium, versus radium alone. Is that due to this issue about flaring the bone up and causing more targets for radium to hit, or is this because you’re affecting soft tissue with abiraterone? It’s not really clear, but again, something we need to study in the future.

So, where should we put radium in this continuum? Should it be right at the start of treatment, should it be at the induction of sclerosis, should it be at any other point in the course of disease progression, we really don’t have a good answer, nor do we have any good modeling for this, in fact. So again, the question is can we take advantage of this flare because we know that abiraterone and enzalutamide can cause flare-up of the bone lesions and this again may make this a more acceptable target for radium.

So, there are prospective trials that are underway. Radium plus abiraterone in a phase 3 study, as well as radium plus or minus, or enzalutamide plus or minus radium, so this may help to give us better answers to whether we can use this upfront. Remember, we’ve used these types of agents late in the disease because of strontium and samarium not demonstrating survival benefit. So it does really make sense to move this upfront in patients rather than waiting until they’re too sick.

This trial has completed accrual and I hope that we’ll be reading out some time this year. This is a randomized phase 3 trial that I led. Our primary endpoint was to look at radiographic progression-free survival to see if we were seeing any difference in scanning. So the control arm, so to speak, is radium-223 or group 1. Group 2 is radium plus abiraterone. And then group 3 was radium plus enzalutamide. So this trial has completed accrual and I hope that we’ll have an answer sometime within the next couple of—you know, a year or two as to what the progression-free survival rate is.

So, a couple of other things that have been seen in the expanded access trial study. The number of injections of radium, the survival seems to be better if you have more radium versus less radium. The only trouble is is that we see the same thing for the placebo arm. So does this mean that the patients will move on to more injections because they’re healthier, I’m not really sure at this particular point. But again, this leads us, we have to be very, very careful when we’re interpreting the biology of this disease. Also we see a better survival with the number of injections, but again, this may be related to biology as well as to the radium injection.

So, some of the predictors for receiving more cycles include higher numbers of anti-cancer treatments, ECOG performance status, as well as hemoglobin. So these, again, may be ways that we can predict who is going to do better with radium overall.

Now, it was noted before in the prior talks that there is this thing called abscopal effect. And what this is is we think that there is actually a release of cytokines when you radiate a patient. Actually, this is also seen with cryosurgery, it’s seen with a number of different local modalities where the distal tumor can respond where the primary tumor does not, or when the primary tumor is being treated, excuse me. So we can exploit this, and it’s thought to be due to an immune mechanism. And one of the things that we’ve seen with treatment such as Provenge is that there is an antigen spread. And there are antigens that are released when cells are dying. So there are two trials that are going on right now that are combing radium along with checkpoint inhibition therapy. Radium is being combined with atezolizumab. This is for patients who have bone disease, but they also have to have a soft-tissue lesion that needs to be biopsied, so it’s a little bit restrictive in the patient population, but nonetheless, it’s going to be answering some very, very interesting biological questions with this. Also pembrolizumab is being combined with radium-223 as well.

We’ve actually found, and my junior – -, Joe Kim is finally getting the paper written up, but we found that there’s upregulation of PD-L1 after radium administration. So this makes this a reasonable approach to go forth with. So you’re releasing antigens with radium and cell death, and then, of course, the immune therapy may actually improve things.

We also should be considering radium upfront. Can we add this earlier with docetaxel and antigen blockade and do even better? I’ve got some problems with this, and I’ll show you why, because I think it’s hard to give full dosages of both. And it may certainly be more reasonable to give this in a patient rather than docetaxel, because some men may not want to undergo that. But we really do need to do a prospective trial, because we don’t know what the long-term effects are of radium at 5 to 7 years in a patient with castrate when they eventually do become castration-resistant, so I think these are important questions.

So why am I a little bit sheepish about giving chemotherapy with radium-223? Because of the data Mike Morris has generate, where he did a phase 1 study where he gave radium and docetaxel at the same time. And, unfortunately, because of the myelosuppression that was seen, he had to wind up giving a lower dose of docetaxel. And the radium was also attenuated to a different schedule. It was given every 6 weeks rather than every 4. So he’s seen that there does seem to be some responses with the combination, radium-223, the PSA responses as well. But again, on the long-term, we’ve seen this with docetaxel, and we actually just published this this summer, that patients who receive more than 8 cycles of docetaxel have a significantly better survival than those who receive less. So I’m concerned about attenuating any drug, and I’m also concerned about attenuating the radium dose. So the question really is, and we do a randomized trial, which is going to be done with cooperative groups, should you add docetaxel to radium. And that was recently, I think, going from the steering committee.

So we need more studies with radium. I think it is best used in combination. I think that hormones plus osteoclast inhibitors do show some interesting patterns, particularly in the expanded access program. I don’t think that chemotherapy is the way to go. I think that immunotherapy is a very, very promising combination with radium. And then we need to move up the hormone sensitive disease and see if that will actually reduce our skeletal-related events, delay progression, and overall improve survival. Thank you for your attention.

Novel Biomarker-Guided Treatment: PSMA, PAR, HDACs, etc.

So to first start off, we basically divide this talk into three different sections. We’re going to talking about PARP inhibitors in prostate cancer. I think this is one of more exciting areas, since we’ve identified a target, we’ve identified patients with prostate cancer who may benefit. So this is really the crux of the matter with PARP inhibition, DNA repair is an important factor that’s involved. There also could be transcriptional regulation. This again is targeting DNA, and the PARP inhibitors will effect this particular area.

So what are we looking at in terms of PARP inhibition? Why is this important? Well if there’s a DNA mutation, in other words, if there’s a break that’s involved, or at least a situation, so if there’s a situation where we have a genetic abnormality in DNA repair, in other words, something like BRCA where we can’t repair double-stranded DNA breaks this can effect recombination and repair in the double-stranded pathway. If we inhibit the single-stranded pathway with something like a PARP inhibitor, which is important to single-stranded breaks, we then find a patient who would be sensitive to this particular drug. So both pathways are shut off. So normally without the PARP inhibitor you would have normal DNA repair, because you’re going by the single-stranded pathway, double-stranded pathway being active, both of these blocks are lethal to the cell.

So this has been looked at in terms of ovarian cancer, BRCA positive mutation carriers have been identified in ovarian cancer, and the FDA has approved a drug called Lynparza to treat ovarian cancer. And this is a PARP inhibitor.

So what about the data in prostate cancer? This is a paper from Dr. Matteo from the New England Journal of Medicine where they demonstrated that in patients with DNA repaired deficits that Lynparza, olaparib is active in these patients.

So overall there were 49 patients entered in this small phase 2 trial who had metastatic castration-resistant prostate cancer. These patients were resistant to docetaxel. Overall 32% of unselected patients, 16 to 49, has responses to Lynparza. And when they started doing genomic analyses of these patients they found that those who had mutations in DNA repair overall there were 16, 33% had mutations. And of those, the remaining patients, 67% had no mutations. Of the 16 patients with identified mutations 14 of those 16 patients responded to olaparib. And of the patients who no mutations 2 of the patients responded, which again I think points toward this fact of heterogeneity and selecting the right lesion to biopsy, because I would bet that these patients had in the lesions that the target lesions, that they had the mutations.

So these are the types of DNA repair mutations that were noted in these patients, BRCA was present, ATM was present, about overall so this is a mixture of different DNA repair enzymes. So this has been designated as a breakthrough therapy by the FDA for resistant prostate cancer.

So there are other trials that are being performed in prostate cancer, both as single agent or in combination. And I think they’re showing some important marker observations. Firstly, Maha Hussain, our good friend who is now the Northwestern University, she moved from Michigan to the University of Chicago, looked at combining veliparib plus temozolomide, which is an alkylating agent just like Cytoxan, and there’s some small single agent data of temozolomide in prostate cancer. But what was interesting was when they looked at this in preclinical models. This is the vehicle, this is temozolomide by itself, and this is the PARP inhibitor plus temozolomide, look at how different or how much cooler these lesions are compared to the single agents. And again, you see synergy between the two different agents when you administer these two to animals who have prostate cancer cells implanted in them. So it makes sense, of course, to go forth with this in patients. And in the combination she found that there PSA responses with this particular combination. And so it does seem to at least have some degree of synergy. Of course, you need a large randomized phase 2 to look at this.

She also was interested in the observation that the PARP inhibitors may actually be more sensitive, or the ETS repair pathway, gene pathway may actually mark sensitivity to PARP inhibitors. So this was a large randomized phase 2 trial that she performed. And this again was based upon the fact that AR signaling and DNA damage repair may be synergistic. So she looked initially at animal models to see if this seemed to be reasonable to go forth with. And so PARP inhibition will add to castration in mouse models with prostate cancer. Is the vehicle, this is a PARP inhibitors by itself, this is the combination of the two, also castration by itself. So we see that there is at least an additive effect of the two.

And when you start looking at ERG positive xenographs, remember ERG is the product, the gene product of TMPRSS2-ERG which is a fusion gene product, which is identified in prostate cancer. It’s a hormone sensitive gene. We see that these xenographs are sensitive to the PARP inhibitors. So it was preclinical justification for going forth with this.

So this trial was designed to look at biomarkers. So what they did was they registered patients, they had to have metastatic tissues biopsied prior to entry. If they did not have sufficient tissue at entry they were not eligible. They were stratified based upon ETS status and then were randomized to receive abiraterone plus prednisone or abiraterone plus prednisone, plus niraparib, which is a PARP inhibitors.

So let’s walk through the data from 148 patients that were entered on the trial. This is all patients. They were looking to see a 20% improvement in response rate for all patients. They really didn’t see it. Single agent, 64% by PSA, combination agent 71%, so 7% difference. Here it’s about a 10% difference if you look at measurable disease.

If you start looking at ETS positive and the ETS negative it really doesn’t seem to be much of a difference at all. Arm A, arm B, it’s a 10% difference and the negatives it’s about an 11% difference. The same thing with soft tissue, so this really doesn’t mark for anything significant. So again, the significance is nil in the different arms.

So they then analyzed the specimens that they had for DNA repair defects. And overall a quarter of the evaluable specimens, and look again, remember they had to have a evaluable tissue to go in, look how many patients you lost. This shows you how difficult it is to do these types of studies. So a quarter of those patients had mutations in the DNA PARA pathway, predominantly BRCA2, but BRCA1, ATM, FANCA and PABL2, so it’s about a quarter of all patients.

So let’s look at the data in terms of the DNA repair, PSA response rate overall for this subgroup of patients, 57% versus 71%, maybe a little bit more a difference. When you start looking at those that are DNA repair deficient for both Zytiga as well as for the combination, it’s a lot higher response rate, but it’s a small N. And then those that are wild-type you really didn’t see that high response rate, but there did seem to be at least an additive effect from the PARP inhibitor. So there did seem to be an improvement in progression-free survival in those patients who were DNA repair damage versus the wild-type, 13.8 versus 7.8 months. So this is moving into a larger phase 3 trial that’s going to evaluate whether PARP inhibition plus abiraterone is better than PARP inhibition alone.

So these are some of the trials that out there at this particular point. Olaparib is looked at in high-risk prostate cancer, but before radical prostatectomy, it’s a biomarker driven trial. There’s another drug called rucaparib, which is made by Clovis. This is being looked at in repair deficient metastatic castration-resistant prostate cancer in TRITON 3, and also in all-comers which are BRCA1 and 2 positive for ATM in the TRITON 2 then TITRON 3 trial. And olaparib is being looked at in metastatic castration-resistant prostate cancer. It’s the primary endpoint is response rate. Olaparib is being combined also with the checkpoint inhibitors, pembrolizumab plus olaparib, pembrolizumab plus docetaxel/prednisone, pembrolizumab plus enzalutamide in this three-arm trial. And again, this is also being looked at with nivolumab in phase 1 studies in combination in lung cancer, breast cancer and castration-resistant disease. So think that this is going to be an exciting area, and this is the reason why, right at the beginning of castration-resistant it’s important to do next generation sequencing.

So what about PSMA? This has been around for quite some time. PSMA, as you know, is an integral membrane protein. It’s expressed in about 90% of prostate cancer specimens. It may be hormonally regulated, or at least seen at a higher rate in more aggressive tissue, and it is different and distinct from PSMA, it’s homologous to a folate transport protein. So it’s been exploited for a number of years with monoclonal antibody study, it’s been linked to other anti-tubulin agents, but there are three approaches now which I think are fairly interesting.

One is combing a—at least using a nanoparticle which has a ligand which targets PSMA, and within this nanoparticle is docetaxel. It’s a way of smartly delivering chemotherapy to a cancer cell. Another way of doing this is actually using a molecule that goes in through the pore that’s made by PSMA and is transported into the prostate cancer cell. This is EC1169, and this is linked to an anti-tubulin agent called tubulysin. So once this gets into the prostate cancer cell it gets cleaved and the tubulysin combined tubulin, tubulysin is fairly toxic drug. If you’re giving this by itself you really can’t achieve levels that would be significant for the prostate cancer cells.

And then ADC approach, which we talked about yesterday in bladder cancer, which is combing PSMA plus MMAE, which is an anti-tubulin agent. Once this binds to the prostate cancer cell it’s internalized and then it’s cleaved in the lysosome by the cathepsin B and you have free moiety which then goes to tubulin and causes its anti-tubulin effect. Again, this drug, if you administer the naked drug to patients you can’t achieve levels that are significant for cytotoxicity of the tumor cells.

So Ben014 had been evaluated in chemo naïve prostate cancer cells. As I mentioned before, it’s polymeric nanoparticle, it’s loaded with docetaxel.   It has reduced clearance in volume of distribution, and in phase 1 60 mg/m2 was the recommended phase 2 dose.

So this has been a little bit disappointing, because the PSA response rates that we are see are really not about the same as what you would expect with docetaxel; 30% objective response rate, about 21%, you can see about 40% with docetaxel by itself. And the CTC conversion rate is 50%. So I don’t think that this is really a quantum leap from what we see from other taxane agents. It was well tolerated, it met the study endpoint with 30 having a progression-free survival of more than 6 months, 21% response rate by resistance. I mentioned before, 30% by PSA, and then the CTC conversion rate was 50%.

Now, one of the things we’re doing with this interesting agent, the EC1169 is we’re using the ligand to image patients prior to going on study. We don’t know if this imaging is going to be predictive of response in these patients, but you can use this small molecule as an imaging agent, and again, visualize the areas in the patients that have PSMA. And some of the scans have been quite impressive.

So then we’re using, as I said before, linked to the tubulysin as a therapeutic agent and eventually we hope to correlate response with the imaging. This certainly has advantages over circulating tumor cells or immunohistochemistry, because of course you’re seeing things in real and can sequentially image these patients with the agents.

So right now we’re in a phase 1 mode for this compound. One of the reason why this phase 1 trial is taking so long is there was cardiac toxicity noted in dogs, and it was the FDA basically telling us that we really shouldn’t go too quickly with it. So we’ve looked at two different schedules and we finally have arrived upon the weekly schedule rather than a three times a week schedule. It’s almost impossible to get patients in for this. And in a very small preliminary study that we reported at the ESMO meetings back in the fall we see that nausea is the predominant side effect with this particular drug. And we are seeing some PSA declines with it. So this in the preliminary stages and again, we may see some activity, but we have a ways to go in our accrual.

I mentioned before that the PSMA targeted therapy that we had worked, Neal has also participated in these trials, has shown some activity. And again, this is a conjugate that’s cleaved by cathepsin B and then releases the MME moiety to attack tubulin. We’ve looked at this in two different groups of patients, and also have analyzed this in terms of both PSA and circulating tumor cells. And the PSA response rates have been modest at best, but we start enriching patients for PSMA expression on the circulating tumor cells. We see that the response rates actually increase, and they’re about 20% overall for the refractory, they’re slightly higher for the non-refractory. The major adverse events that we’ve seen with this have been peripheral neuropathy, as well as neutropenia. The recommended phase 2 dose was 2 mg/Kg. And so the overall, the PSA response rate was 14%, 21% in the chemo naïve, but the – – tumor cell responses and PSA responses were more prominent in those patients who had a high PSMA expression, as well as low neuroendocrine markers. As I mentioned before, the major side effects where neutropenia, fatigue, and neuropathy.

Raoul sort of talked about this target previously, the heat shock protein inhibitors. These are a class of targets that will effect the androgen receptor, and they actually regulate androgen receptor activity on two different levels. The first, of course, is binding of dihydrotestosterone where this, the HSP90 protein is basically ejected so that the molecule can dimerize and then complex with HSP27, this can then enter the nucleus, bind to DNA and become – – active. We see that there is a large complex that occurs in wild type, and again, with HSP70 and HSP40 as well.

So there are a variety of different compounds that are being evaluated with the heat shock proteins. Those that are targeting HSP90, basically showing a very, very low PSA response rate, and really there have not been any marker driver trials to select these.

HSP27 has been looked with an anti-sensitive compound, OGX427. Again, modest PSA response rate seen combined with docetaxel. Also, modest PSA response rates seen when this is combined with prednisone. So this is again I think a little bit disappointing in its overall PSA response rate, but these are first generation drugs which, of course, need to be refined.

Clusterin has also been targeted. This is a protein that’s present in prostate cancer cells in the nucleus. It’s upregulated with castration. As we know, both of the trials that were looked at in terms of chemotherapy combing anti-clusterin antisense in the docetaxel naïve patients, as well as those patients who were refractory to docetaxel, combing with cabazitaxel did not show a significant improvement in survival.

So those are the areas that we were looking. I think that was have a lot of work to do as far as our markers are concerned, and certainly the phase 3 trials are now underway, as I’ve outlined. And we certainly ought to be moving forward with these new targets, as well as others.

Targeting AR in Castration-Resistant Prostate Cancer

My goal today, we’re going to talk about targeting androgen receptor in castration-resistant prostate cancer. And these are my disclosures

Where I want to go with this talk is I’m not going to talk too much about drugs. Neal gave a wonderful presentation about all the newer agents that have been approved, specifically since 2010. I think most of you in the room have heard this, have read about all the new agents. But I really want to stress the fact that I think for—if you’re interested on managing prostate cancer, especially as we move from this volume to value-based medicine, as many of you know, we have been preaching for many, many years that we want the urologist to be involved in the total continuum of care. And specifically, especially as we become less and less invasive, you know, my father was the first urology resident at the Lahey Clinic. I’ve been around this all my life, and I love David’s video that he just showed. But I think as we are progressing to even though we still are a surgical subspecialty, as we become less and less procedure driven, and as we get more and more of these great agents, and the challenge of treating metastatic castration-resistant prostate cancer, I think it’s imperative that we start to understand the molecular mechanisms and the drivers behind what’s driving this disease. So we all know, it’s the Huggins and Hodges in 41 as the video just showed, basically they proved that prostate cancer is an endocrine-driven disease. And the mainstay of therapy, once patients progress with prostate cancer, has always been knocking out testosterone.

Tom Keane showed this slide earlier. We know that there’s basically three sources. Obviously, the majority of testosterone production that comes out of the testicle. You get about 3% or 4% that comes from, that has this paracrine production from the adrenal gland. And now we know that through mutational changes sometimes that is actually pressure treatment driven, like Dr. Pinthus talked about, that you get this autocrine production, where the tumors themselves are producing their own testosterone. And when I talk to my patients about what that means, the analogy that I use is that it would be like a car making its own gasoline. It would be great if you had that type of car, it’s not so good if you have that type of tumor.

Okay. So this actually is in a graphical form, not as cool at the video that you saw. It’s basically the history of how androgen deprivation, how we’ve been successful in lowering serum testosterone. And when you look what we’ve done in the past, especially for those of us that trained in the 90s, obviously, surgical castration, or excuse me, before 1990, surgical castration was always the mainstay. But again, a lot of us use diethylstilbestrol or DES, which was a great drug. The problem with DES at the 5 mg dosing, it did a wonderful job in controlling prostate cancer, but it was also very associated with thromboembolic events. And it also turned out be teratogenic. Then we’ve used anti-androgen. David, probably some really landmark papers on complete androgen blockade. And then as well as we have androgen synthesis inhibitors. But again, the mainstay, especially as patients advance, has always been knocking down the testosterone to less than 50, which is historically been the definition. Now, we can have a whole other discussion whether it should be less than 33, less than 20. I think most of believe the lower the better. But ADT still is the cornerstone, but at the same time, it is not without risk. It’s not without complications. And as you know, a lot of times it’s the urologist, we start ADT, especially in the setting of a biochemical recurrence for those patients who have been definitively treated. And again, it’s got some major problems. And I think all of us, we owe it to our patients to really discuss this with them. And again, this is becoming more and more—people are becoming more and more aware, and again, as we move into this post-macro world of alterative payment models, bundled payments, maximum-intensity projections (MIPs), one of the things that we’re going to need to be tracking is quality of life. So I think ultimately, this is just sort of a sidebar, I think we need to be, again, especially in the area of biochemical recurrence, we need to do a little bit better job, we need to be more judicious in our use of ADT. But again, we all know what the complications are, hot flashes, anemia, sexual dysfunction, neurocognitive dysfunction, which can be really bothersome, and I think we’re becoming more and more aware of that, osteoporosis, and I think Lenny Gomella is going to talk about that tomorrow, and obviously, this pseudo metabolic syndrome, which includes obesity, insulin resistance, dyslipidemia and hypertension.

We know that these patients, once we get them on ADT, they will progress. Not all of them, but they will progress. And when you look at the NCCN with this concept of what we call castration-resistant prostate cancer, we talked about earlier today why that nomenclature has changed. I’m going to give you some of the molecular reasons why. We’ve gone from this concept of hormone refractory, androgen insensitive to castration-resistant prostate cancer.

So the first area is this area is this area called M0, where by definition, the definition of castration-resistant prostate cancer, you’ve got to have a diagnosis of prostate cancer, you have to be on LHRH therapy, your testosterone levels need to be in the castration range, which right now by definition is less than 50, and you have to have a rise in your PSA. And again, as you know, most clinical trials define that as elevation 25% to 50% greater than the prior with between one to two weeks of it being drawn. If you then studied them radiographically we know that about a third of these people who you think are non-metastatic usually based upon their symptoms in fact are symptomatic; excuse me, are metastatic. So it really is incumbent upon the urologist for us to be early identifying these patients. But we know that there is this subset of patients who really do not have radiographic spread based upon bone scan and CT. Now, I think many of us believe especially with some of the new advanced imaging that are coming out, and I think Dan is going to touch on that soon, is that this area, this niche of patients will probably become smaller and smaller. But sufficive to say right now if you truly are in this M0 CRPC category your treatment options are clinical trial or observation. None of these cool drugs that we have are currently approved for the M0 patient. You have to have metastatic disease. And the older therapies, including the first generation anti-androgens don’t have a survival benefit.

But then as you get into the M1 disease space, which again is this CRPC, but they do have radiographic mets, then the whole world opens to us in terms of all of these new therapeutics.

These are kind of the key clinical trials that have been put forth since 2004. These are the positive trials. But again, I think when you sort of look at this, all these different agents all are different mechanistically. And again, this is sort of a summary slide that many of you have seen looking at the survival benefit of all these particular agents. However, and this is where the meat of the talk is going to come, many of these agents, what still remains central to the progression of these patients is this androgen receptor. And I will say that if you would have told me ten years ago, Conceptcion, if you want to manage advanced prostate cancer you need to be fully aware of the androgen receptor and where it’s located, and those types of things, I would have told you you’re out of your mind. I don’t think you can begin to understand or begin to treat and know about these drugs until you really have a good working knowledge and definition of the AR.

So, sufficive to say is that it’s found on chromosome 11.   And the androgen receptor actually has four major domains. It has the N terminal, it has the DNA binding area, it has the ligand binding domain, and then there’s actually a hinge region. So this is all found on chromosome 11, and these are the various exosomes that are associated. And how the androgen receptor works is on—what I want to point out to you is on the left side of this slide. This is what I sort of call the canonical pathway. And so we’re going to go through this pretty quickly.

So what tends to happen in normally functioning prostate cells in men is that testosterone really circulates. Most of it is bound by sex hormone binding globulin, but most of it, but the functional activity of it is actually free testosterone. So what happens is that testosterone disassociates from sex hormone binding globulin. It diffuses through the membrane of the prostate cell. Once inside the cytoplasm it then encounters the androgen receptor. Now the androgen receptor when it’s not locked into the ligand it can be found with what we call a chaperone molecule, which is usually heat shock protein. Testosterone, once inside the cytoplasm gets converted intracellularly by the enzyme 5alphareductase to dihydrotestosterone. Dihydrotestosterone is a much more powerful androgen. When it comes into association with the androgen receptor you get disassociation of the heat shock protein, you get binding of the ligand to the ligand-binding domain of the receptor. You then get this dimerization of the ligand receptor complex. What then happens is that you get nuclear translocation. Once inside the nucleus the N terminus then binds to DNA, which then starts the whole process of transcription and translation. That’s how it works. And what do we get for that? Well, we get PSA production, we get cell growth, we get cell survival. Remember, and it’s a very important point, and we forget this sometimes, especially as we’re treating advanced prostate cancer patients, PSA is a function of androgen binding, it is an androgen driven event. But as we get into these pathways of castration-resistance, except for—and as Dr. Pinthus talked about, except for the true neuroendocrine dedifferentiations in the small cells, which often lack AR expression, a lot of the escape mechanisms still revolve around the androgen receptor. So that’s why we have moved into this change in nomenclature of these patients being hormone resistant, androgen insensitive. I think Dave had a very nice suggestion a couple of years ago, that these should be called endocrine resistant.

So when you look at this, and this is a series of slides that actually I borrowed from Phil Kantoff, is that these are all the various targets that we could be potentially looking at on how to control this disease. Well obviously, the first one is to do what we always do, which is look at circulating testosterone. So we can do that with LHRH analogues, castrations, surgical castration. And again, what that’s going to do is drive down circulating testosterone.   You can knock out the paracrine or intracrine production, which is basically at the adrenal gland. And again, we know that ketoconazole used to do that, and now we also know that abiraterone acetate has its effect there as well.

You can actually degrade the androgen receptor as well as blocking some of these chaperone molecules. You can, obviously, block the androgen receptor, and obviously, the earlier ones were these first generation anti-androgens, including flutamide, bicalutamide, nilutamide, but then also we now have the second generation, which includes enzalutamide, also what you’re going to get is ARN509, also now known as apalutamide.

You can prevent AR nuclear translocation. And how do we do it. If you heard the lunchtime talk we know that enzalutamide can block nuclear translocation, but one of the great questions that Dan Petrylak has said is that, true or false, taxane chemotherapy has a role in the androgen receptor, and the answer is true, because we think that because of its microtubule inhibition it can also block nuclear translocation. You can interfere with AR enablers. And again, these are some of these escape pathways. You can block coactivators, as well as you can block these downstream effectors, which again, get into these whole areas of molecular drivers.

So again, what’s key here, what’s what common here, again, it’s still the presence and the working of the androgen receptor. If you want to read a great article, this was published in the Journal of Clinical Oncology in May of 2013. This came out of the University of Michigan. This was Arul Chinnaiyan’s group. Arul basically is obviously one of these most talented guys when it looks at looking at molecular drivers for prostate cancer. And this is a very nice review article. And what he was able to do, he basically summarized looking at clinically relevant genomic alterations. And I’m not going to read all of these, but this is what basically we’re starting to talk about TMPRSS2-ERG, transcription factors, obviously, alteration in the androgen receptor, PTEN loss. We talked Aurora kinase and those types of things. And then these are some of the targets that you can go after. So again, this is a very nice article that I would encourage all of you to read to sort of get a baseline in terms of trying to understand these molecular drivers.

And again, this is just a little bit of a different way looking at it. And again, we’re looking at obviously the androgen receptor. But then you can also look at basically the effect of tyrosine kinase receptors in all these alternative pathways, including P13K, again PTEN loss, and again, in green here are potentially all the potential drugs that we can use to alter these pathways.

So again, what I’m trying to get you to understand here is that we’re understanding more and more, and it’s becoming more complex. Neal talked about today that what happens is that these cells, they’re going rogue and they figure out a way to evade apoptosis. And so that’s really the problem that we really have now, is that we have lots of cool agents, all of them different mechanistically, but there’s nothing to help us to guide these therapies. And again, we know that these cells with treatment pressure selection will actually undergo mutational changes. And one of the things that a lot of people are focusing on right now are these androgen receptor splice variants.

This depicts just a few of them. Again, there’s probably 40 or 50 of them out there, but a lot of attention has been towards this what we call this ARV7 splice variant. So again, this is where the understanding of the makeup of what the androgen receptor does becomes very, very important. If you don’t understand the makeup of the androgen receptor you really, it’s hard to kind of get head around why ARV7 is so important.

So basically, AR splice variants are associated with poor prognosis and treatment resistance. The translation of splice variants results in protein with altered activity, visa vie the androgen receptor. So again, we know that in exons, so again, this is the full length, this is the wild-type AR like we talked about. This area right here is the N terminus, it has nothing to do with ligand binding. This is sort of the DNA binding domain, as well as the hinge region. This is all involved in transcription. Now, the C terminus, this ligand-binding domain is coded for by exons 5 through 8. And so what happens, one of the mutations that happens is that you get this drop out exons 4 through 8 which results in the loss of the ligand binding domain. So you would think that’s a good thing, right? You can’t bind dihydrotestosterone, you can’t bind testosterone, nothing should happen. Well the problem is what have figured out, what they have figured out is that the receptor stays active. It stays active. And what’s the data to suggest that?

So, many of you have seen this. Neal presented some of this today. This was basically the work done by Emanuel Antonarakis at Johns Hopkins. This was written up in the New England Journal of Medicine. And so what this was, this was a prospective study of M1 CRPC patients who were eligible for either treatment with abiraterone acetate or enzalutamide, and through the use of circulating tumor cells, looking at the transcript they were able to identify who was ARV7 positive or negative. And so what I want you to do is go down to this bottom line first. So the patient treatment standard, what was a prevalence? And this is an interesting number to remember. What’s the prevalence of ARV7? So before any patients got either enzalutamide or abiraterone we think the prevalence of ARV7 to have this mutation is about 12%. So obviously, that’s just due to a patient being on androgen deprivation therapy.

And so what they did, is that they measured baseline ARV7 using circulating tumor cells. And in the treatment group that was going to get abiraterone they found 6 of 31 patients, about 20% were ARV7 positive, and in the enzalutamide group, again, 31 patients, it was a little higher at 39%. So basically in the ARV7 positive category those were the numbers. And then what they did is that they started them on therapy and then looked at these various responses. And so remember, if you’re ARV7 positive manipulating the androgen access, whether you put them on an androgen receptor blocker or you put them on a androgen synthesis inhaler, it’s not going to make any difference because it can’t bind the ligand. So low and behold, when they looked at the response rate looking at drops in their PSA of greater than 50%, what they found in the abiraterone treatment group is that if you were ARV7 negative, so you still had the wild-type ARV7 receptor, low and behold about 70% had a PSA drop of greater than 50%. The number was zero if you were ARV7 positive. Overall survival, excuse me, radiographic progression-free survival 2.3 months in the ARV7 positive group, greater than 6 months in the negative group, overall survival better, obviously, in the ARV7 negative group. And the same pattern held true with the enzalutamide treatment group. Again, if you were ARV7 negative the chances of you having a drop in PSA, which again would make sense, was over 50%. You had a longer RPFS, and the overall survival had not been reached, but again, when you look at the ARV7 positive group the numbers were markedly less. And then when you look at the patient treatment status, again, there was about a 12% prevalence at baseline. Post enzalutamide, that went to about 25%, 50% for abiraterone, greater than 60% if you had both.

These are waterfall plots. And again, Neal had mentioned this today, you did have some outliers, but again, in blue are all these patients who are ARV7 negative. And for the most part you had significant drops in your PSA. So that was the enzalutamide treated group, and this is the abiraterone treated group.

Again, the point here is that if you’re V7 positive, and that’s where it helps to understand the makeup of the androgen receptor, you’re not going to bind ligand, it’s not going to have an effect, the receptor stays active, and as Dan had mentioned earlier, you could make a case potentially of putting those patients, if you knew that upfront, you would skip abiraterone, you would skip enzalutamide, and potentially you could make a case for going right to a taxane.

And again, this was survival benefit. And again, this is for the enzalutamide group, the abiraterone treated group, and again, this held true.

So that’s just one mutational defect. That’s just one resistance mechanism that these cells develop. The problem is, as we know, prostate cancer, it’s a heterogeneous disease, its heterogeneity. This concept of it starts here and that every tumor cell enjoys the same characteristic, and then as it progresses it maintains, it’s not—that’s just not the case. That’s why we know looking at these clones, there’s areas of Gleason 3 plus 3, but within the same tumor itself you’re going to have Gleason 4 plus 4, you’re going to have 3 plus 4, you’re going to have a 4 plus 3. At a molecular level once these patients start to progress the challenge is is try to figure out which mechanism, which driver is causing these to progress.

Another mutation is a gain of function mutation in dihydrotestosterone synthesis in patients with CRPC. So remember what we talked about is that dihydrotestosterone is formed from the conversion from testosterone to DHT by the enzyme 5alphareductase. And so what they found is this mutation in 3BHSD1 which actually will produce dihydrotestosterone from variant precursors, not testosterone. So in other words, are you taking other ligands that’s not testosterone and converting it to dihydrotestosterone. So again, it’s another mutation, it’s another way to drive the androgen receptor without altering testosterone production.

You can also activate the glucocorticoid receptor, which confers resistance due to anti-androgens. And again, this was a study, these were patients on enzalutamide. And what they found, and this was actually out of bone marrow biopsies, these patients got enzalutamide, they continued to get it. And then what happens is that they actually tested, and what they found is that you had activation of the glucocorticoid receptor. So even though you were blocking the AR it was escaping, the cells were escaping by activation of a glucocorticoid receptor.

So the bottom line is that this is a challenge. And again, we have to be very aware of all these mutations. This was really great, another great article published in Cell back in 2015. This is basically the Standup to Cancer Group. Funded heavily by the Prostate Cancer Foundation. Robinson and Charles Shores and these guys, and again, this is a wonderful article that I think everybody should read.

So I’m just going to wrap up. And so these are the challenges. All these different drugs, how do we find, how do we know who to treat, how do we know which drugs. David has convened another working group, this Radar Two, trying to come up with some semblance, some order on how we need to think about this. And this becomes very daunting. So here’s the prostate cell, we have to deal with the bone microenvironment. We can manipulate the immune system, which I’ll talk about later. You can also have angiogenesis. So all these things come into play. And again, they’re probably all in play. And we have to figure out a better way, liquid biopsy, CTC, cell-free DNA, tumor DNA, micro-RNA, all the things that we talk about in terms of monitoring, what’s the best way to sort of dictate how we manage these patients?

So I was telling I think Gerry Andriole, so this actually a really good book, I would suggest you read it. This is Mukherjee’s book. This was his followup. He’s a medical oncologist at Columbia. He wrote Emperor of all Maladies and 2011, which won the Pulitzer Prize. And this book actually is called the Gene. I think it came out the middle of last year. And he really talks about this whole concept of genomics, transcriptomics, proteomics, and epigenetics. And really what drove him is that—what drove him to write this book was his family history of schizophrenia. So he was trying to figure out, is there some sort of genetic profiling. So again, I would strongly encourage you to read this.

So in conclusion, the AR, the androgen receptor continues to be a majority driver in the growth and survival of prostate cancer cells, even in the CRPC patient. As urologists we really need to understand the nuances of resistance mechanisms and genomic alterations. And despite all the recent advances, there remains multiple challenges and opportunities for researchers to better understand the disease and possible development of novel targeted agents. Thanks so much.

Neuroendocrine Prostate Cancer (NEPC)

Neuroendocrine cells are actually part of the normal prostate. You can detect them in the benign prostate as well if you do the right staining. This is with chromogranin and synaptophysin. They’re probably part of the normal, they are part of the normal architecture of the prostate, they are in the basil cell compartment. They have dendritic cells and they play a regulatory role via their trophic neuropeptides, bombesin, calcitonin, serotonin, PTH, VEGF and so forth and so on. Those are terminally differentiated cells, so they don’t have a proliferative capacity and they express anti-apoptotic factors.

But the neuroendocrine cells can come and present themselves as a prostate cancer tumor. In an extreme case, which I would not talk much about, is the primary de novo, if you will, neuroendocrine prostate cancer. This is a very rare disease, less than 1% of prostate cancer patients. Usually in the form of small cell carcinoma of the prostate. They are sometimes large cell neuroendocrine carcinoma or carcinoid. There’s different and new pathophysiological classifications. It’s phenotype of frequent visceral and bulky soft tissue metastases, lytic bone lesion, and they’re usually responding early, but for a short time cytotoxic chemotherapy, cisplatin or carboplatin in combination with taxanes. They do not secrete PSA, they have very low levels of PSA, but high levels of another surrogate marker, the chromogranin (CgA).

But what’s interesting is what happens with neuroendocrine cells during the evolution of prostate cancer. So as I mentioned here on the left you can see normal neuroendocrine cells within benign prostate. They are in every hormone naïve adenocarcinoma there are neuroendocrine cells that residing there, and I’ll show you in about 25% of at least of patients with castration-resistant prostate cancer, if you look for that you will find it, unless it will express itself by frank neuroendocrine carcinoma, and that has a prognostic significance and a special clinical entity which I’ll talk about.

So neuroendocrine differentiation in hormone naïve prostate cancer, up to 10% prostatic adenocarcinoma contained clusters and aggregates of neuroendocrine-like malignant cells, focal neuroendocrine differentiation. They have the same genetic material, if you will, or genetic origin from the neighboring adenocarcinoma cells, and we talk about the – – arrangement. And their prognosis, their presence there is unclear in terms of prognosis.

But what’s very interesting, I think that would be the topic today is the secondary development of neuroendocrine prostate cancer. So it has been estimated that about 25% of lethal prostate cancers are neuroendocrine prostate cancer in large phenotype. And it’s a trans-differentiation actually from adenocarcinoma cells probably due to epithelial plasticity because of selective pressure. And the selective pressure is androgen deprivation. And the more the merrier, if you will, and cytotoxic chemotherapy. There is also some thought that they have a common progenitor as the adenocarcinoma cells. I won’t get too much into that.

The interesting thing is those neuroendocrine prostate cancer cells are resistant ADT. And they actually can act as an inner stimulant for tumorginicity, because they act as a source for paracrine signals via their secretion of serotonin, bombesin, calcitonin, et cetera, and we’ll talk about that.

So how common is that? This is actually from an abstract that was presented in American Society of Clinical Oncology (ASCO) in 2014. I couldn’t follow that with a paper, actually paper, but that was a very interesting study. They looked at their cover material from a prostatic biopsy signs and stain if with a neuroendocrine markers, and you can see that they excluded small-cell carcinoma, but you can see that up to 50% of the tumors, or the metastatic deposits showed positive staining for neuroendocrine markers. So 44, and that was also observed in 44% of the hormone sensitive cases, and up to 56% of the castration-resistant prostate cancer, so it’s very, very common thing.

You can add to that the observation that circulating tumor cells from patients with neuroendocrine prostate cancer are identified in about 10% or 11% of castration-resistant prostate cancer patients, so it’s there.

Does it have prognostic significance? It seems to be true when you talk about castration-resistant prostate cancer, this is just one example; a Japanese study looking at 28 patients with castration-resistant prostate cancer at the time of progression, and they showed in a multi-varied analysis that the lack of androgen receptors and a strong neuroendocrine differentiation staining were related to adverse prognoses once castration-resistant prostate cancer occurred. So not only it’s there, it’s important.

So this is a very interesting observation. So we know that the ERG gene rearrangement is kind of a hallmark of adenocarcinoma, genetic phenotype, genetic genotyping, if you will, of prostate cancer, adenocarcinoma. But that actually exists in neuroendocrine cells, and this actually an example of the extreme end of neuroendocrine differentiation of small-cell carcinoma, so this study looked at small-cell carcinoma of the lungs, small-cell carcinoma of the bladder, and small-cell carcinoma of the prostate, and only in small-cell carcinoma of the prostate this ERG gene rearrangement was present. So this finding supports a very common origin for adenocarcinoma and small-cell carcinoma, or if you will, neuroendocrine carcinoma of the prostate.

So let’s go through the evolutionary transformation of classic adenocarcinoma to a neuroendocrine cancer, so as you saw above in the histological staining, you have it in benign prostate, then you have it hormone naïve prostate cancer, and that shows rearrangement of the TMPRSS2-ERG gene supporting a common origin. But then with the development of castration-resistant prostate cancer through the evolution of prostate cancer you can see that there are typical genetic changes that would explain the aggressiveness of this tumor. So first there is the loss of AR, so androgen-regulated genes. Neuroendocrine prostate cancer cells do not express the androgen receptor. Now, with that, after that comes the induction of neuroendocrine in neural program. And that is accompanied by first loss of tumor suppression, so TP53, RB1, commonly, or deleted or suppressed in neuroendocrine prostate cancer, which leads to genomic instability. And on top of that, the final heat is the upregulation of aurora kinase-A, which we’ll talk about MYCN amplification which results in a significant mitotic activation. So those are specific molecular pathways with the androgen deprivation therapy can not touch.

I’ll give you an example. Here is this study that we did, actually, back when I was doing my PhD, so this, we used to take prostate cancer tissue from patients and plant them into mice and try to develop a different unique xenograf. So this, we called it a WISH-PC2, Y22 – -, WISH-PC2. This was from a patient that had a very aggressive adenocarcinoma of the prostate, treated long-term with hormones. We took the tumors. We implanted into mice, and what you can actually see is that these xenograf developed into a small-cell neuroendocrine prostate cancer. Now, interestingly enough, you could see that if you treated these mice with a testosterone the tumor still; although, it didn’t not have the androgen receptor, still got bigger. So it grew faster. And this is very interesting, because this would potentially talk about the fact that we still need to need androgen deprivation therapy to these patients, because it’s always a bit of a mix between adenocarcinoma and neuroendocrine prostate cancer cells, and the effect of androgens can effect the surrounding stroma, and that would fit back to the prostate cancer cells. For example, through VEGF and so, so there’s still some advantage of castration in these tumors, and this has been shown here.

This is a classical neuroendocrine prostate cancer. You can see that if you implant into a mouse’s prostate you develop a tumor, neuroendocrine tumors, which completely replace the tumor. It can cause liver metastases, which is typical as a visceral metastatic. You can see here that if you put it into tibia it can induce lytic, typical lytic bone lesions. What’s not shown here is that this tumor model actually secretes chromogranin-A, which is surrogate and correlate with the tumor volume.

So transdifferentiation from an epithelial-like phenotype to a neuroendocrine-like phenotype can be a consequence of treatment induced selective pressure. And I think this is a very important point. So we are creating in our hands a neuroendocrine prostate cancer, and I believe, it is really my belief that we’ll see more, and more, and more of those with all of the manipulation that Neal described to you.

Let’s see how that works, okay. So this is a classical work, looking at LNCaP cells, those are prostate cancer cells that have the androgen receptor, and if you delete androgen you will induce neuroendocrine differentiation. If you will restore androgen you will suppress the neuroendocrine differentiation. And what’s very interesting, and I think it’s very relevant in our era, and there is an aquisition of neuroendocrine phenotypes in prostate cancer cells which can be induced by chronic exposure to docetaxel. So it’s not only the androgens, you can pressure cells, or prostate cancer cells to become neuroendocrine cells.

How does that happen? There are many explanations. This is one example. Androgen inhibits REST. REST is a gene that actually regulates neuroendocrine differentiation of prostate cancer cells. In this example it’s LNCap cells. And you can see that if you add—if you silence the REST there is neuroendocrine differentiation. If you add androgens that does the same. And here is on the left you can see an area of genes that relates to neuroendocrine differentiation, and you can see that REST induces them. And when you abolish androgens you can see that REST is inhibited, and therefore you’re gaining the phenotype of adenocarcinoma.

I’ll skip that one. So here’s another thing, okay, so we deprive androgens from adenocarcinoma, from a very aggressive adenocarcinoma cells, so we are treating actually the exocrine prostatic cancer cell, the adenocarcinoma cells, but we leave behind the neuroendocrine cells that actually act as an inner engine, because these cells secretes significant trophic factors, such as; for example, bombesin, calcitonin, PTHRP. So not only that we are not targeting the neuroendocrine cells that do not have the androgen receptor, we actually leave them to secrete their trophic signals, which can act on the adenocarcinoma cells in an androgen-independent pathway. This is just one example here. You can see that neuroendocrine cells in a benign prostate, or adenocarcinoma do secrete IL8, for example. This works on the CXCR2 and that activates the P53. But the thing is that with neuroendocrine prostate cancer cells there is no P53. So what you’re left with is a vicious circle of autocrine proliferation.

So what do we do with that? This is a very nice paper, and a very nice actually I think life-long work by the group of Mark Rubin and Dr. Beltran, and they looked at the molecular characterization of neuroendocrine prostate cancer cells. And what’s very interesting, and I’ll just give that, because this is the bottom line, is that Aurora kinase A and MYCN are over amplified in clinical specimens with neuroendocrine cells. Now the interesting thing is that it goes early on as in unselective, if you will, primary prostate cancer to primary prostate cancer patients who progress to neuroendocrine prostate cancer. And you can see the gene amplification of both the Aurora kinase A and MYCN, so it’s very, very, very common. Look at what happens in metastatic treatment induced neuroendocrine prostate cancer. And treatment-induced neuroendocrine prostate cancer means it’s a disease that we induced with our androgen deprivation therapy. It’s highly, highly over expressed.

Here’s another example. AURKA’s over expression primary prostatic adenocarcinoma patient who developed progression to neuroendocrine prostate cancer cells. So it’s actually there even before the development of castration-resistant prostate cancer and neuroendocrine prostate cancer, so it’s early on within the patients who are destined to develop neuroendocrine prostate cancer.

MYCN is a proto-oncogen encoding transcription factor which regulates—which is in normal physiology, if you will, is important early embryogenesis for neural stem cells. But it is upregulated in neuroendocrine prostate cancer cells and causing the proliferative effect and the differentiation to neuroendocrine tissues. And the interesting thing is that the Aurora kinase A, which is a cell cycle regulator, works on the assembly of the mitotic spindle apparatus, so the chromosomal separation in the mitosis, this stabilizes MYCN. So they go out together. And Aurora kinase A I think is the hallmark, at least from what I can understand now in the biology of neuroendocrine prostate cancer in the development of this lethal disease.

And you can see it here again. And this is important because there is a specific drug that can target the Aurora kinase A. This was licensed with Takeda, the name is alisertib. And that has been shown in preclinical studies by Beltran, et. al., which is a beautiful study, to show that it can inhibit significantly or treat neuroendocrine prostate cancer on the basis of the fact that Aurora kinase A is over expressed in neuroendocrine tumors, and actually also in other carcinoma cells that are destined to become neuroendocrine prostate cancer cells.

So this is the clinical trial that was recruiting. It’s an orally administrated AURKA inhibitor given orally, 50 mg twice daily for 7 days, and repeat the cycle in 21 days. They did a study which looked at open-label phase 2 trial, mainly looking at progression. The problem was, and this has been presented in European Society for Medical Oncology (ESMO) in 2016, now the recent ESMO, showing that it had an effect, but that was kind of a limited effect. So about 3 patients of the 60 had complete response or significant response, but the progression to—radiology progression in 6 months was quite high, and the progression-free survival in 6 months was only 15%.   They explained it in the fact that they were not really enriched for neuroendocrine prostate cancer. But I think this is a very interesting drug, I think because Aurora kinase A amplification is also presenting in a primary adenocarcinoma of the prostate and predict late-stage development of neuroendocrine prostate cancer and castration-resistant prostate cancer, perhaps one can envision the integration of Aurora kinase A inhibitor early on before the disease is full-blown, and this is something that is of interest.

So to wrap up, just to give you what I call a cognitive doggy-bag, if you will, a take-home message, I think neuroendocrine prostate cancer develops from adenocarcinoma of the prostate, okay. This process results from selective pressure, and please be aware that we inducing it in our own hands. This is the trade-off of this sophisticated deep castration, as well as the addition now of cytotoxic agents, and it involves specific molecular pathways. And if you have to remember one, please remember the Aurora kinase A. There is increased incidence of neuroendocrine prostate cancer in the current era of novel ADT agents, which is suspected. I didn’t see really hard data on that. And we have to compare it to historical control, and they have their own selective advantages. And one thing perhaps to target them is to target their own secretion, which fuels up the neighboring adenocarcinoma cells by virtue of their paracrine factors, and there is potential targeted therapy, Aurora kinase A inhibitors, which I think needs to be used more selectively. Thank you.

New Concepts in Androgen Deprivation Therapy

We’ve all seen this slide for a million years, but it is a brilliant slide, and we have to awknowledge that, thank you, David. That’s your addition. If you look at the far side, however, we see where the future is, and it’s in new androgen receptor targeted drugs, immunotherapy, biomarkers and genomic testing, and that’s really, these are all bull’s worth that we have today. But we have to look over the last five or six years, there has been some tremendous advantages. And the debate and discussion that just took place highlights some of those changes.

It all started with this man, this is Dr. Huggins, but even he alluded to the problems that may be facing patients with treatment, and that is despite regressions of great magnitude it’s obvious that there are many failures of androgen therapy to control this disease. So he recognized the existence of castration-resistant disease even then. So in 2016 we have a completely different landscape for castration-resistant prostate cancer treatment options. Most, as I’ve said, have only been available since 2010. But when you look at them, we have our abiraterone, we have our enzalutamide, the anti-androgens, we have radiopharmaceuticals, we have immunotherapy and sip-T, which I to believe is probably under utilized and we need to figure out what its role is, and when it should be given. And then we have our chemotherapy options.

Now, looking at ADT alone, we all know the LRH agonist option, that has multiple different durations of dosage, if you like. GnRH antagonists don’t have the flare, but they have one major problem, there’s a 28-day shot and a lot of patients don’t like that. Anti-androgens, typically we know what they’re used for. Then we have our secondary ADT options, our ketoconazole, and our newer options, which would be enzalutamide and abiraterone, and I’ll talk some more about those in a little while.

This is the traditional mechanism of action and in relation in cardiovascular risk. On the one side we have the degarelix, which provides a rapid suppression of FSH, LH and testosterone with no microsurges. On the other side we get a reasonable suppression, and then a recovery at one year typically of FSH and certainly of alkaline phosphatase when you look at these agents. And we have microsurges on repeat injections. We have inhibition of the GnRH receptor with the degarelix. We have stimulation of the GnRH receptor initially with the leuprolide and or any of the other agonists. And then when you look at the prolongation of the action of suppression there are distinct differences between the two.

So I’m going to personalize this a bit, and we’re going to start off talking about some of the cardiac problems which can exist in ADT. This is an article which was published in Circulation in 2016. And it’s a very good article. It basically just lays out and documents and talks about the cardiovascular effects of androgen deprivation therapy for the treatment of prostate cancer, and it gives you an A, B, C, D, E step for cardiologists to reduce cardiovascular disease in their patients with prostate cancer. And it was the American Heart Association has been talking about ADT and cardiovascular problems. And the A, B, C, D, E stands for awareness, aspirin, blood pressure, cholesterol, cigarette cessation, diabetes management, diet and exercise, which may reduce cardiovascular disease. And they give you an algorithm which you can follow with your patient to say if you’re going to go on this therapy, these are the steps that you should be taking to perhaps avoid some of the complications, particularly the cardiac and the vascular complications that can occur.

These are the options of medications which exist. You can see the agonists, antagonist, the anti-androgens, the new novel therapies, they’re all listed there.

So is there a difference between the agents in terms of cardiac risk factors and ADT? Well, the first thing is you’ve got to look at the structure of the two different agents. On the top are all the agonists, on the bottom are all the antagonists. You have to change one amino acid to make an agonist. The reason it took so long to make an antagonist is you have to change seven. They’re not the same agents. They’re not the same options. Most acute cardiovascular disease events are typically caused by rupture of a vulnerable atherosclerotic plaque.

This is a typical example of a vulnerable plaque. The thin cap covering this area, which when that ruptures you’re going to bleed in here and that vessel is going to be blocked. The presence of inflammation is a sign that this is weakening, and you very frequently see this on high-powered examination. Here’s two different plaques, one is stable, one is vulnerable. The differences are in the cap, thick versus thin, in the composition, rich and smooth muscle cells in matrix, rich in inflammatory cells. In lipid content, differences, and in the inflammatory state, differences.

So the incidence of both prostate cancer and cardiovascular events we know are shared in older men. The older you get the more likely you are to have cardiac problems or cardiovascular problems, the more likely you are to develop prostate cancer. And men with prostate cancer and preexisting cardiovascular disease are known to have an increased risk of death, as is shown here. And the influence of prostate cancer therapy and mortality is not mentioned in this study by Jespersen. This just shows you that men with prostate cancer and preexisting cardiovascular disease have a higher likelihood of dying over time.

If we look at some data from the Europeans, the EORTC and the data, the second leading cause of death in these trials were cardiovascular disease. This association has been confirmed with other types of ADT. And here you see them listed, GnRH agonist, orchiectomy, complete androgen blockade. And then more recently O’Farrell has looked at the timing of cardiovascular death. And your patients are at maximum risk for a cardiovascular death within the first 6 to 12 months of going on ADT. And he showed that from this Swedish database, 41,000 patients plus on ADT compared to 187 patients who were not on ADT who had prostate cancer. And the high-risk time is in the first year, primarily the first 6 months.

So these data led to a move by the FDA after consultation with the American Heart Association, the American Cardiac Society, and the American Urological Association (AUA) to actually put a warning out. And their warning in October 10, the FDA asked manufacturers of agonists to add extra safety information on drug labels dealing with this problem. The EMA was prompted to do the same thing, and they actually added the risk to both the agonists and the antagonists. This risk has been shown to be increased in older men and those with comorbidities. And these are two studies by Damico where he confirmed that the patients aged 65 years of age receiving 6 months of ADT had shorter times to fatal MI compared to patients on radiotherapy alone. And then he also showed that moderate or severe comorbidities existing in these patients had a risk of fatal MI when receiving radiation plus ADT.

So if you take that, as well as those with preexisting cardiac disease, you can see from these, there is in 33% of the patients in this trial, this was receiving estrogens, had a cardiovascular event during estrogen therapy. And if you add that, based on the studies that have been shown, the increase in the risk of cardiovascular disease in men treated with ADT, meaning orchiectomy, estrogens, or GnRH agonists appears to be increased by 20% to 25%. Which to put it in every day is the same as the risk of smoking versus non-smoking and developing a cardiac problem.

We don’t have data on the antagonists, at least randomized controlled data. There isn’t any. So in the absence of that there is a pooled analysis which was performed where they looked at 6 studies where the antagonist was compared to an agonist in a randomized control trial. It resulted in over 2,000 patients, approximately 1,500 of the patients had received degarelix, 837 had received an agonist. In terms of cardiovascular disease history, the proportions were equal. And what it showed, when you selected baseline demographics there was no difference between the two groups. But when you went to the overall incidence of cardiovascular events you were twice as likely to have a cardiovascular event if you were on the agonist. And this was in men who did not have an existing cardiovascular problem. When you looked at the overall survival there was a significant difference between the two groups, depending on if they were on the agonist or the antagonist. Prostate cancer, sorry, that was the wrong way around. This is the agonist, that’s the antagonist. Prostate cancer was not the cause of the death in the majority of these patients. And then when you brought in the existence of cardiovascular disease there was a lower risk of cardiovascular death in the patients who received degarelix. And when you looked at the men who had preexisting cardiovascular disease those risks, again, where further doubled. And what you got was a hazard ratio of 0.44. When they adjusted for common cardiovascular disease variables the ones that stood out were degarelix, hypertension and baseline testosterone, and smoking.   And when treated with degarelix compared with a GnRH agonist patients with preexisting cardiovascular disease had a relative risk reduction of over 50%, and an absolute risk reduction of 8.2%.

Now what’s the mechanism? Well, here is the data which shows that the GnRH receptors are expressed by smooth muscle cells in atherosclerotic plaques. This is data from Professor Nilsson in Sweden who has made a lifetime of studying this. There’s also again from him, he showed that leuprolide induces necrosis in stable oscillatory shear stress-induced plaques. He took animals, fed them a cholesterol-rich diet for 18 weeks, then at 18 weeks he induced an atheromatous plaque. He then put them on either degarelix, leuprolide or left them untreated, and then sacrificed them, and looked for evidence of necrosis. The maximum area of necrosis was present on the animals who we receiving the antagonist, the antagonist and the untreated were extremely similar.

So, there are potential mechanisms for differences in cardiovascular risk with different forms of ADT. And what’s causing these problems? There’s three options, metabolic changes, GnRH receptor activation, or perhaps FSH levels. And we’re not sure of which of them it is; however, this is one of the mechanisms that has been detailed. This the T-cells expressed in the GnRH receptors, and this is the differences between agonist and antagonist. Here’s your T-cell, here’s the agonist, it binds to the GnRH receptor, increased proliferation and activity leads to fibrotic path disruption and plaque instability. On the other side, if you look at the antagonist, there’s complete blockade without any stimulation and inhibition of a stimulated response. Looking at it another way, here is the T lymphocyte. Basically what happens when it gets stimulated, interferon gamma is released. Interferon gamma effects the smooth muscle which I produced in the collagen fibers. You get a faulty production of that. Here is your phagocytic monocyte, which again, when exposed to CD40 starts to release a matrix metalloproteases, which basically further breakdown the collagen, further breakdown the plaque instability and you have an increased risk of developing stroke.

Looking at it another way, T lymphocytes may be the key drivers of collagen metabolism in atherosclerotic plaques. Interferon gamma secretion, inhibition of collagen synthesis, fibrotic cap disruption and plaque instability, combine that with CD40 released upregulation of collagenases, fibrotic cap disruption, and increased risk of a thromboembolic event.

So as we look at these, we’re trying to figure out which one it may be. Well, in terms of the agonist versus the antagonist, it’s unlikely that long-term castration effect is going to be the cause of it, because we know it occurs early. It’s perhaps possible, there’s a potential for the agonist to have a plaque destabilizing effect due to the inhibition, as I mentioned, of T-cell function or stimulation of T-cell function.

And then, again, the last one, we get prolonged suppression of FSH, LH, and testosterone. It may be that that has a role to play, I’m going to look at that in a minute.

So let’s look at obesity and testosterone. There are changes in the metabolic syndrome. And the metabolic syndrome that exists when you go on ADT is not the same as the metabolic syndrome that develops in men as they get older. Metabolic syndrome is a disorder of energy utilization and storage, diagnosed by the co-occurrence of any of the three listed here. Metabolic syndrome increases the risk of developing cardiovascular disease and leads to insulin resistant accumulation of fat, lipid, increased glucose levels and these abnormalities. When you compare them side to side, this is the metabolic syndrome, this is metabolic changes with ADT: increased visceral fat, increased subcutaneous fat, reduced HDL, increased HDL, decrease adiponectin, increased adiponectin, increased C-reactive protein, normal C-reactive protein. There are differences between these two states.

FSH, let’s have a look at that. We know preclinical studies have shown that mice treated with degarelix have lower FSH levels than those treated with LH agonist or orchiectomy. Degarelix treated mice gain less weight and visceral fat than mice treated with agonists. Remember, I’m going back to the overall survival, how do we explain this difference?   Well, let’s go back the original CS21 study. Here is one year, and one of the secondary endpoints was PSA progression. And there was a significant difference in the number of patients who progressed on the agonist versus the antagonist. Then the FDA requested that all patients be converted to degarelix. So there was a switch over which occurred. And when you look at the event rate for the leuprolide patients who we switched over, prior to being switched over they had an event rate of 0.20.   And after being switched over that event rate dropped down to 0.08, which led to the change that you see in the slope of the curve for failure. People looked at that, they’re trying to figure out what was going on. Well, one of the other very interesting things that occurred was here is the FSH levels at one year. These are the patients on the agonist, these are the patients on the antagonist. And when you converted the patients on the agonist over and switched them to the antagonist there was a further 63% reduction in FSH levels, which was sustained. This is not new. Marc Garnick showed this in 2002 when he first looked at abarelix. There’s a tighter control on FSH. And FSH has been looked at. There’s an excellent paper in 2010 by Ragni where he did an analysis of samples from 773 patients with prostate cancer, all samples expressed FSH reception in the tumors; whereas, normal tissue had no expression. And when he looked to co-localize them he found that when he looked for the FSH receptor and for the vascular endothelial growth factor they were co-localized in the same location. Then they looked and found that there was a higher density of blood vessels present in the tumor compared to the normal tissue, which is what you would expect, because this is a tumor. But when he looked to localize them and see where that higher percentage of vessels were it was at the leading edge of the tumor, which is the leading edge of the invasion, that’s where you’d expect to see them.

So the conclusion is that the data indicates clinical benefits with degarelix, including a significant improvement in PSA progression-free survival and overall survival. There’s a reduce incidence of joint and musculoskeletal events, which I haven’t gone into, when compared with the agonists.

What about high-volume metastatic disease? Very quickly, in the patients with the high-volume metastatic disease there’s a rapidity of castration and PSA suppression, there’s a lack of flare and mini-flare on re-dosing, better FSH suppression, better suppression of serum alkaline phosphatase, there were less sclerotic-related events seen, there was a longer duration of the hormone sensitive prostate cancer state, and these differences were more apparent in the patients with metastatic disease in the study or those patients with a PSA of over 20.

So let’s look a little more. What else has happened, what else has gone on in the last four years, or five years? Well, we’ve discovered that the prostate itself produces its own testosterone, and that we don’t have hormone refractory, we have castration-resistance, because this organ is producing excess testosterone. This has led to the introduction of abiraterone. Here’s its mechanism of action, it’s a CYP17 inhibitor. And there’s been two trials. As we all know, there was COUGAR 301, which was after chemotherapy in castration-resistant prostate cancer, and then there was 302, which was prior to chemotherapy in prostate cancer, metastatic prostate cancer that was castration-resistant. Enzalutamide came along at the same time. There three trials that I know of in this. There was the AFFIRM, which was the same as COUGAR301, post-chemo. There was the PREVAIL, which was pre-chemo, and the difference in the PREVAIL trial was this was the first trial to demonstrate a benefit in soft-tissue metastatic disease, visceral metastatic disease. We never looked at it before. And it turned out that it was highly effective. And there was the STRIVE trial, which basically looked at bicalutamide in castration-resistant prostate cancer versus enzalutamide.

Now, the PREVAIL trial just had an extended analysis, which was published in European Urology this month. And there was a reduced risk of radiographic progression by 68%, or death by 23%. Radiographic progression-free survival was now 20 months versus 5.4 months for placebo. And median overall survival is now at 35.3 versus 31.3. Remember, there was some concern that the overall survival benefit wasn’t that great. Well, with more time it has come back into line. And again, adverse events, back pain, constipation, fatigue, and arthralgia were the major medical side effects seen. There were no difference between them in the placebo or the enzalutamide dose.

The STRIVE trial, which I mentioned, this was enzalutamide versus bicalutamide in men with prostate cancer progressing on ADT. That was published recently also. And there was 198 patients in each arm. PSA over—or progression-free survival overall was significantly better in terms of enzalutamide. Time to PSA progression, significantly better. Percentage PSA response over 50%, significantly better. Duration of radiographic progression-free survival, significantly better. It hadn’t been reached the medium. Best overall soft-tissue response, 60% versus 14%. And adverse events and quality of life, no differences. So it appears bicalutamide, even at the 150 dose doesn’t hold a candle to enzalutamide at the present time.

This is the area that we’re in. These are the agents that have come along, and their timing. And now I want to go to one new concept, should these advances be applied to hormone sensitive prostate cancer? And I’m going to put my little 3 cents in here. And if so, which agents, and when should they be applied?

So we have the CHAARTED data, we have a comparison that I’m going to look at GETUG 15, but much shorter as a result of the two previous speakers. And then I’m going to ask the question, who should receive docetaxel, the high versus low-volume risk disease debate, and then safety and toxicity considerations. I’m not going to show you CHAARTED again. Suffice to say it was ground breaking, it was the biggest change that we’ve seen in the delivery of chemotherapy and ADT in metastatic disease in probably the last 20 years. And one of the questions was high versus low-volume disease.

I will say it now, we do not have a proper staging system for the trials that we do. It’s very difficult to compare one trial with another because extent of disease varies from trail to trial disease, disease burden cannot be explained clearly. What we need is somebody to come down, a group of them to get together and say all advanced prostate cancer trials need the one staging system so we can compare and contrast, because we’re not comparing apples with apples. And again, you can see this stuff shown here.

This is the GETUG trial. And again, as you look at it there were significant differences between the two trials. One was the difference in high-volume disease. Another was the discontinuation for toxicity and toxicity-related deaths. There’s a summary of factors that may have contributed to differences between GETUG 15 and the CHAARTED, study size, statistical power, prognosis and staging definition and disease risk volume were different. And toxicity, which hasn’t been looked at, but deaths and early discontinuations and the use of other subsequent therapies were distinctly different between the two trials. In the original GETUG trial most of the new novel agents were not yet available, so they didn’t go on to the same number of secondary therapies as some of the CHAARTED patients did.

Febrile neutropenia needs to be looked at. The grade 3 to 5 hematologic toxicity, this is comparing it to tax327, which was the original docetaxel trial. It didn’t have estramustine that the Southwest Oncology Group (SWOG) study did so that’s why it was picked. And when they compared that to GETUG versus CHAARTED you can see here that the toxicity, febrile neutropenia is surprisingly large, more than you’d expect to see even in the patients who were on the original tax study. This was giving chemotherapy later. And the key conclusion is it’s tough to interpret toxicity data with incomplete information and with other factors from what that we’re waiting from for the CHAARTED study. But suffice to say that after 56% of the patients had been treated the people in GETUG started to receive GMCSF and antibiotics because of the febrile deaths.

Now, what’s the explanation for that?   The explanation is here. This is the docetaxel PK varies with castration state. And when you look, this is 10 non-castrated and 20 castrated with similar demographics. Clearance of docetaxel in castrated men was 100% increased with a two-fold reduction in the area under the curve. What that means is that the castrated men throw out the docetaxel way quicker than the sensitive men. And if you’re giving the sensitivity to that you’re going to see more toxicity. And a 50% decrease in docetaxel clearance is associated with over a 430% increase in the odds of grade 3 to 4 neutropenia. Which then what are the implications of these PK differences? Well, they may explain some of the grade hematologic toxicity, but also some of the survival benefit observed in castrated sensitive patients compared castration-resistant trials. Why was there greater hematologic toxicity in the GETUG 15 compared to the CHAARTED? Well, the answer is the time that the men underwent castration. In the GETUG 15 trial they had only got to be on ADT for two weeks before they received their chemotherapy. Well, if you think about that we know it takes three weeks probably before you’re rendered completely castrated with an agonist. How much GCSF was used in these trials, we’re not sure. So for the practicing clinician perhaps he should consider waiting until after one to two months of ADT, or castrate testosterone levels have been reached before starting docetaxel, which makes sense. They should use GCSF at least for the couple of cycles until castrate. But let me just move back. Sorry; I wanted to go back to one more thing I was saying. But if you have that increase toxicity it’s also possible you may see increased efficacy. And again, this has been mentioned that thankfully STAMPEDE came along and supported the findings of CHAARTED, because there was a serious question that one study was outlier. It doesn’t look to be.

So this is the question I’ll leave you with, if the toxicity is greater with the use of docetaxel in the pre-castrated state, might not efficacy also be? And we need a trial. And basically we have a trial, finally. This is a phase 2 study of docetaxel before medical castration with degarelix in patients with newly diagnosed metastatic prostate cancer. These patients are going to receive 4 cycles of docetaxel and then be rendered castrated, but we’re not going to wait the 3 or 4 weeks, they’re going to get degarelix and they’re going to be castrated within 48 hours, and then they will get further chemotherapy treatments. It’s through Institutional Review Board (IRB). We have permission for 50 patients, and we’ll be recruiting hopefully within the month.

So, I’ll leave you with this diagram, which I know you’ve seen before, but I have changed it a little bit. If you have a history of cardiovascular disease in your patient you should definitely, if you’re going to put them on ADT, consider the antagonist. The evidence is plain. If you have a PSA of over 20 over nanogram per mL or mets, the one randomized control trial that’s out there, which looked at the agonist and compared it to the antagonist showed a benefit. I know it was one of the secondary analyses, but it did show it as a secondary endpoint. And then finally, if you’re considering giving your patient a combination of ADT and chemo upfront and you want to do it, and you want them castrated quickly afterwards, you should probably consider putting them on an antagonist because you will shorten the time for castration, and they’ll have had their 4 doses, 4 cycles and then they’ll be castrated and they should not have the same toxicity, hopefully. That trial we’re doing will hopefully prove that. Thanks very much for listening.

Point-Counterpoint: Early Chemotherapy is Better

THOMAS E. KEANE, MBBCh: This is going to be a session on advanced disease. And we’re going to start it off with a point, counterpoint question regarding early chemotherapy. We’re going to have a pro and a con. And pro is going to come from Dr. Dan Petrylak,  the con from Dr. Michael Cookson. And I will ask the speakers to come up and state their points of view, please.

DANIEL P. PETRYLAK, MD: So, I’m going to be presenting the pro opinion for early chemotherapy for metastatic prostate cancer. So these are my disclosures.

It’s been actually 14 years now, 13 years since the initial presentation that docetaxel improves survival for patients with metastatic castration-resistant prostate cancer. Unfortunately, the survival benefit that we saw in castration-resistant disease was rather modest, about three months overall. And this is why in metastatic disease we reserved chemotherapy for those patients who are symptomatic, those patients who are rapidly progressive, rapidly rising PSA, doubling time of less than three months, or those patients with visceral disease who may not respond to primary hormone therapy, especially they may not respond to abiraterone or enzalutamide. We are having better ways to select out these treatments. Hopefully ARV7 will get approved which will tell us that the patient should not go on a drug such as abiraterone or enzalutamide, and you may want to favor chemotherapy in that situation.

Now, we should be considering chemotherapy for patients with extensive disease at the initiation of androgen blockade for metastatic prostate cancer. So I’m going to present the data that supports this. So Chris Sweeney ran a trial ECOG3805, which was the CHAARTED study. This was a randomized trial that took patients who had metastatic disease. They were stratified by the extent of metastases, either high versus low. And this was defined as more than four lesions on bone scan, or the presence of liver metastases, age, ECOG performance status, whether they had androgen blockade within 30 days. They were allowed to androgen blockade or at least go on chemotherapy within 4 months of starting androgen blockade. And then whether they had prior adjuvant androgen deprivation therapy along with their primary hormone therapy.

So arm A was 6 cycles of docetaxel with the standard dose of 75 mg/m2. Prednisone was not included in this regimen. And then the standard of care arm was just simple standard androgen blockade with LHRH agonist plus bicalutamide. Patients were evaluated, followed for survival and for progression. So again, as I mentioned before, these were the eligibility criteria. Prior androgen deprivation therapy was limited to 3 months prior to randomization or less than 24 months with no progression within 12 months of local therapy.

790 men were recruited between July of 2006 and November of 2012, and this trial was terminated in January of 2014 after median follow-up of 29 months. There were 136 deaths on the androgen deprivation arm, and 101 deaths on the chemotherapy arm.

So these are the survival curves based upon extent of disease. We see the biggest difference in those patients who have the extensive metastatic disease. The median survival for the combination therapy was about 50 months. It was 32 months for the androgen deprivation therapy alone. Interestingly, the low-volume disease at the first analysis did not show a significant difference in survival. And in fact, Chris Sweeney updated this data at the European Society for Medical Oncology (ESMO) meeting back last fall, and this continued to be almost superimposable. So the low-volume disease patients really don’t seem to benefit, the high-volume disease patients do.

What about some of the other indicators that would tell us the chemotherapy is improving outcomes? Well, of course we like to look at PSA and we know that from Maha Hussain’s data that if you normalize your PSA within 7 months of starting androgen blockade, those patients are going to have a fairly good prognosis. If you don’t normalize your PSA as defined as a PSA of 4 or greater, your survival is 13 months, which is pretty poor.

So when we start looking at normalization of PSA at 6 months and at 12 months it is a significant difference in favor of the combination therapy. The median time to castration-resistant disease is about a 6 month difference, and the median time to clinical progression is about a year in difference between the 2 different arms. So again, all the indicators seem to be going in the right direction.

Now, patients did receive therapy beyond progression, including docetaxel and cabazitaxel. There’s still some analyses being performed on this. But as we see here, 49 patients in the combination arm got docetaxel. And then 150 patients, or about half of the patients on the androgen deprivation therapy arm alone received chemotherapy. And that’s what we generally expect in clinical practice. About half of the patients eventually do receive chemotherapy. So I think that this is a relevant and clinically useful study.

So the interpretations at 6 cycles of docetaxel should be considered as an appropriate option for men with hormone sensitive prostate cancer who are suitable for chemotherapy, and the benefit seems to be greatest in those patients with high-volume disease.

So, of course, we like to see confirmations of studies, and this a study from Europe by Dr. Gravis, who’s he called the GETUG trial. It was a smaller trial, 385 patients. So it’s about half the size of CHAARTED. It had an 80% power to detect a hazard ratio of 0.62. Different chemotherapy administration regimens. 10 cycles were permitted. The median cycles were 8. They included prednisone as well. And 48% of patients received 9 cycles. Neutropenia and febrile neutropenia were seen in these patients, and these were observed in the combination therapy arm.

So this is the median biochemical progression-free survival. About a 10 month difference in favor of chemotherapy. Clinical progression-free survival, it’s about a 7 month difference, but the overall survival was not any different between the two different arms. This was fairly disappointing. So the question is really why.

So there did seem to be a higher proportion of low-volume disease patients treated in the GETUG trial. We start seeing that when you start separating out the high-volume disease patients this is really underpowered. It’s about a 4 month difference in the median survival. So that’s unfortunately not going to give us confirmation. So as I mentioned before, this is an unpowered study. It’s half the size of the ECOG trial. And interestingly, there was a high rate of non-prostate cancer related deaths which also may have contributed to the lack of survival difference.

The STAMPEDE trial was performed in Britain. This was a trial that has been going through multiple iterations over the years. It basically treats either locally advanced or metastatic patients with standard of care, which was androgen blockade, or standard of care plus zoledronic acid, or standard of care plus docetaxel, or the trifecta, the three combined together. Primary endpoint was overall survival. The secondary endpoints were failure-free survival, which was defined as a PSA failure, local or lymph node failure, distant metastases or prostate cancer death. They also looked at toxicity, quality of life, skeletal-related events, as well as cost effectiveness.

So when we look at overall survival with docetaxel plus standard of care over standard of care alone, there was a significant improvement, a significant difference in the median by about 10 months. And this for all-comers in the trial. If you add zoledronic acid to docetaxel it doesn’t contribute at all to the survival benefit, not surprising since the primary data demonstrate no survival advantage for zoledronic acid in the regional trials by Fred Sodd [phonetic]. If you look at overall survival, failure-free survival with zoledronic acid compared to the standard of care, again, no difference.

So we start looking at the metastatic analysis from this trial. We see that there is a survival benefit for the M1 patients. There is a trend, but not a significant difference for the M0 patients. Not surprising, these are the patients you may say have low-volume disease. So again, this seems to be consistent, but the problem is they did not stratify patients based upon that criteria they mentioned from Sweden. As one would expect, more toxicity in the docetaxel arm, 12% of patients developing neutropenia, and 12% febrile neutropenia.

Now, if we start looking at the time to first life-prolonging therapy compared to the standard of care, docetaxel does appear to delay this, and there does seem to be an equivalent use of life-prolonging therapy in patients who received docetaxel. So you can’t explain this based upon the fact that patients may have gotten cabazitaxel or other drugs subsequently to docetaxel on the other arms.

Is there other confirmatory data from other trials, the answer is yes. This was presented by Harry Sandler two years ago at American Society of Clinical Oncology (ASCO). He basically gave chemotherapy earlier to a poor-risk group of patients. Gleason score 9, localized disease, PSA of less than 150 or 7 to 8 with an intermediate level of PSA between 120 and 150, or T2 disease, Gleason 8, with a PSA of less than 20. These patients received androgen blockade plus external beam radiation therapy, versus androgen blockade, radiation therapy, followed by 6 cycles of docetaxel. And there did seem to be in this very, very immature trial a difference in survival by about 4% at 4 years. Biochemical failure was also superior in the combination arm. And then disease-free survival was also superior in the combination arm as well. Interestingly, distant metastases at any time was significantly different. But look at these numbers, they’re again fairly small. This is, again, why I’m a little bit hesitant about this particular study because of the small numbers. Death due to cancer, 23 versus 16, so that’s about a 7 absolute patient difference. Again, it’s significant, but this study does need further followup.

Michael Aday [phonetic] I believe is going to be presenting some other adjuvant data this year. Finally, we’ll see the results of other chemotherapeutic trials in this disease. Mitozantrone plus prednisone, plus blockade was combined to blockade alone in high-risk patients. The question is, of course, whether mitozantrone will improve survival. It doesn’t improve survival in metastatic castration-resistant state so the question is does earlier use have any difference.

And unfortunately, there have been other adjuvant trials that have not seen the light of day as far as overall accrual. This was Mario Iesenberger [phonetic] study, where he took high-risk patients, randomized them to observation, androgen deprivation therapy. This is post prostatectomy or combination therapy. This trial closed early due to lack of accrual. We may have further answers from the study that’s being done in the CLGB. This trial is comparing neoadjuvant docetaxel plus radical prostatectomy to radical prostatectomy alone. And Dr. Eastham has been instrumental in running this trial, and hopefully we’ll have an answer within the next two to three years on this.

The real question is why, why does early chemotherapy give you this big difference? And my answer I think comes from ARV7 and circulating tumor cells. So we know that we can isolate circulating tumor cells with a variant androgen receptor in patients with castration-resistant prostate cancer. When we look at the heterogeneity or the responses to hormone therapy and taxanes in these cells that have this mutated androgen receptor there does seem to be a better outcome in the mutated patients with chemotherapy than with the next generation anti-androgens. So perhaps we’re wiping these clones out earlier or preventing them from occurring.

So in conclusion, androgen blockade plus docetaxel is standard of care for first-line high-volume metastatic prostate cancer patients. Unlikely, subsequent therapy impacted on the outcome. More than half of patients in the control arm received effective cytotoxic therapy when they progressed, and unfortunately, the confirmation was not seen in the European trial I think predominately due to trial design, but we have seen confirmation in STAMPEDE. So I’ll stop there and turn the podium over to my opponent and he will present his view.

MICHAEL S. COOKSON, MD, MMHC: Good morning.

We know that androgen deprivation therapy is the most effective first-line therapy for men with metastatic disease, and control 18 to 24 months is certainly there. Cytotoxic chemotherapy is effective in metastatic castration-resistant disease, and that’s been shown. Earlier use of use of cytotoxic chemotherapy is certainly attractive. It might kill some of these cancer cells that are going to be unresponsive, as shown by Dan. It may also add an opportunity on the early end for some individuals, but the trick will be who those individuals are. We know that the management of these patients is highly dependent on the growth and the rapid proliferation of these cells. Some of these metastatic patients are not moving so quickly and others are. And androgen deprivation therapy sort of slows down the cell cycle in many of these patients, which may sort of make them less susceptible to chemotherapy.

So I’m not here to talk much about the cell cycle, but we know that in the S phase and in the mitotic rapidly proliferating state of these tumors that’s where chemotherapy has its best bang for its buck, and androgen deprivation therapy in responders slows them down into sort of a G-zero state. These mitotic inhibitor drugs, such as taxane, such as docetaxel, they work in those active growth cycle states of the cell cycle. And so that just points out that really their primary mechanism of action is in these high-risk, rapidly proliferating type of tumors, perhaps not all of our metastatic patients are in that state.

As Dan pointed out, there are three trials that have really attacked this issue. The French trial, which he highlighted, was the first one. This trial failed to show a significant advantage to early chemotherapy, and they didn’t just do 6, they did—they attempted 9 cycles in these patients in a randomized fashion. These are the curves for their overall survival, and we see that there really wasn’t a difference in early versus deferred chemotherapy. And I’ll get back to that in a minute. But up until three years there’s really no difference at all. So it doesn’t appear that the chemotherapy sort of prevented these early deaths, which you would have hoped for in administration earlier on. And then yet, there is a separation about 36 months, which suggests that there’s probably some benefit in some patients as we go further out.

There were some deaths related to chemotherapy. There was some toxicity related to chemotherapy. So I think we have to consider those. And when we talk about applying this sort of one size fits all. This was discontinuation in their trial, up to 1 in 5 patients couldn’t tolerate it due to toxicity and some of the side effects, like neutropenia, neutropenic fever, and death were noted in the trial. They updated their follow-up with longer follow-up, and again; although, there is some separation at—it wasn’t statistically significant. Gets back to Dan’s point, perhaps this was an underpowered trial.

The main trial that got attention in the United States first was the CHAARTED trial that he’s already outlined, so I’ll try to go quick. This was a positive trial, adding 6 cycles of chemotherapy to what we would conventionally do in androgen deprivation for these patients with hormone naïve metastatic disease. They did separate the patients into low and high volume. And remember, all of these patients in these trials had good performance status. All the patients in your clinic don’t have good performance status, so we’ll get back to that.

What they found was overall an improvement in survival with all-comers. The best bang for the buck was in the patients that they divided up into the high-risk. And the patients that were in the low-volume, or lower risk group didn’t see a separation, and we’ll come to that in a minute. This again points out that this has got some toxicity to it, and your patients in your practice will experience some of this, so to recommend this type of treatment to all patients should be brought with a little bit of discussion and caution.

The trial knew when they started it that the high-volume patients were the ones to target, but they had trouble accruing so they opened it up to all-comers, and in the end about 70% of the patients in this trial were indeed high-volume. I’ll just skip a little bit quicker through some of this, but to say that the trials that gave longer chemotherapy didn’t show benefit. The French study had longer follow-up, and then I think we kind of glossed over a little bit on the toxicity. In regular practice patients are not going through the scrutiny of enrollment with their performance status, et cetera, so the trial patients are sort of the best case scenario, younger, fitter, healthier type patients with less comorbidities.

The STAMPEDE trial was indeed presented, and it was a positive trial in favor of early chemotherapy; however, they really didn’t give us that snapshot of high versus low volume so it’s really hard to interpret that for all patients that come in. And if you look at a comparison of the three trials, a couple of things you notice is that the CHAARTED trial was more enriched with higher-volume patients, that’s clear. That the salvage treatment for the failure patients is notable. In the French study, which didn’t show a difference, up to 80% of those patients ultimately received chemotherapy. And in the other two trials it was less than half. So that may be what happens in real-world, but I almost think it’s a crime that a patient should die from prostate cancer and never have received potentially helpful cytotoxic chemotherapy.

This was the update of the CHAARTED trial, because when they first presented that low-volume versus high-volume they were worried. They thought well maybe if we just wait a little longer we’ll see a benefit. And indeed, the high-volume patients still see a benefit, but the low-volume, even with longer follow-up failed to show that benefit. So I think that’s an important point that we need to consider when we say all patients who present with metastatic disease should receive chemotherapy.

This is sort of the two trials that we can low versus high-volume, because the STAMPEDE didn’t differentiate, and in the high-volume patients I think it’s clear, and in the lower volume, or the slower moving type metastatic patients it doesn’t seem that I clearly tell them they’re going to get a benefit from early institution of chemotherapy.

So my conclusions are that studies to date demonstrate that patients with metastatic hormone-sensitive prostate cancer differ in their presentation, their disease burden, and their response and outcomes, and toxicity is greater, and median survival is shorter in unselected non-trial patients. Patients with high-volume metastatic prostate cancer have inferior outcomes compared to those with low. And the high-volume patients should therefore offered docetaxel and ADT upfront with clear risk/benefit discussion, but I think it’s there. At this time I think low-volume hormone sensitive patients should not be offered a one-size-fits-all early docetaxel. And 60% to 70% of the patients in published trials who present with high-volume de novo metastatic disease may respond differently than these low-volume patients.

Regardless of the volume of disease, patients with metastatic disease who progress through their androgen deprivation therapy should be offered docetaxel at that time. And this delayed approach would reduce the overtreatment that would potentially give them that same survival advantage and reduce some of the morbidity that could be associated with early chemotherapy.

So who would I not recommend docetaxel to right off the bat, low-volume metastatic disease, perhaps the oligometastatic patient, and those who have had a really slow and protracted development of metastatic disease over many years. So we may be sort of a biological surrogate to the activity.

And then if you look at the National Comprehensive Cancer Network (NCCN) guidelines where they do incorporate the use of docetaxel, they have a little box at the bottom and it talks about the possibility that the low-volume patients may not be the right ones to include with that recommendation. So I think Dan and I hopefully are saying the same thing, but instead of all patients, I would say we have to be judicious about it, offer it to those patients with high-volume disease, those who fail to respond to the initial ADT, and reserve the cytotoxic chemotherapy for the low-volume patients when they fail. So thank you very much.

S.A.²M.² : The Best “Natural” and Researched Heart Healthy Pills for Patients Concerned About Prostate Cancer

I didn’t want to give the exact same talk. So now I’m going to call it S.A.M., but SA squared, M squared, the Best Natural and Research Heart Healthy Pills for Patients Concerned about Prostate Cancer. There was a quick reason why I came up with this acronym, Sam is a unisex name. It can be for a boy or a girl. This is the same advice we give to breast cancer patients, colon cancer patients, prostate cancer patients, there’s are thousands of over-the-counter pills and different pills patients can take, and you only have so much time to discuss them. So if you could just get in three to five pills on a discussion with a prostate cancer patient, you obviously can’t talk about the 100 different supplements. So which are the top ones to talk about to make sure the patients are working with their primary care to see if they qualify. And so my argument has been if you memorize the acronym SAM, S-A-M, that’s good enough to discuss the natural pills that patients should prioritize before they take other pills out there, over-the-counter, for example.

So the mantra in 2017 is the same. When I was 29 and I came here long ago, heart healthy is prostate healthy. First do no harm. So the idea here is can we recommend a pill that in the worst case scenario just reduces the risk of a cardiovascular event, and the best case scenario reduces the risk of a recurrence and a cardiovascular event, but ultimately first do no harm? The patient wins every time. And the reason why I think this is a good place to turn for the future is we’ve spent a lot of money on some important trials, but in the end they were all negative trials, so we’re not recommending any of these products. From SELECT we know that vitamin E and selenium was a problem. But earlier trials, ATBC carrots showed that betacarotene in smokers actually increases the risk of lung cancer. And then lycopene really didn’t go anywhere. And now people are really excited about vitamin D, and I think it’s interesting, but before I jump on that vitamin D bandwagon you’d like to see more information, because a lot of people thought a lot of other supplements were going to work and it ended actually doing harm.

And then the latest de jour from last year was pomegranate, so people were all excited about pomegranate and that’s kind of died down. What happened, what was the result? And I would argue I never jumped on the pomegranate bandwagon because I never saw anything heart healthy about it. It was just a lot of sugar and a lot of calories, but how is this going to work out in prostate cancer?

There you go, three randomized trials up against placebo. So people getting excited about pomegranate juice and pomegranate extract really got excited based on non-controlled trials, looking at historic controls. Then finally you throw a placebo in there, no difference is detected between groups with regard to PSA, kinetics, and pain scores. Then you’ve got one, pomegranate extract did not significantly prolong PSA doubling time (PSADT). We’ve been waiting in this one for about a decade. And then the surgical neoadjuvant trial, our primary endpoint in modest size short-term trial was negative.

Three placebo-controlled trials and three showing no better than placebo, so that’s why I continue to push the idea that if you can talk about just a few pills, talk S.A.M.. These are natural, they’re all generic, they’re dirt cheap, like me, they’re heart healthy, and I get more excited about supplements in cancer for side effects. So these are three drugs that all came from natural sources.

The first one is statins. And I’m not sure if you know, the latest meta-analysis just came out in the past few weeks in The Journal of the American Medical Association (JAMA). So show me another pill in all of the medicine that can make this statement for primary prevention. You have completely healthy individuals, they have a slightly higher risk for heart disease, they haven’t had a heart endpoint, they haven’t had a heart attack, they haven’t had a stroke, no clinical event, and you put them on a statin and what happens? In adults it increased cardiovascular risk but without prior CVD events. It was associated with a reduced risk of all-cause and cardiovascular mortality, and CVD events with greater absolute benefits in patients at greater baseline risk. What you tend to hear by the statin conspiracy theorist all the time is there’s not enough trials in healthy people. 19 randomized trials, 71,000 individuals, average age running 51 to 66, and then the trial is 28 to 97. And in this meta-analysis they couldn’t find a serious event overall greater than placebo. So statins tend to get criticized a lot, but in reality when you look at the data and sum total it’s quite impressive in terms of primary prevention. We have nothing better. But it does with a catch, which I’ll show you in a minute.

This trial just finished, so it added to the statin data, another primary prevention trial, but this is 21 countries showing benefit across the board of 10 mg rosuvastatin, which is Crestor, one of my favorites, versus placebo. And just within five years showing a significant difference. So the trial is essentially stopped. But here’s the criticism I just lay on statins, some people taking statins don’t need a dose that high, but they can go to a lower dosage, or go on no statin at all if they made moderate lifestyle changes. So when you look at a number needed to treat of 1 in 100, or 1 in 75, you just wonder if some of these patients at intermediate risk were more active and changed their diet slightly if they would do as well in this situation as a drug. And my guess is I think they would. But some people do everything right and still can’t get that number down, like my father, and I understand that, so they qualify for pill.

So I want you to remember only one web site from today’s talk, CV risk calculator.com. It’s a fabulous web site, the American Heart Association, the American College of Cardiology put together for men and women. It takes you 20 seconds. You type in your numbers and it spits out whether or not the benefits of a statin might outweigh the negatives. We’ve been waiting for an absolute risk calculator like this from a legitimate organization for a long time. So this takes pooled cohorts and establishes a risk, and based on that risk decides, and opens up the discussion with your primary care doctor, does benefit outweigh risk, or does risk outweigh benefit?

If you look at latest meta-analysis we’re also seeing enough benefit here, we’re seeing benefit especially in radiation therapy. Not enough data amongst radical prostatectomy patients. But you could argue there’s just not enough surgery data to really have a strong meta-analysis as of yet.

So if you start seeing some of the newer data coming out, 2014, 2015 presented at American Urological Association (AUA) and other meetings, you do see some surgical data that shows that post RP statin use is associated potentially with a lower risk of recurrence. Now, in the end people always say to me, but this, a lot of this retrospective, you don’t have that much prospective data. But all we’re doing is reducing the risk of a cardiovascular event in men, and it doesn’t reduce the risk of recurrence in prostate cancer, the patient still wins. That’s why I like this idea.

And this is a new stuff coming out, which is exciting. Whether it’s from Boston or from Canada, the new stuff being published shows that it might actually enhance the effects of ADT, and these are very large databases, or allow more off of ADT, and more off treatment intervals, longer off treatment on IAD, for example, intermittent androgen deprivation. So these are very large databases. These are next publications you’ll see. This is not going away any time.

If you look at the Boston group, they argued in this study, because they’ve done some basic science with it, that actually statins compete, the molecule competes with DHEA and some other precursors that could stimulate the growth of an existing tumor. But there’s probably many, many mechanisms. And so I just decided to list all the mechanisms that I have read about and followed over the past 25 years. You could give it a variety of reasons why it could be helpful against a variety of cancers, from reducing, inhibiting angiogenesis, possibly VEGF, for example, reducing inflammatory markers, like CRP, which is used prognostically in some cancers. There’s been some talk about using it in prostate cancer, just stabilizing plaques, or just simply lowering LDL reduces oxidative stress. The list goes on and on.

And then there’s a new pathway that I should have memorized long ago, but this is a new pathway. We learned that the liver makes cholesterol and that you need to block that cholesterol production from the liver, and that’s how statins primarily work, and that is interesting. But we all know in medicine now after all these years that it’s not black and white, things are very grey. What organ is second to the liver in terms of cholesterol production and uptake, it’s the prostate. So if you actually block that precursor then you also reduce the number of intermediates downstream. And as more basic science is being done, larger amounts of these intermediates downstream then are possible stimulants or stimulators of well-known oncogenes. So there’s a lot of pharmaceutical development in blocking some of these other pathways to see if then you could have an effect on the progression of the disease. Now, no one is saying that you should get rid of all cholesterol. In fact, some of the most concerning patients that I talk to are the ones that think they want to take their LDL down to 20 or 30, but you need cholesterol to make vitamin D, you need it to make testosterone, your steroids. So one of the concerns I see is some men get their LDL down to 20, 30, 35, and then you start seeing their testosterone low. So sometimes the explanation for a low testosterone, a minority of cases, is the LDL is far too low.

And then the question is, well, which one? Most of them are now generic, which is fabulous. So they’re now affordable. I talked yesterday about Jim Fixx, who had the number one selling book 40 years ago, the Complete Book of Running. We didn’t have statins that were that accessible. He had high cholesterol, and my understanding is he wasn’t on a statin. So exercise alone in someone like that is not going to help, you need something synergistic, a pill with exercise. If I had my druthers, which pill would I use for the next chemo prevention trial, or let’s say you wanted to reduce recurrence after radical prostatectomy, or you wanted to do a trial of ADT, which one would I use? I would use the ones with the longer half-life. And the reason for that is if you miss a dose or miss several days the drug still works just fine. So we exploit this all the time. Here’s rosuvastatin, which is Crestor. It has a 19-hour half-life. So now you’re starting to see publications in cardiology where patients that can’t tolerate statins will go on a Crestor one time a week, or Monday, Wednesday, Friday, and they still get 20% to 30% reduction in LDL. So when I hear patients tell me I can’t be on a statin, generally in my experience 9 out of 10 times it’s because they don’t understand this chart. They have a lot to play with, a lot of different half-lives, and most people can tolerate a statin one day a week, three times a week, but you’ve got to exploit the ones that have the longer half-life.

So in the Primary Prevention trials, again, rosuvastatin was used here, Crestor. These are people who are perfectly healthy but they have high inflammatory markers. And then when they got their statin they got their cholesterol down to 70 and their CRP low, then below that you saw these very large reductions. So this is a phase 3 trial of rosuvastatin that was actually stopped in healthy people in less than two years in a phase 3, can you imagine that, because it already reached its cardiovascular endpoints and they had to instruct the placebo group that, hey, even though your cholesterol is running about 100 to 110, taking it down a little bit below 100 actually seems to be beneficial. I think we should be copying this in the future, this model if we end up doing a statin trial in prostate cancer, because I hear all the time that there too many patients on statins and so you can’t do an objective trial. I don’t agree with that, because some of these numbers we’re talking about, I rarely see, unless a patient has already had a cardiovascular event. So I think there’s plenty of room to do such a trial if the funding is there.

I want you to also remember that anytime there’s a successful drug, most of the time, there’s going to be a supplement that rides the heels of it. There’s going to be a supplement that makes a claim that it’s just as good as the drug. In some rare cases it is, in most cases it’s just a copycat trying to copy on the profitability of a successful medication. So patients should be aware of that. Do we have a cholesterol lowering drug over the counter, of course we do, it’s called red yeast rice, and it has a bunch of different components. But one compound in there is called monacolin K. It’s identical to Lovastatin. It’s basically a natural statin. So a lot of patients like it. In the old days we used to recommend it a lot, but now it’s become more expensive than the statins, so this is generally something that people utilize if they’ve gone through every statin and they still have side effects, and they want to try something different. But it’s just a statin in disguise, diluted, but it has potential. And people don’t realize that outside of this country there’s been very large trials of supplements. Some of the most successful supplements in the United States are actually just prescription drugs in other countries. It’s all perception versus reality when it comes to the word natural. So let me repeat that, some of the most successful selling supplements in the United States that work are actually prescription drugs in other countries, so it’s all perception versus reality. A good supplements is actually just a drug in disguise.

Another option if you can tolerate any statins is actually Zetia. It’s a cholesterol absorption inhibitor. In Boston and other places they’ve done basic science work on it. It’s an FDA approved drug. It can be added to a statin. There’s a suggestion, at least basic science-wise, that by reducing cholesterol or the cholesterol from food you can impact microvessel density. But this hasn’t gone much outside of the basic science area, but is now becoming a more and more popular drug, because it’s an alternative statin use. You won’t get the statin reduction, but then again, the side effects has been the same as placebo in most clinical trials. Again, this works differently. This blocks the absorption of cholesterol from food. There’s one standard dose, 10 mg, and it’s always an option for people that can’t tolerate a statin.

The A in S.A.M. is aspirin. Aspirin is a natural drug. It comes from willow bark, and it is dirt cheap, and aspirin is having a couple of really good years here. So in colorectal cancer right now the US Preventative Services Task Force is saying there’s enough randomized data that it reduces the risk of the colorectal cancer, even baby aspirin, in men as well as women. They made the announcement in 2016. So in men as well as women. Does it reduce deaths, we don’t know. And there’s all these other trials being initiated of aspirin to not only prevent cancer, prevent the recurrence of cancer, even a baby aspirin.

So the meta-analysis in prostate cancer, people get all impressed about aspirin in colorectal cancer, but we fail to mention that, look, when you have 39 studies suggesting a benefit of aspirin in prostate cancer, that’s interesting. There’s serious toxicity though, so it’s not be first choice, but as much we’re excited about colorectal cancer we should be excited about trials in the area of breast and prostate cancer.

This is a study that you haven’t seen yet that was presented at meetings this year. Actually, last year, and this is most impressive data you’ll see on aspirin thus far in prostate cancer. This is the Physician’s Health Study-1. It’s one of the first studies to look at taking aspirin prophylactically to reduce heart attacks. Only physicians were in this study, healthy physicians, and essentially they have now followed these physicians after 27 years. This is the longest duration of following a patient population to see prostate cancer risk, and they’re going to report in their future publication a 27% reduction in mortality, taking a greater than 3 tablets a week. So it’s only going to up the interest in using aspirin in the future in some capacity.

But again, I want to warn the audience, anytime it’s natural does not mean it’s better. Poison ivy is natural. Arsenic is natural. That doesn’t mean I recommend it to patients.

So, if you look at some basic phase 3 data it’s chilling. These are completely healthy women taking a baby aspirin, and after ten years they have significant increases in major GI bleeds and peptic ulcers. We have to do a better job to see who qualifies for even a baby aspirin. And this was a baby aspirin. And in this study it was every other day, and you still saw that kind of toxicity. And people think the word baby, when you think baby you think soft and cuddly. It’s not going to do any damage. It did a lot of damage in this study, so we need better tools on how to predict who goes on aspirin. That’s why I go back to CV risk calculator.com. It helps predict whether or not the benefit outweighs the risk. And so all you have to in urology and oncology is send them back to their primary care, have them go to this web site. Have a discussion, and if they qualify, great. If they don’t, based on cardiac risk, I’m not excited about them taking it for prostate cancer. I think that gets a little reckless.

The last one—oh, I want to mention one more thing about, there’s a natural aspirin out there. Remember, aspirin came from willow bark, but the active anti-inflammatory in aspirin is salicylic acid. And for of those of you who really enjoy history, like I do, imagine that you’re Bayer in 1900 and people are complaining that when they take aspirin they vomit and it tastes horrible. So a couple of scientists get together and say, “I know who to actually take this molecule and we’ll add an acetyl group on there and we’ll reduce the bitter taste. And they add this acetyl group and low and behold, that’s the group that impacts the platelet that causes the blood thinning. So by pure serendipity it became a blood thinner. It’s naturally not a blood thinner in its natural state. It’s when we slightly manipulate it. The moment it’s digested in the GI tract you lose that acetyl group, but then the active anti-inflammatory salicylic acid. Interestingly enough, you find salicylic acid in many healthy foods. So most of the fruits and veggies out there, and spices, you see low quantities of sort of natural aspirin out there. And you also see it being sold in supplements as white willow bark.

My last pill to talk about it metformin. That’s the “M”. Here you have meta-analysis showing that it has a potential roles somewhere in prostate cancer. I want to reiterate though about these three pills, S.A.M.. I think people expect too much from them in later stage disease. I’m not as excited about using these in metastatic disease. I think we expect too much from a pill that has very little toxicity. The excitement here is I think to prevent disease or to prevent recurrence of high-grade disease. I think when you ask for it do some incredible job for metastatic patients I think most people would be disappointed. But in metformin, at least, it’s use has been for side effects in ADT.

Here is the trial always published a while ago. This is the Nobes study using 850 BID. And look at this. When is the last time you saw a group of patients on ADT actually lose weight and blood pressure comes down. No change in lipids, but they actually become more heart healthy with a generic pill like metformin.

There’s one small study at ten Swiss centers of CRPC. They’re claiming a potential benefit of metformin even in early stages of castrate-resistant prostate cancer. Again, I’m excited about this, but this is not the time I would ideally want to use it. I’d want to use it earlier on, especially potentially with androgen deprivation, because for metabolic syndrome it can reduce the risk of most of those things. Metformin is arguably the safest, greatest drug ever invented in the United States for weight loss that doesn’t have an indication for weight loss. Why is that? Because it’s generic now, and we’ve learned that one of the mechanisms of how it prevents type 2 diabetes is patients lose weight. So it’s one of my favorite weight loss agents because it’s a heart healthy weight loss agent, unlike most of the weigh loss drugs we’ve approved in the United States, which end up getting pulled from the market because it helps you lose weight, but it was heart unhealthy, like sibutramine or Meridia.

There’s a phase 3 breast cancer trial going on, and there’s a little glimpse of what’s going on in the trial. It’s metformin versus placebo to reduce the risk of recurrence and possibly death. And we’re probably going to get data on this trial in the next few years. If this trial is a failure who gives a damn? And what I mean by that is that patients were still winning. Within six months of those allocated to metformin the average insulin drop is 11%, CRP 7%, the average weight drop is already 4 pounds in the first 6 months versus the placebo group, which is gaining almost 2 pounds. So the patients are at least becoming heart healthy on this product in the phase 3 trial.

And I want to reiterate something, because last night at the midnight I was on the phone with an individual who had lung cancer. And she wanted to go on metformin. And the doctor said, “Don’t do that, it doesn’t change your glucose that much, and the body is still going to make glucose and feed the tumor.” That is a naïve answer. The truth of metformin is it reduces insulin to significant amounts, in many of the clinical trials by one-third. That’s the mitogen, that’s the signaling agent. The great thing about metformin is it puts your glucose in cruise control, it doesn’t let it go too high or too low. So in these trials they’re seeing maybe a 1 point drop in glucose. They’re seeing it basically stay at the same number. It’s the insulin that’s dropped significantly.

And here’s the new trial that got me really excited. Here’s the polyp prevention trial from Japan. Average glucose is 100. So they’re not even basically pre-diabetic. They have a normal glucose. And after one year they stopped the trial because it was a 40% reduction in polyps. And did anyone notice the dose? I don’t know if anyone knows this trial has now been published. Did anyone notice the dose in the material and methods section? Get ready for this, remember the average dose that used in primary care is anywhere from a 1,000 to about 2,000, but the average runs about 850 twice a day. In the Japanese trial for prevention they used 250. So I’m now telling patients to buy a pill splitter. And many patients since this trial has been published do very well on 250 in controlling their blood sugar and reducing insulin levels. So maybe we’re using a dose that’s too high, because as you go to higher dosages you go to a higher rate of side effects. But this is fascinating to me.

My final thoughts is now the dose range runs 250 to 2,000. This is the highest dose, this is the most common dose. It’s being used in a lot of cancer trials. Maybe it’s too high. You have to take it with a meal, otherwise you will run into GI symptoms, like diarrhea, soft stool. Weight loss is one of the side effects, but side benefits. You’re not supposed to use it at the time of contrast agents or if there’s renal or liver insufficiency. The biggest catch I actually see with metformin, besides using too high of dose, is it will in some patients significantly reduce B12 and magnesium levels. You have to monitor patient’s B12 and magnesium levels in clinical trials and in the clinic if they’re going to take metformin daily. It’s well published, it’s well put out in meta-analysis, and I have personally seen it so many times.

So with that, I have three minutes to go. And I just want you to remember what I said last time, which is—which I said yesterday, don’t get too excited about pills too often, because the trial that launched metformin had a third group in it where people just changed their lifestyle to lose weight, and they exercised more. And at the end of ten years the lifestyle changers still beat the drug. But you never hear about the lifestyle change group, which was the third arm of the trial. What happens if you combine lifestyle change with metformin? I think you see synergism. I get excited. But clearly there’s benefit to lifestyle in terms of losing weight that might be equal to the drug.

The copycat for metformin right now that’s selling over-the-counter in Canada and the United States is called Berberine. You may have never heard of it. It’s an herbal product. It mimics metformin. I’m nervous about it because it has huge quality control problems. So if a patients look, I want to take that metformin, natural metformin over-the-counter called Berberine, I’m excited about testing a high-quality product, but there’s been a lot of quality control issues, so we still are just kind of watching it.

I just want to mention one other drug, just for the next time I see all of you, or some educational session. The other “A” in S.A.M. should be acarbose. If you haven’t heard of this drug, this actually blocks the uptake of carbohydrates. So patients have to take it two or three times a day. So every time you take carbohydrates you take it with your meal. The first bite of your meal. This has been out for decades. It’s generic. And for those people who can’t do metformin, this has data that’s arguably as good as metformin, especially in the area of cardiovascular risk. So they’ve had large trials showing these potential benefits in terms of improving lipids, increasing weight loss, improves blood pressure. And again, this blocks the uptake of sugar from food. It’s a wonderful mechanism, but it’s more of a pain in the gluteus, because you have to take it multiple times a day, generally with each meal at the first bite. But this is something we should look into too. It’s more popular in Asia than metformin, which I think is interesting.

The last thing in “M” as I finish up is multivitamins. Right here is Centrum Silver. It’s the only multivitamin involved in a phase 3 trial that showed it was safe with prostate cancer. That’s my point here. And I find so interesting, I’ll travel, and I don’t want to mention any cities, Boston, but the reality is I went there, and the CME bozos there said to me, “You can’t mention Centrum in your slide, because that’s favoring a pill.” And I said, but it’s reckless if I don’t mention that Centrum was used in the only randomized trial, because then I’m endorsing generic multivitamins, which are all the place. There are some generic multivitamins that say six pills a day. So I’m not going to mention the generic, I’m going to mention the one that went through the randomized trial that had quality control. So in CME we have to understand that it’s not like pharmaceutical, you have to mention the actual product because not all products are the same over-the-counter.

The Benefits and Challenges (Present and Future) for the Urologist Treating mCRPC

I’m going to talk the benefits and challenges for the urologist treating CRPC. These are my disclosures.

So I’m going to try to convince you why you should be treating patients with all these advanced therapies. So this is a snapshot of our practice. We have 16 urologists, a radiation oncologist. We incorporated a medical oncologist. We built our center ten years ago. We’ve just gone on our tenth year anniversary, and we provide all outpatient urology services under one roof. And the only thing that we don’t do is some of the surgery that requires outpatient surgery. We have a surgery center, radiation oncology, pathology, and we have a very robust imaging. We have a very robust research department, which I head. And I’ve now gone on my 20^th years of doing clinical trials and have, as of my last count, 214 trials under my belt. And I’m also the chairman of the Advanced Prostate Cancer Committee.

And this is our pathway for treating prostate cancer, whether it’s castration sensitive or resistant, we really believe that it’s a multidisciplinary approach that’s required. We have the urology, oncology, radiation oncologist, pathology, pathologist. And we also incorporate palliative care. We even have one managed primary care group that will not allow their patients to get any of these advanced therapies until they talk with a palliative nurse. And they have the nurse that talks with them, and then they’ll okay, they’re approve the therapies. We also have a nurse navigator that navigates these patients through. We even have our advanced prostate cancer tumor board monthly. All of these people show up. We even have our billing people so that when we try to sit down and make recommendations together that we’ll know whether or not these patients are going to qualify for the therapies. We have an advanced prostate cancer clinic that meets weekly. I’m one of the docs. We have another one of our physician campaigns that does it, and also our medical oncologist is involved in our clinics. Our medical oncologist really when it comes down to it administers the chemotherapy, and he does that at his office. Otherwise, everything is administered in our office. We also have a bone health management. That’s really what got us started years ago. It’s run by our physician extenders. They get the patients started, and then eventually the urologists are managing these patients. And in addition to this, we have a GU tumor board that meets monthly for all the GU cancers.

So this is the treatment landscape since 2017. I think that Mike Cookson, and Dan Petrylak, and Lenny have shown you all of these drugs, but basically these are the therapies since 2010: sipuleucel-T, radium-223, enzalutamide, abiraterone and cabazitaxel. We start our—the minute patients start on ADT we put them in our bone health clinic. They get a DEXA scan and they get started on vitamin D and calcium, and as time goes on if they need antiresorptives they’ll get denosumab or bisphosphonates.

So we have the five new therapies that have been available, each with a unique mode of action. And it’s imperative for the urologist to know how to treat these patients when it comes to the administration, dosing, and adverse events. And I got this quote from Chuck Ryan, the right, so that we can administer and determine the right therapy for the right patient at the right time. And all these therapeutic options now allow us to sit down with the patient and have our patient physician shared decision making on their therapies.

So this is classically the way that the protocol went before 2010. This is the pathways. Urologists usually would have the patient, start the patient on ADT and maybe some of the first generation anti-androgens. Once they progressed, got pain, became symptomatic we sent them to the oncologist where they’d get docetaxel, or they might have been started on some of these secondary hormone therapies, like ketoconazole and DES. And what I found was, you know, docetaxel was approved back in 2004, first one, therapy approved on overall survival. We would get the patients, they would be somewhat symptomatic, they would progress. We’d send them to the oncologist, the oncologist says well, the patient is not ready for chemo yet, send them back. Then the patient would come back and then he would get worse, and we would send him to the oncologist, and the oncologist would say, ah, the patient is too advanced, we really can’t, we’re not going to help. So that’s the kind of frustration that we had initially.

And then as far as the radiation oncologist, we would send them patients that needed spot welding, severe pain from a bone met, or if they had impending spinal cord compression they would take care of that. And then they were using the radiopharmaceuticals, like beta emitters that were around, samarium and strontium, they had a lot of side effects. There were no overall survival advantage. So, and they weren’t using it that much. But that was the pathway before.

So now why should urologists treat mCRPC patients, I’ll try to tell you. We have the patients. They’ve been with us since diagnosis, we know them, they trust us. I believe we can provide better continuity and patient care, and if done right I think we can facilitate it better. So why stop at ADT and then hand off to the oncologist when we have all these new therapies available to us? So, if we don’t figure out how to treat these patients someone else will, and of course, it would be the medical oncologist. And I think that Dave was mentioning that most medical oncologists are busy treating other cancer types. So to get a specialized GU oncologist you’re either going to have to go to the university or do what we did and we got our medical oncologist to really be tuned up on all GU therapies. And radiation oncologists, how are they getting into the mix here?

I can just give you an example, in our neighborhood there was a radiation oncologist who hired another radiation oncologist, and he administers a lot of therapy for prostate cancer. But he just recently hired a medical oncologist who had a pretty big practice in the city, and so now they—and they advertise. And so I think they’re trying to get in the mix of capturing these patients and treating them. So here’s our other competitors on the playing field. And it’s interesting, because the university just acquired that practice. And then there are hospital systems that will do it, whether they’re academic or non-academic. They all want to compete for that prostate cancer business. And then, of course, there are cancer centers and Centers of America. So if we don’t do it these patients are going to get treated, but they’re going to get treated by someone else. And I’ll show you why we need to be doing that.

What should treatment for mCRPC be multidisciplinary, yes, of course, absolutely, but the urologist should be the quarterback of the team. And if we don’t learn how to be the quarterbacks then I think that we’re going to be relegated to being the water boys. And I think that now that we’re seeing all these payment models, and bundled care that’s coming down the pike, we’re going to have models where I think eventually they’re going to—the payers and especially Medicare are going to come out and they’re going to say we’re going to give one group all the money to treat, to take care of prostate cancer. And so we don’t want to be in position where we’re the subcontractors. We want to be the contractors in this business. So I think it’s imperative for the future, if you’re going to want to continue to treat these patients that you’re going to have to move into that kind of position.

Now, this is just an aside. I know that Dave, he’s married to a beautiful wife, Jody, and he’s very athletic, he’s very virile, and that’s why I’m worried that he loves football and he loves our two quarterbacks who are Super Bowl quarterbacks, Peyton Manning and John Elway. And I’m afraid that if he keeps looking at these pictures for too long he’s going to develop priapism, and one of these talented urologists are going to have to treat him.

These are some of the caveats. If you’re going to be in this you don’t want to be a dabbler. You don’t want to just be able to use one of these therapies and then just hand-off. You need to be as knowledgeable or more knowledgeable than the players on the field. And I think Dan made a good point, this really should go to the people that do it best. And I think that we need to make an effort to learn how to do that best. And we have an opportunity to do that. And that’s with these advanced prostate cancer clinics. And I give credit to the AUA, LUGPA, guys like Neal Shore, Mike Cookson, who have put on these programs to teach us how to develop an advanced prostate cancer clinic. The material is out there, we just have to learn how to utilize it and implement it.

This is a newer model for urologist to take charge. And it provides the ability to expand your practice and sustain a higher quality of care and improved patient outcomes. And I agree, I agree with Dave, and these patients—and Lenny, that these patients actually, I’m seeing better outcomes in our managed program. These patients would live for a year or two. I’m seeing that it’s not uncommon to see these patients going on for four years. So I think we get better outcomes. We can retain our patients, we’ll grow our revenue and promote a center of excellence.

And so this is what’s involved in creating a successful advanced prostate cancer clinic. You have to identify a physician champion, a nursing champion, administrative champion. You’ve go to integrate that into your business, and you want to collaborate with multi-disciplines so that you can have a multidisciplinary approach, but we’re going to subspecialize in prostate cancer, and eventually GU cancer.

So if can improve the patient care. We can actually be proactive in their management so that we can start treating them earlier and they can get the advantage of these therapies that we offer. We have protocols, we can integrate this and give comprehensive treatment, it’s coordinated, and it’s convenient for the patient so that the patient doesn’t have to be going all over town. And we try to integrate this so that we can make it really patient friendly. And I’ll show you what else we do.

Patient satisfaction is a win-win for you and your practice. And if they’re dissatisfied it’s also a lose-lose situation for you. And I’ll tell you why, because patient satisfaction is one of the metrics that being used in the value-modifier methodology, and I’m going to talk about this in a later slide.

When we treat patients we can have them remain in our care longer. And these patients don’t want to be transferred or shipped off to other specialties. They’ve been with us for so long that they get to know our staff, they’re comfortable in our offices, so they don’t to have to go off and see other people that they consider strangers.

And so prostate cancer treatment can offer revenue opportunities also. So in addition to our ancillaries, like our radiation oncology, imaging, pathology, we now can do in-office dispensing and set up our pharmacies. And it’s not that difficult to do. And we’ve been able to do through UROGPO, which is a group purchasing organization that’s actually going out throughout the country and trying to help your practices set up an advanced prostate cancer clinic. But as far as in-office dispensing, it’s not that terrible to do. All you have to do is apply for a National Pharmacy Number, it takes about a month. And then there is the QS-1, which is a national plan benefit processor. You get their software. What they can do is they’ll figure out the eligibility of the patient, and they go through the payers. They’ll figure out how much the patient has to pay. And they have a program that we can just print off the prescriptions. And so I think that it’s something you need to look at.

Now classically, and I’m going to look a commercial model, but as far as pharmacy dispensing, classically we’ve had the suppliers like, and these are just examples, I just throw these names up here, but McKesson, Cardinal, Besse, they supply—so if you write a script for abiraterone or enzalutamide for your patient, they’re going to take it to a specialty pharmacy. Now CVS, Walgreens, Rite Aid, they actually have specialty pharmacy subdivisions. So these patients can’t just go into a Walgreens or a Rite Aid, but these are the ones, and also Diplomat and some others, that are the specialty pharmacies and they will get the prescription for the patient. They go through the suppliers. And through this existing model we also go through the suppliers and get things like GnRH, radium-223, denosumab, and sipuleucel-T.

That’s the existing model. The new model now is where we have a purchasing organization that can buy at discounts from the suppliers and we can order, if we order abiraterone or enzalutamide we can do this in-office dispensing, and it will go through the UROGPO, and also for your in-office things like radium-223, sipuleucel-T, denosumab, we can get that through this new model.

And Medicare is a similar kind of model, except that we’ve got Part D, which are prescription part. And Part B is the office dispensing, where we do the infusions and things like GnRH. And so the new model also kind of mimics this. We go through UROGPO. Again, the oncologists, US Oncology which has oncology practices across the country, they act as a group purchasing organization. So this something to think about.

And so what are challenges? Well, the biggest thing is you get your practice to commit to this. So you need to get these champions, the physician, nursing, the administer, and that’s what I outlined before. But the biggest thing that I see is convincing partners to refer patients to the physician champion. So I’ve gone out and helped groups try to setup an advanced prostate cancer clinic, and I think this is the biggest stumbling block for a lot of them. It depends on your economic system, now the economic system we have at TUCC is we’re communists for capitalism. And so we share in everything. If you are in a traditional kind of a group where you bill, you get compensated for all your patients then it’s difficult to do, but you’ve got be thinking along a different model as we move forward, and that’s the only way that you’re going to be able to integrate all this into your system. So you have to allocate staff, and in some cases hire additional staff, or use your existing staff. We hired a nurse navigator this last year that’s really been just a tremendous boost for our clinic. You’ve got to integrate the EMR so that you identify pathways and patients. From the financial end you’ve got to be able to do the billing, approve the costly therapies, make sure that you’re getting the pre-authorizations so that you don’t lose any money. If you have one sipuleucel-T patient that doesn’t get paid you’re going to lose a lot of money. But it’s pretty well worked out and we haven’t really lost any in doing that.

And then you have to have space. Usually you can maximize your existing space, and if not, sometimes you have to get new space for infusions, injections, and patient visits. And then the big thing is to operationalize this whole thing, so that you can balance the clinical excellence with your protocol development, identifying patients and balance that with your business.

So these are some of the challenges for the physician champion. You really need to know this. You need to know this landscape, you need to know how to manage these patients, know how to manage their adverse events, and stay on top of the latest innovations and options. And we treat patients according to the FDA indications. I think the urologists are pretty strict about this, because if you treat a patient that let’s say the M0 space where the FDA hasn’t approved that drug you may not get paid, or the payers may not even allow you to use those drugs. And then we use the accepted guidelines, like the AUA and the NCCN. And even at our advanced prostate cancer tumor board every month we sit down, we have all the input from the docs. We have a copy of the AUA guidelines and the NCCCN. And at the end of that visit for when we talked about the patient, we actually generate a letter, we put down that we followed the guidelines and they qualify for this reason, or they’re a level one. And we send this letter back to the primary care physicians. And the primary care physicians understand what we’re doing. And I use them pretty liberally. If I have a patient that develops problems with hypertension or diabetes, they’re happy to help out. So we do integrate primary care to that extent. And then you also have to—need to, the champion has to develop these treatment pathways.

So, experience with this disease can expand our horizons. Neal Shore just talked about this yesterday, where we now have therapies for metastatic bladder and renal cell that I think we can learn to administer. And they’re in the pipeline. Lots of immunotherapy. I think this made me go back to TKI inhibitors for renal cell. But I think we can become more involved in other cancers. And then it may even spark some interest in clinical research trials.

Again, I think with the all—the NCCN on the first page it says all patients with cancer should be offered a clinical trial. And it’s nice to have that in your practice, because that’s another thing that we do. We offer patients a clinical trial if it’s available. So we can offer, through research, tomorrow’s therapies today. This will either be no cost in most cases, or a very low cost to the patient. It gives prestige to your practice, and again, we get into that patient satisfaction metric. They’re very happy in these clinical trials. It generates income if you can do it right. It’s kind of tricky and you just have to make sure that know what you’re doing and taking on the right studies. But I think this is something that you should really think about, if you’re not doing clinical research, especially younger guys, to develop this kind of a program in your practice. And then the physician, referring physicians want their patients to get the best. And they can get that, they can get these cutting edge therapies in research. In fact, again, we have this managed care group of physicians who they love it when we put patients on trials, because they’re not having to pay for the abiraterone or the enzalutamide, or any of these, or sipuleucel-T or whatever therapies we’re giving.

So, I just want to spend a minute talking about the shifting paradigm in medicine for our reimbursement. We’re going from a volume-based system to a value-based. And this is changing rapidly. It’s here today, The Medicare Access and CHIP Reauthorization Act (MACRA) is here today. And this can open opportunities for forward thinkers to enhance their urology practice. So this kind of emphasizes the need to develop a specialty clinic where you can be efficient, you can offer higher quality of care, and hopefully at a lower cost.

So this is what’s happened, this is MACRA. This has replaced the Sustainable Growth Rate (SGR), remember the SGR? Every year we kept getting threatened that we’re going to have to pay back 2%, 5%. It got to the point where I think we were up to 20% or 25% that we were going to have to pay back to Medicare. So MACRA replaces that system. And now Medicare is tying fee for service to performance. And this incentivizes us to do these advanced or alternate payment models.

Now, I know that probably none of us are involved in alternate payment model (APM) unless you’re like in a pioneer accountable care organization (ACO) at this point. But if you are in an approved APM then you will get 5% increase in your annual reimbursement. If you’re not, which that’s where we all fall into right now, we go into this maximum-intensity projection (MIPs), which is an incentive program that’s based on this whole program here, which is the value modifier. Now, how do they calculate this value-modifier? And you’ve probably already heard this year already where you are with respect to this. But it is a composite of quality over cost. And how do they measure all this? Well, you’ve got your clinical care, patient experience, patient satisfaction, care coordination, efficiency. I don’t understand how they’re coming up with this final number at this point, but that’s going to go into the composite score for quality. And then we have our cost. So in order for you to either increase, you can be positive, neutral or negative. And so if you’re positive you’re going to get a few percentage points above Medicare, neutral, you’re going to stay the same, and negative, you can lose. And I don’t know, Neal, is it up 5%? So you can either gain up to 5% or lose up to 5%. And so that’s here right now. And so I think it is incumbent upon us to try to develop these alternate payment models.

And I have to credit LUGPA, Neal Shore is the president at this point, Gary Kirsh, who is the past president, is now the chairman of the task committee to develop some of these pathways. And this is going to take a lot of work. We also have Raoul Concepcion, who was one of the past presidents who was on the – – connect side of things. And so what the initiative is that they’re going to look at two diagnoses, and I think it’s infection after prostate biopsy and localized prostate cancer, so that we can get into this bundled program. And this is where the Medicare wants to look at things where we have a diagnosis code across the country, and there’s a whole variation on how people treat. So we want to have all the urologist swimmers swimming in one lane so that we can improve the quality and decrease the cost. That’s the only way you’re going to get to an increase in your Medicare. And so, but if you’re in an APM, if you’re an approved APM then this goes out the window and you don’t have to worry about this. So it’s going to be incumbent upon us to try to get these implemented. LUGPA has really taken the initiative and we really have to give them a lot of credit, but it’s going to take a lot of work. And they’re going try to develop these programs, and it may or may not work. But this is really the only way that we can try to be innovative. And there’s no question, reimbursement is going down. We can’t expect to be making a lot more money over the years, we just don’t want to lose a lot. And so it’s incumbent upon us. And also we’re hoping that patients are going to get better care.

So, with all of that, I want to conclude by saying seize the day, carpe diem. There are new therapies, new challenges, and there are new opportunities. I’ve been practicing for 30 years. I’ve always felt that the glass is either half empty or half full. I’ve always looked at it as being half full. We’ve always been told the sky is falling, we’ve still managed to make it, and I think we have some new opportunities to try to excel in the future. So I think that urologists can and are playing a greater role in the care of patients with metastatic castration-resistant prostate cancer. So thank you, and I hope you enjoy the rest of your stay.

Advanced Disease: A Real Need for Understanding and Shared Care

The real issue about shared care, who should be treating these patients. So the treatment of advanced prostate cancer should be formed by the individuals that have the most experience in a given area, regardless of their subspecialty. So I think the best way you should think about this is would you want your prostate taken out by somebody who does one or two procedures per year. I certainly wouldn’t, I’d want the person with the most experience, the most ability to handle postoperative complications, because really it’s the situation where you get into trouble, the panic that ensues when there’s a toxicity or a bad result, that’s where the difference occurs in patient care.

So we want to maximize our clinical benefit for patients. And the multidisciplinary approach involves all treating clinicians, the urologist, medical oncologist, radiation oncologist, and now the primary care physician to manage some of the more complex internal medicine problems. Other key members I think that are important to the care team include a nutritionist. As we’ve seen from this meeting, diet is important, exercise is important, I think now a physical trainer also should be included. Pain management, we neglect pain in patients. In fact, now it’s a standard assessment in all of our patients at Yale that they have their pain measured, and that we include a palliative care physician. The hospice discussion I think occurs too late in the course of castration-resistant prostate cancer. You certainly don’t want a patient surprised that there are no further options. It’s a very, very fine line between destroying hope and being realistic about what the situation is. So we really want a person who is going to focus on each stage of prostate cancer management.

The benefits of the multidisciplinary approach have been documented by two different institutions, Lenny Gomella at Jefferson implemented a program and demonstrated that his survival rate was better when compared to the SEER data for the same area. So this suggested that the outcomes in many men with localized and high-risk prostate cancer were better, and certainly this would impart a better survival. And David at the University of Colorado has basically also shown the same thing, that this shows an elevated survival rate in the region. And these are again the histogram plots of the observed versus the anticipated survivals with this approach.

So this is not uncommon for other tumors, lung cancer, breast cancer, colorectal cancer. At Yale we have a multidisciplinary clinic for lung cancer. We have a de facto multidisciplinary GU clinic where we have tumor board once a week. And my office is actually in the urology department. So if there any questions that I have for the urologist, or vice versa, it’s very, very easy to have that approach where John Colberg is across the hall from me, or Brian Shuch is down the hall from me as well. And we can talk about cases, and we often do.

So, we want to improve the access to specialty therapies, we want to be more efficient with the patient’s schedules. It doesn’t have to be a physical multidisciplinary clinic, and we have to coordinate to avoid redundancies.

So I think that one of the things I’m going to outline in this talk, I’m going to go through each individual drug, is there’s a lack of clarity as to what the trigger points are with disease progression. And then who should be managing which of the individual side effects. This has been historically difficult. We’ve been very, very compartmentalized, but we really need to effect a change. And I think the EMR, one of the few positive things about the EMR is the fact that it’s easier to communicate within an institution. But as Dr. Cookson noted before, it’s difficult in practices. These EMRs don’t talk. In fact, one of the things that I had the good fortune of last year was going to the White House to talk about the Moon Shot, and talking with Senator Coburn and Vice President Biden, I found out that the EMR was offered to the Affordable Care Act (ACA) by both the Mayo Clinic as well as IBM. So we could have had a universal EMR that communicated. This would have facilitated data management, the multidisciplinary approach, and it didn’t happen. So I think that that’s to me the biggest disappointment of the Affordable Care Act.

So again, we also need to have feedback. When we discover that there’s a medical error, when we discover that there’s a difference of opinion, there needs to be an open and frank discussion as to what is going on. This only can improve patient care. And as we’ve seen from statistics recently, physicians are reluctant to admit errors. I think it’s because of the structure of our systems now, but they’re reluctant to do so. And I think we have to encourage that we disclose, and we then improve our care based upon this.

I think we’re moving away from the later referral of prostate cancer patients for therapeutic options, and I think that this has, again, been an advantage of the multidisciplinary approach. We have better quality treatments for this disease, and of course, there are differences of opinion as to how to administer these treatments.

It’s going to become more important, because the population is aging, we’re seeing more prostate cancer. But we’re also seeing fewer oncologist in the United States. There’s going to be a shortage, as well as fewer urologists, so we have to coordinate our efforts.

So, why is it becoming more important? It has to do with the sequence. This is 2010, two drugs, or actually basically three types of treatments; secondary hormonal manipulations where there was an unclear survival benefit. A three month difference with docetaxel, and then mitozantrone. Now this is actually 2017. Now we see that we can sequence agents differently. We have immunotherapy with sipuleucel-T, chemotherapy with docetaxel, and then as Cookson noted before, do we implement docetaxel as our first-line chemotherapy?   We don’t have any data what the affect is of the adjuvant docetaxel on subsequent docetaxel administration. And I think that that’s something that we really do need to look at carefully, because we clearly don’t want to treat patients unnecessarily, and perhaps we should use other chemotherapeutic agents up front.

To note here, the only agent that is sequence specific that does not require prior, or actually does require prior treatment is cabazitaxel. Sipuleucel-T is actually approved for all stages of castration-resistant disease as long as they do not have visceral metastases. In fact, 15% of patients on the IMPACT trial did receive sipuleucel-T, did receive prior chemotherapy; excuse me. Zytiga, enzalutamide can be given pre and post chemotherapy, and of course, docetaxel is now being used earlier. So the only sequence-dependent drug here is cabazitaxel.

In shared care we like to think of this in terms of our classes of agents, and I think that this is important. Again, how do we select these immunotherapy with sipuleucel-T? Perhaps we’ll start seeing the checkpoint inhibitors approved over the next couple of years. Second generation hormonal treatments, such as abiraterone and enzalutamide. Cytotoxic treatments, which also fit into the hormonal category, as we mentioned before, docetaxel and cabazitaxel, and the DNA damaging agents with radium-223.

So what are the individual specific roles of each of these healthcare professionals in administering these treatments? Well, the urologist will diagnosis the disease. Sometimes the oncologist does if they get a primary referral for a metastatic lesion, but I think it’s extremely rare that I’ve seen this, at least as far as a primary care diagnosis is concerned. They administer local therapy with surgery, with cryosurgery, and they administer androgen blockade. The medical oncologist administers androgen blockade and chemotherapy, both of which can quarterback the administration of these other drugs. The primary care and the internist will help with managing side effects, including hypertension, diabetes, as well as pain. And the radiation oncologist will palliate symptoms, administer local therapy. And then there is, of course, the differences as to should be administering isotope therapy, should it be the nuclear med or the radiation oncologist. That’s institution dependent.

So, administering these agents, we like to break these up in terms of symptomatic versus asymptomatic. Rapidly progressive disease versus slowly progressive disease, visceral versus non-visceral. The pre and post docetaxel I think is becoming less and less clear at this particular point, and I think in the future we’ll be moving these biological markers. And again, who is going to manage this at the different stages of the disease? When should the genetics been sent off? My opinion is it should be as early as possible.

So, this is just simply the way in which castration-resistant prostate cancer develops. There are many, many roads to Rome, as we’ve often said. And this can occur from mutation of the androgen receptor. And Barret modification we saw yesterday with the heat shock proteins, alternative splicing, as well as intra – – synthesis of the androgen receptor. All of these lead to different pathways. And we have different drugs which can forth with this. We saw this yesterday, the IMPACT study, which led to the approval of sipuleucel-T for castration-resistant prostate cancer. Again, my opinion it should administered early. This can administered really by any healthcare professional, urologist, medical oncologist. The toxicities are fairly minor, but as we saw yesterday, this should be talked about early in the course of disease. It is clear that from the retrospective data that those patients who have the early administration of sipuleucel-T have the best benefit. It’s about a 13 month difference in the median survival, compared to a 2.8 month different if you wait later. So again, each of those professionals that we have seen before has to be educated to refer either through the urologist or the oncologist to administer this particular drug.

How do we manage side effects with sipuleucel-T? I think, again, this could be easily managed by any of the healthcare professionals I mentioned before. Chills, pyrexia, headaches, flu-like syndromes, myalgias, hypertension, hyperhidroses, as well as potentially groin pain in some patients. Very, very rarely do we see a serious adverse event. So again, I think that any healthcare professional, as long they know that they have to give something like Demerol for rigor when it occurs on a rare basis, can administer this particular drug.

We’ve talked a lot about the second generation hormone treatments over the last several days, particularly Zytiga and enzalutamide. As we know, these drugs will inhibit the synthesis of androgens. But there’s also a feedback mechanism that goes on with the increased secretion of ACTH and cortisol. And we know that these drugs improve survival in our patients, both in the chemo-naïve as well as the chemo refractory setting. And this is the chemo naïve data where we see a survival benefit. All of the different parameters with Zytiga are going in the right direction. Time to opiate use, time to chemotherapy initiation, these again, I think need to be discussed with the patient from a multidisciplinary standpoint. What are your goals of treatment? Are you trying to palliate symptoms, are you trying improve pain. All of our drugs that we have, really expect for sipuleucel-T, can have that potential. And these, again, have to be weighed by all healthcare professionals. And this the pre-chemotherapy COUGAR 302 data showing a survival benefit.

So again, we have to employ the use of all healthcare professionals in managing patients in this situation. There’s some, of course, that are more easily managed by the internist. In my opinion, cardiac disorders, fluid retention, this can managed by all three individuals, but I think the internist has the best experience in managing cardiac issues. I certainly can do that, as a medical oncologist I also have a background in internal medicine, but again, I feel more comfortable having a cardiologist or internal medicine physician manage this because they’re more up on the literature. We all can look at liver function abnormalities, and there was actually a warning about recently about this with sipuleucel-T. Hypertension, again, the internal medicine physician is best suited for this, because they’re up on the new drugs for hypertension. We were talking the other day about how do you monitor this. I recommend that our patients get home blood pressure monitoring, because often what I’ve found is the blood pressure that we see in the office is different than the blood pressure they have at home. The patients do develop white-coat syndrome. They feel nervous and anxious when they see the physician. They’re worried about their PSA going up or what’s the next treatment. So I think that this is really well managed by both the internist, as well as the other healthcare professionals. You have to watch out for hypokalemia. This can be issue, and patients need to have their blood monitored on a regular basis. Again, all three of these healthcare professionals can do so. Fatigue, anemia, back pain, these are routine types of questions, as well as laboratory results that you have to monitor them when you see your patient.

Enzalutamide is an androgen receptor antagonist. As we know, it has a basically three-pronged effect on the androgen receptor. It prevents binding of the androgens to the receptor. It inhibits translocation, and it also inhibits binding to DNA. And we know that, again, as we see with abiraterone, that we have survival benefits both in pre-chemotherapy and in the post-chemotherapy situation. PREVAIL was the pre-chemotherapy trial that again showed a survival benefit, a 30% reduction in the risk of death, and a proven progression-free survival. This is the overall survival for the PREVAIL.

So again, how does the internal medicine urologist and the medical oncologist help to manage these particular issues? I think again, the important issues here are seizures and fatigue. We have to really counsel our patients to make sure that they report to us when they’re feeling tired, when they’re having issues with drug management. I think that there’s really a great area where we can improve supportive care for this particular drug. Nobody has really defined the role of things like stimulants, like Ritalin or other agents which may help to overcome the fatigue. As we saw the other day, this is particularly related to GABA. Cardiac disorders can occurs with enzalutamide; although, they’re I think a little bit rarer than they are with abiraterone. And you can see seizures, which is the other big issue here. I don’t think you really need a neurologist to come on board, but again, these are things that you need to communicate to the internist, as well as to the oncologist. All three of the subspecialties need to be involved in that decision.

So in conclusion, the optimal sequence of agents is yet to be determined. This I think again needs to be discussed amongst all healthcare professionals. Certainly you’re going to use different agents for different comorbidities. As we saw the other day, docetaxel chemotherapy should be offered to these patients in the early setting, but it depends upon what their other general medical issues are. And I think the other important issue is immunotherapy should be given earlier. But all these treatments need to be administered by a coordinated effort, because the important issue is not who takes care of the patient, but what the outcome of the patient is.

An Update of the European/Swedish Screening Trial

I’m going to give you an update of the best screening trial in the world. And it’s mainly based on data coming from my own country of Sweden. So I have disclosures, of course, Ferring, I’m working a lot for Ferring right now. And there are two minor companies in Sweden, and then the Norwegian one. So Ferring, for instance, is interesting because it started in my own city of Malmo 60 years ago, and it’s the son of the founder actually who is running the company at the present time.

So you know very well where our three large-scale randomized trials. In fact, the two on the right side actually belongs to the same European randomized screening trial. And then you have a gentleman sitting in front of me, Gerry Andriole, introduced his PSCLO trial.

So the history of European randomized trial actually that was founded and initiated by Fritz Shroder in the Netherlands, and it started out in the Netherlands in Belgium. And then we in Sweden joined it. It was actually Jonus Hugosson, a professor now in Göteborg in Sweden in the mid-90s with 20,000 males. And then some other European countries like Finland, Spain, Italy, and Switzerland joined, and finally, France. So we’re talking about in total eight European countries. And more than 160,000 men between the age 55 and 69 were randomized. So the study is actually still ongoing, and I was happy before I left the EUA as secretary general that we gave them some money to continue that study, to follow the patients over time. And Fritz gave over his PI Jonas Hugosson, who initiated the Swedish arm of the European randomized trial.

And here you see the first publication, actually one of the first ones actually by Fritz Shroder, looking at European randomized trial and including all the centers. Ending up in a 25% reduction in prostate cancer deaths at 13 years. The – – is you have only 25, 21%. On the other hand and also what is negative, the number needed to initiate is close to more than 800, and number needed to diagnose is 27 is absolutely too much. So then we have a Swedish arm of the same trial, and I will explain to you the difference between the Swedish arm and the entire cohort of European randomized clinical study, because here you found all of the sudden we – – to follow-up reduction in mortality by 44% is quite astonishing. And that was also published later on in Lancet in 2010. And the number needed to screen went down to close to 300, less than 300, the number needed to diagnose was 12. So it was astonishing. And why can you find the difference like this when compare the Swedish arm versus the other centers involved in the European randomized trial, I will allude to that a little bit later on. And now we have a fresh paper actually with 18 years of follow-up in the Swedish arm of this randomized population based prostate cancer screening trial.   And of course, the hazard rate should be diagnosed first years, 5.2. And you can see the prostate cancer mortality in the screened arm, close to 1%, but in the control arm 1.5, and you see the hazard ratio and confidence interval, but in the end 35% relative risk reduction. And that is quite amazing actually.

So even if the relative difference in mortality is decreasing between the two arms we’ve long to follow-up, the prostate cancer incidence difference is also decreasing. And secondly, this taken together, it will decrease absolute difference in prostate cancer mortality results in more favorable outcome measures, number needed to invite, 231, and number needed to diagnose, 10. So – – to follow-up you can see the difference. I’m coming back to that in a minute.

When I’m coming back to this trial and the followup I found it’s been accepted for publication in Cancer, Gerry. And that’s with PCLO. And you can see there’s no real difference between mortality in the organized versus optimistic screening with the 15 years of followup in this PCLO trial. And the reason for that is written clearly in this cancer paper. Gerry, check this now if I’m correct or not, but 90% of the control participant had at least one PSA test before or during the trial. And then 86% of the men in the control arm, and 99% of the men in the intervention arm received any PSA testing during the trial with the 15 years of follow-up. And finally, yearly PSA testing rates were 46% and 84% respectively. So it explains to a certain extent why you fail to really show difference between the screening arm and the control arm.

When it comes to PSA testing in Europe, and especially Sweden, you had—we introduced PSA in the early 90s. It was fairly low. And the national guidelines in my country of Sweden, we didn’t recommend PSA screening whatsoever. And we still don’t. Only 3% we’re actually prescreened in the Swedish arm of this screening trial. And exposure to PSA testing however has increased over time, and of course, if you had starting out in the screening trial ten years later on you would find a totally different picture, probably quite similar to the PLCO trial. 40% of the cancers in the control arm, in the control group, and the Göteborg were diagnosed through opportunistic screening. And an asymptomatic men at 18 years of follow-up.

But look here at the difference between organized screening and PSA testing in Göteborg, reducing the risk of dying from prostate cancer, but increases, of course, the number of cancers being detected. So you can see here the prostate cancer incidence in the Göteborg screened arm. If you compare organized screening versus opportunistic screening. And of course, it leads to overdiagnosis, but on the other hand you also find more high-risk prostate cancer patients.

When it comes to mortality you can find a real difference here, if you have organized screening going on you can actually decrease the mortality significantly. I’m coming back to that in a minute. So opportunistic screening, if you want to introduce screening you have to do it in an organized way rather than opportunistic screening. So here you found now no effect in terms of prostate cancer mortality. So although twice the number of men needed to be diagnosed to say – – men from dying from prostate cancer with opportunistic screening compared to organized screening. You can see here the difference between organized screening versus no screening, opportunistic screening. The number needed to diagnoses, 13 versus 23. A significant difference indeed.

So coming back to possible reasons why the Swedish arm in the Göteborg trial show a large reduction in prostate cancer mortality. Well, we had younger men to start. We started actually at the age of 56 at baseline, and then in the European other centers, 60. We had a lower PSA threshold for prostate biopsy, 2.5 to 3.0, in the European randomized trial we had mainly 3.0 to 4.0, so it comes down what David told us this morning, but maybe we should even lower that threshold, but I don’t think so. More intense screening, every two years. And the other centers across Europe it was between 4 and 7 years, unfortunately. And also long duration of screening, every 2 years from the age of 50 up to 64, and all the way up to 70. And the medium was 10 years. High biopsy compliance, look at this, 93% of all the – – were complied to undergo biopsies; whereas, in the PLCO trial, correct me if I’m wrong, it was only one-third of the men being screened. Limited contamination and long reported follow-up, now up to 18 years, so it makes a difference. And I’ll come back to that in a minute.

There was also an interesting comparison between the screened population in Göteborg between—and my own center in southern Sweden, Malmo, because we have access to a freezers where we have blood samples stored for more than 40 years in the preventive project, were initiated by my former teacher and professor. So by using all these blood tests from Malmo, we shipped them over to Memorial Sloan Kettering because they’ve been able to recruit four of my best residents, including Hans Lillia, because they have the resources and money. Jim, I’m not accusing you here, and Peters Scarino, because they could do a much better job in your center. We didn’t have that kind of resources. So see, – – is just an example of all these very brainy people.

So looking at this screened group and unscreened group actually it’s very interesting, because there is a major difference when it comes to a ratio of benefits to harm of the PSA screening various with blood levels at the age of 60. So here you can find really a difference between screened populations and those not being screened whatsoever. And we found ourselves when we looked at the medium PSA at the age 60, around 1.0 nanogram per mL, but also for men with a PSA less than 2.0 nanogram per mL that two-third of the population age of 60. Continued screening led to a large increase in prostate cancer incidence, but no decrease in mortality over a 15 years to follow-up. I think that’s a very important statement. So if you have a PSA of less than 2.0 you cannot expect that you can decrease mortality with the 15 years of followup. However, if you have a PSA at the age of 60 above a 2.0 it makes a difference, because then you can find a large reduction in prostate cancer deaths, and also decreased number of patients needed to invite, 23 in numbers needed to diagnose of 6. That was published by Sigrid Carlsson in a British medical journal a couple of years ago.

So now hold your breath, because this is fresh data published we see in European Urology by Sigrid based on the screening trial in Sweden. Starting regular screening at the age 50 and 54 reduced prostate cancer mortality, believe it or not, by more than 70% within 17 years follow-up compared to no screening whatsoever. And the number needed to invite, as you can here, 176, number needed to diagnoses, 16. I would like, of course, to reduce those numbers as well, of course. But look here the difference between the screened and the non-screened population. And for my own country of Sweden, astonishing.

So another screening trial that is going on was initiated recently in Stockholm. That is the Stockholm-3 study, by H. Gronberg and coworkers. You can see they introduced not only with kallikrein, but those two genetic markers and clinical data, volume PSA, so not PSA examination, DRE, et cetera, et cetera. And we are talking about almost 150,000 men and with a PSA 1.0 and above. And 10% of these Stockholm-3 risk of high-grade prostate cancer is equal to sensitivity to PSA 3.0 and above. And you can also see there was a consistent with prior observations like Phi and 4Kscore already mentioned here this morning. Adding kallikrein markers the Stockholm-3 model, that improves predictions of the high-grade prostate cancer over PSA alone. However, there are some un-clarity because it’s unclear whether the genetic score adds predictive value to a protein marker since it was added to the stepwise model before the markers. And secondly, feasibility of DRE and TRUS, of course, volume screening tools it was not really elucidated in the paper. On the other hand, it showed clearly in the first paper published in Lancet Oncology, that you can reduce overdiagnosis by 17% and unnecessary biopsies by one-third. On the other hand, the number of high-grade cancers caught or missed by this model compared to PSA alone was not reported, unfortunately, due paired design, so that’s the drawback of this trial in my opinion.

So this is my last slide, David, a summary and update of the European, especially the Swedish screening data. First of all, with longer follow-up in the trials the effect of regular PSA-based screening on significant—it’s associated with significant reduce of prostate cancer mortality. And it is sustained.

Secondly, the number needed to invite, the number needed to diagnose become favorable with longer follow-up, so that is clearly demonstrated here today. And screening should not start too late in life. We say definitely not later than 55. I would say 50, and some of us in Europe actually, 45. And if you have a family history we have an agreement in my country we should start already at the age of 40. Regular organized screening maybe more beneficial than opportunistic screening in terms of net benefit. And I’ve shown some evidence for that. And finally, screening can be risk verified and based on all the lectures this morning, I think we can do a better job not using PSA alone, and taking into account the man’s age, PSA levels and general health to determine who, when, and how often to screen. So that really the end of my presentation. I really appreciate your attention. Thank you very much.

Non-genomic Biomarkers for Early Diagnosis and Prognosis Prevention of Prostate Cancer

Today I’m going to talk about Phi, PCA3, ConfirmMDx, and one we haven’t talked about, Exo106, the exosome test. There’s been a lot of, especially if you went to breakfast this morning, redundancy on a lot of things test, and to save time for the panel I’m going to move through them fairly quickly, and maybe just focus a little bit on the science of them as opposed to the data that’s already been shown.

By way of disclosure, I’ve been an investigator for all these companies.

I’m not going to talk about these other biomarkers, not because they’re not important, actually I’m seeing them quite often in my clinic now, there’s just not enough time. 4Kscore has been fabulous. My patients are bringing it in. We don’t actually have the access to run it at Hopkins, but I’ve seen a lot of it. The other tests that Gerry just talked about, we have that magical mystical pathologist that can do be PTEN at Hopkins so we do quite a bit of that, and maybe we’ll have a question about that at the panel. So the only reason I’m not talking about these is because I only have 20 minutes.

The first test was Phi, and it was FDA approved in 2012. This was a paper a large group of us worked together on to get the data together to send it to the FDA. And as you know, Phi is what’s called a complex mathematical equation.

But this is what happens with Phi. And we use it on every patient we see now. I tend to believe in our 1.5 paper that we put out, that we need another test when the patient comes in. We try not to use it for PSAs above 10, but everyone that comes in gets a Phi test for initial and repeat biopsy so that we can try to determine whether or not the biopsy is actually needed.   This was a paper out of Italy just before, actually just after FDA approval, that showed they were able to decrease, and that would be the specificity, when they added Phi to multivariable model, the number of unnecessary biopsies by 41%. So Phi is better than PSA alone. And this was just in detecting prostate cancer.

Here’s a nice paper by Stacy Loeb in the Journal of Urology, where she used area under the curve, and the blue line is the Phi, to try to predict all cancers. The second graph was to try to predict the Epstein significant cancers, and the last one was cancers with a greater than or equal to 7 Gleason score. And you can see in that large study the Phi was the superior marker.

Here was a small study done by Ashley Ross and our group at Hopkins, published in Urology just last April, where we looked at its ability to help predict high-grade cancer in African-American men. And with this cohort, Phi was an excellent marker in trying to also help predict high-grade cancers.

Now finally, the next test, PCA3, we’ve heard a lot about this morning and today. It is an excellent urine test for trying to predict whether you have prostate cancer. It’s really not that much better than just doing PSA alone. It does require that horrible vigorous digital rectal exam that patients hate. It’s sort of disappearing, I agree with David. This company went head-long into trying to couple PCA3 with TMPRSS2 and for some reason just sort of dropped off the face of the Earth. So I do still see a few patients coming through that are having this test done, but it’s not as popular as it had been. And I’m just going to go through this quickly.

We did a really nice study no on showed this morning on PCA3. John Wei led a group of us from the National Cancer Institutes Early Detection Research Network. A fairly large study, and we broke the test down into its positive predictive value use, and its negative predictive value use. So if you want to use it on initial biopsy and you want really high positive predictive value, because you don’t want to miss cancers, if the score is greater than 60, and for those of you that have used it that’s not that common, but it does happen, it has a positive predictive value of nearly 90%, or 80%; sorry. However, if you have a patient coming back for a repeat biopsy a score of less than 20, which is pretty low, would give you a negative predictive value of 88%.

We’ve heard a lot about these Epi genetic tests. What they’re talking about with this methylation is simply placing a methyl group usually in the promotor area of a gene to shut that gene down. It doesn’t mutate it, it doesn’t delete it, it doesn’t make you have multiple copies of it, it just stops it. This is a very sensitive test that we’re using. You can find it in paraffin. That’s why we were able to do retrospective studies on it. And you can detect a cancer cell among 10,000 normal cells with this test, so it’s very specific.

We talked about this paradigm that every year we’re biopsying a little over a million men, but only about a quarter of them were found to have cancer. Leaving three-quarters of those, or about 750,000 men walking around with a negative biopsy but still having a PSA of 6.4 and not knowing what to do. And a lot of men also had, as Scott showed us, high-grade PIN and atypia. And that’s where as we’ve seen in these pictures, there is a halo effect around these tumors and you can detect in a negative biopsy core that there’s something going on in that area. We talked about this algorithm in Dr. Crawford’s talk, that if the ConfirmMDx test is positive you might want to consider something else, get that MRI, or do some kind of mapping biopsy in that area. Scott very eloquently went over the MATLOC study, the DOCUMENT study, and we saw that the negative predictive value of this test is excellent, approaching 90 in MATLOC, and 88 in the DOCUMENT study. Scott also showed these slides about the odds ratio being great for the Epigenetic test in an initial. This was the study on the repeat biopsy. And here’s some data, I’m not sure if Scott showed this, but you can use this test to clinically detect significant cancer, because if the algorithm that they’re using for this Epic score, get right to that, it has an odds ratio of 16 for detecting Gleason score greater than 7, which is now, again, this is looking for aggressive cancer, not whether you have cancer, far greater than atypia or the other high-grade PIN, age, et cetera.

Now, this last test is called Exosome 106. This was presented in, or published in The Journal of the American Medical Association (JAMA) Oncology in March of 2016. It was presented at the American Urological Association (AUA) in 2015 by Jim McKiernan. Again, we had a pretty large group, Gerry, in the audience, was on the study, where we were taking a look at urine specimens to collect these exosomes. Exosomes are kind of like Twitter, since our President does it so much. The exosomes are sending out Tweets and getting Tweets back to the cells, talking back and forth between the microenvironment in these cells. So they collect up a bunch of information, and just like the President, just spit it out into the area around the cell. And the other cells pick it up and try to figure out what’s going on in that cell. And likewise, they can suck up information from the cells surrounding them and talk to each other. These exosomes are—and I have a great slide I didn’t put it in here that I use for the patient groups, showing the little Twitter phone doing that. They put a lot of information in these little bubbles. There’s RNA, protein, DNA, and hopefully some new markers that we weren’t even aware of. So in this study you just collect a sample of urine. They like you to get a clean catch. This company now has a special cup that collects only the first 20 ccs, it seals the cup off so the rest can be discarded. No DRE is needed. Right now they’re looking at three genes, two of them are oncogenes. The other is the PCA3 RNA that we talked about before. And in a multivariable algorithm the probability of high-grade cancer being present in the prostate carries with it an excellent ROC. And if you take it to the negative predictive value it’s 91%. So that’s a fresh catch urine, no DRE, and they’re able to, again, provide us a negative predictive value of 91%.

So in conclusion, the exosome will messenger RNAs for those oncogenes and PCA3 can be analyzed on a first catch random urine. We talked about which tests we’re doing. It has an excellent negative predictive value. And this test is now available through CLIA lab testing.

And I put this slide together. It matches some of what Dr. Crawford showed us. Most of these tests are now available. I get that question from a lot of crowds, is this is just something I can get at Wash U or in Colorado. No, if you’re willing to go out there and talk to the representatives you can get all these tests. The costs are variable. There’s major differences between some of them. I find now that a lot of them have programs to try to help our patients get these tests so that they don’t have to sell their car. It’s working out very well. And of these tests, expect for PCA3, we’re not really having any problem getting them done. Thank you.

The “Who’s” of Genomic Markers: Who to Treat

Everybody has seen this, talked about it, conventional biopsy, completely misleading. We don’t have to beat that any further. And so if you really want to know if the guy in front of you actually needs treatment, you might want to turn to some other tests, and there’s some immuno-histochemical tests, there’s Prolaris, Oncotype, Promark test and Decipher. And just a shout-out to PTEN, it’s cheap, it’s not commercialized, it can segregate between lethal, or very lethal, and less than lethal prostate cancer. These immunohistochemical markers, including PTEN and KI67 were looked at by the NCCN guidelines panel and basically not recommended because they’re there’s some heterogeneity in how the study tests are done and interpreted, but there probably is some truth there. And if you had a boutique pathologist who could do a good job they might actually be helpful for you.

Okay, what about the genetic tests, the Prolaris test, 31 genes involved in the cell cycle progression, mRNA levels using quantitative PCR are scores developed from fixed tissues. The earliest studies now about 25 years ago in men who underwent a TURP, had cancer detected, treated conservatively, you can see how their prostate cancer specific mortality segregated on the basis of their score. And this study was sort of replicated in men diagnosed on a needle biopsy and conservatively managed, again, in the early PSA era. And you can see, again, that the score correlated with the 10-year probability of prostate cancer mortality. This was validated at UCSF, Matt Cooperberg and colleagues, showing that for men with low-risk disease on the basis of score you could stratify their risk of prostate cancer mortality.

Here’s an example of the Prolaris report. I’m sure many of you have seen this, describing the man’s risk of mortality and how aggressive it is in comparison to men with other similar clinical characteristics and pathological characteristics.

The information you get is actionable. This is a decision impact trial where the treating physicians felt that about a third of their diagnosed cases should be monitored, and about two-thirds treated; however, after the results of this test were made to them and the patient only a quarter of the patients were deemed to require intervention. You could see the changes. A quarter of the men who were to have non-intervention were then determined that they should warrant intervention, and 15% of the patients deemed to warrant therapy before the test was known were not offered therapy because of the reassurance from the Prolaris score.

Prolaris can also be used, and we’ll talk about this about this a little bit later, to determine whether a man who’s had some adverse pathological findings on a radical prostatectomy warrants early adjuvant radiation therapy, versus monitor him for later progression. The NCCN guidelines panel looked at Prolaris and recommended it in the scenario to determine whether treatment is necessary for men with newly diagnosed prostate cancer.

Another genomic test is the Oncotype DX GPS score. These slides were given to me by Alan Shindle, a former resident of ours who now works with Genomic Health, so there’s some animation here that shows how they threw a lot of genes into a funnel and out of that funnel came 17 GPS genes in this test. Very similar to the Prolaris test, knowledge of the GPS score even within NCCN risk classification, so very risk patients, low-risk patients and intermediate-risk patients show different probabilities of harboring aggressive disease.

This is a GPS score. Now, this is reporting not mortality, the ten-year mortality from prostate cancer, which is what the Prolaris score is reporting, this is reporting the probability that this individual who harbors Gleason 6 disease on biopsy actually has favorable pathology and/or harbors Gleason pattern 4 and 5 cancer that was undetected. And you can see on a histogram where this person’s GPS score ranges in comparison to other men with similar clinical characteristics.

This was also looked at by the NCCN guidelines panel, and is also recommended to help make the decision between surveillance and intervention. Similar to the data I showed you from the Prolaris study on decision impact trial, you can see that with the knowledge of the patient’s GPS score, a higher proportion of men in the low-risk category were deemed to be appropriate for active surveillance. The same was true for low-risk and intermediate-risk disease.

How about the Promark, this isn’t really a genetic test, this is a quantitative expression of 8 proteins that can be measured from the biopsy. These proteins predict the tumor aggressiveness independent of the clinical and pathological variables, but the report you receive is a combination of the information from those 8 proteins, as well as the clinical variables. This the initial validation study. And you can see that the Promark score has a very, very robust probability of differentiating favorable pathology from unfavorable pathology for men who underwent a radical prostatectomy. Similar to what was shown for the Prolaris and the GPS tests, there’s a lot of heterogeneity even within a given risk category, so NCCN, very low-risk clinical tumors. You can see some of them were very unfavorable when the Promark score was known.

And this is a look at a Promark report. And again, it tells you the probability that if the patient is deemed to have a clinically low-risk tumor here’s his probability of having unfavorable pathology at a radical prostatectomy. And again, you can see where that individual patient’s score sits in comparison to other patients evaluated with the test.

Finally, the Decipher genomic signature is available. The initial studies have been undertaken to predict the development of metastases in patients who have had a radical prostatectomy. So you can see that the genomic classifier predicts the probability of metastases in men who’ve had a radical prostatectomy, with the high-score patients having a much higher probability of metastases on followup. Furthermore, you can see that men with a very low genomic classifier score do just as well whether they receive adjuvant or salvage radiation therapy; whereas, a men who has had a radical prostatectomy who has a high genomic classifier score, if you wait to administer salvage prostatectomy he will not do as well as the cohort of patients who had received adjuvant radiation therapy. So this is a very robust way of determining which patients need early adjuvant aggressive radiation therapy after a radical prostatectomy.

Similar to the other decision impact trials, you can see how knowledge of the genomic classifier result changed clinical decision making for these patients.

Here is a look at the Decipher report classifying the probability of metastases within the next five years, and giving you a sense of where your patient’s score is in relation to the other cohort of patients. I actually like this. You get these reports periodically from the company. I sent a man who had a Gleason 4 plus 3, high-volume radical prostatectomy and I wanted to know if I should use salvage radiation or adjuvant radiation therapy. And you can see that he was in an intermediate group, but actually relatively favorable when compared to all the other men with that type of pathology.

The Decipher test has also been looked at in biopsies for its ability to predict later metastases, and it does. But thus far, at least to my knowledge, the studies are rather small. And you can see here there’s only 57 patients that within a given a NCCN risk group the Decipher score can be segregated into low, intermediate, or high. I would say that just eyeballing this it bothers me a little bit that some of the men who developed metastases, while they were NCCN high risk, but the test, the Decipher score was considered low; nonetheless, he developed metastases. And you can see that I guess only two of the five patients who were considered in the high-risk group ultimately developed metastases. But it’s a very, very small study and I’m sure we’ll be hearing more about that in the future. And again, the Decipher test was looked at by the NCCN guidelines panel and is recommended to help make the decision between adjuvant and salvage radiation therapy.

I’ll call to your attention the fact that there’s a lot of genetic variability in prostate cancers. You know, many men who have a radical prostatectomy harbor multiple tumors. I guess the average is between 6 and 7. And if you perform these individual tests on each of those tumors you may actually get different results. And furthermore, the same tumor evaluated by each of these different tests may score differently. So we really are at the very early stages of understanding how to use these tests. And I’m hopeful that at the panel discussion later we can maybe vet this chart that Eric Klein has been recommending, and how to use these tests to determine which patients need treatment, and which is most appropriate. I think that it’s best to reserve that for the panel discussion later.

Thank you very much for your attention.

The “Who’s” of Genomic Markers: Who to Re-Biopsy

I’m  going to be talking about the who to re-biopsy market here. And why are we even talking about this particular thing? Well, here’s by way of disclosure, I do work on the advisory board for Genomic Health, but I’m not talking about their marker when I talk today. The reality is that over a million biopsies are performed in this country every year, and only about 25% of them on average are diagnosed with prostate cancer, leaving the vast majority being negative for prostate cancer. However, we know because of sampling issues with needle biopsies in the prostate that a negative biopsy does not really necessarily mean no cancer. Studies have shown that the prostate biopsy is really somewhere between 50% and 85% sensitive. So if you do repeat biopsies and if look at big databases, like CAPTURE database, and if you do repeat biopsies on most of these men, again, about 25% of them will have cancer. So the majority of repeat biopsies are again negative. So it puts you in this quandary, this is sort of PSA purgatory, if you will, where you don’t know if you’ve got really a true negative test that if you perform repeat biopsies could increase your risk of complications, or if you just missed a cancer as a false negative, and if you ignore that, that that cancer could progress and you’ll miss your window of opportunity, particularly if it’s a high-grade cancer, for curative treatment. So what I want to talk about today, as a pathologist we see these negative biopsies, and it’s in our best interest to pull out the maximum amount of information from these needle biopsies as we can. Despite the fact that in a 12-core biopsy you’re sampling less than 1% of the prostate, is there information there at the prostate level that will lead you to believe that there’s an increased risk for the person to have cancer, and that’s what I want to talk about.

Certainly, we can look at pathologic findings on biopsies, and I’ll just touch this a little bit. These haven’t gone away, things like high-grade prostatic intraepithelial neoplasia (PIN) and atypia, or atypical small acinar proliferation (ASAP) have not gone away, but what is added to this regimen now are the genomic markers, and we’re going to talk about a couple of them, DNA methylation and the Prostate Core Mitomic Test (PCMT). Let’s start up here look at pathologic findings on biopsy.

Looking at large databases, about 11% of biopsies are diagnosed with isolated high-grade prostatic intraepithelial neoplasia. And on average about 5% of biopsies so-called atypia or ASAP. Let’s really define what we’re talking about here when we look at these. When we talk about atypia and ASAP you’re talking about architecturally abnormal glands that lack a sufficient pathologic criteria to knee-jerk them as cancer, sometimes because there’s too few glands associated with them, sometimes because they don’t have a lot of cytologic atypia. So there is a certain level of comfort of the pathologists looking at the case on whether or not he diagnoses ASAP or not. And although it’s about 5% across the country, my experience in our institution is it’s more like 1% of cases. However, you have to realize that it is not an entity per say, ASAP is really saying I don’t know. I see something abnormal but I’m not sure if it’s cancer. So if you go back and look at who has been re-biopsied in those situations, and here’s a number of studies that have looked at this, you see that anywhere from about a third to 50% of the time when you re-biopsy you find cancer. So if you’re really looking at something that’s under sampled cancer, this is not surprising. So weighted average here is about 40%. So it is still a good indication for re-biopsy.

Well what about PIN? PIN less cell, if you look at large major studies here you see that the weighted average is only about a fifth of the time. If you re-biopsy them you’ll find cancer on repeat biopsy. So it’s kind of fallen out of favor. In fact, what we saw in the prostate cancer PREVENTION trials, if you just re-biopsy everybody, all the people that we re-biopsied in the setting of having a negative biopsy during that trial, we found about 15% of them were diagnosed with cancer. So it’s just a little bit better than just if you re-biopsied everything. However, more recent data has suggested that there may be a difference in the amount of PIN that you see. This one study. This happens to be a Korean study, but it was a well-designed study, and it was a large volume study, looking at patients who had been re-biopsied after a negative biopsy. And if you just biopsied and had benign tissue without PIN or ASAP, again, about almost 15% of them would have cancer on re-biopsy. PIN was just a little bit better as a total, but if you look, if they only had one focus of PIN, one core, it was about the same as benign. But if you had two more, multiplicity, suggesting a wider field effect that that doubled. And it was almost as great as their ASAP rate upon re-biopsy.

But it’s still, when you look at these data you see very clear that of the negative biopsies 85% or more of them don’t show these features, don’t show high-grade PIN, don’t show ASAP. So what do we do with those? And that’s where the genomic markers are here to help us in this setting. And I want to talk about two of them that have made it to commercialization, DNA methylation, which is the ConfirmMDx study, and the Prostate Core Mitomic Test, which is fairly recent, a lot less known about that, but I’ll touch a little bit upon that.

The idea here is that there a field effect that occurs in prostate. It may antedate or it may subsequently occur with prostate cancer, we don’t know for sure, but there’s a widespread phenomena that in benign tissue there are functional changes that are below the resolution of the microscope, and that these can be picked up if you have the right test. And if you look at DNA methylation it’s one such candidate for here. What are we talking about? This is an enzyme-induced methylation of specific areas of promotor regions of genes. It’s a widespread phenomena, it occurs in cancer, not just prostate cancer, but a lot of cancers have this expression. And what it does is it blocks protein expression. So it may be some of the earliest changes that you see in prostate cancer. The interesting thing about its field effect has been demonstrated, for instance, in this study out the University of Wisconsin. What they looked at is methylation of a number of genes in prostates that were not associated with tumor. This would be non-tumor associated prostate tissues, and those prostatectomy specimens that contain tumor in which they not only looked at the tumor, but they looked at adjacent normal, or even normal tissue at some distance from the tumor, up to a centimeter away. And what they showed, these are a number of different genes that showed methylation. And they showed that compared to normal that cancer certainly had either increased or decreased methylation, you can have hypomethylation as well. And if you look at these non-tumor tissues that were some distance away, that they also had increased methylation when compared to normal. Not the same height at the cancer, but elevated nonetheless. Suggesting that this field effect can be seen at some distance from the cancer.

Now the ConfirmMDx assay is a commercialized version of this, looking at a multiplexed, a three-gene multiplex panel. The three genes are GSTP1, which is an antioxidant protein, and two tumor suppressor genes, APC and RASSF1. These are multiplexed in a methylation specific PCR reaction. So you’re looking for things within this window right here that you can mark as positive for the test. To be a positive test suggests that you have increased methylation of any one of those three genes in at least one core when you test all the negative cores in the prostate. This is one of the first real good prospective studies done out of Europe, multi-center site which they had 483 men with initial negative biopsy were analyzed using the ConfirmMDx test, and followed by re-biopsy within 30 months. And as you can see here in a multi-varied analysis, the ConfirmMDx test had the highest odds ratio when compared to the things I’ve talked about, atypia, high-grade PIN, and of course PSA and age. So it was the best indicator. And this study, abnormal DRE also was important.

But here’s an important aspect, here’s the actual study assay performance characteristics, the sensitivity, specificity you see here, but this was powered for negative predictive value. So giving a negative predictive value of 90% is important, because if you’re going to use this test to decide who not to re-biopsy you want to be comforted that you’re not missing cancer here, and so you want to power it strongly for negative predictive value. This was followed up by United States multi-institutional study, the DOCUMENT study, a validation study that again looked at 320. This was a retrospective study looking at men who had had two consecutive either negative biopsies, which control, versus those who were subsequently found to be positive. And again, the DNA methylation out performed all the things I’ve been talking about, PIN and atypia in terms of predicting who was going to have cancer on biopsy. And there’s the area under the curve, 628, and again, the negative predictive value was high at 88%.

The interesting thing about this, reflecting on what Dr. Crawford said earlier, do we just want to find all cancer, or do we really want to focus on those cancers that are likely to be aggressive, high-grade cancers? And there’s some data that suggests that quantification, or semi-quantification at least of the degree of methylation could aid in this. And this is a study looking at predicting high-grade disease, defined as Gleason score 7 or above, using a semi-quantitative approach to the methylation. How many genes were methylated over how many cores. And that’s combined methylation events over all cores into what’s called EpiScore, and that’s in yellow here or in blue here. You can see this area under the curve, out performs things like PSA and something near and dear to my heart, the Prostate Cancer Prevention Trial Risk Calculator, which is this line right here. And you can see that even if you combine the EpiScore with other things like DRE status, atypia, high-grade PIN that there wasn’t that—a mild increase in the area under the curve, but by far the most important thing was the EpiScore. And over here you can see that it out performs all the other factors in multivariant analysis. A DNA quantification of methylation may be important.

And what about the Prostate Core Mitomic test? A lot less is known about this.   This came out of Canada, by Genesis Genomics. This is, again, a PCR-based assay, and again looks at DNA isolated from negative prostate biopsies. The difference here is you’re looking at mitochondrial DNA alterations. And very common deletion, a 3.4 kilobase deletion that occurs here in DNA has been identified in prostate cancer, and also has been interestingly found to be a field effect in adjacent benign tissue.

Looking at this, again, taking negative cores from men who had re-biopsy outcomes, they did a small study of 100 men of which 20% of them showed cancer on repeat biopsy, again, using thresholding of the PCR where you’re more likely to have prostate cancer down here, and less likely to have prostate cancer on higher cycle thresholding. They found a threshold of 31 cycles, again, maximized their negative predictive value, here 91% with a reasonable area under the curve here, it’s been smoothed, but area under the curve for predicting prostate cancer. Now, notice the data, the study, this was a 2010 study and we haven’t really seen a good follow-up study, and we need a larger validation study for this before this can really make its way, and I haven’t seen that yet, so it’s availability is still questionable right here.

So where are we going with this? I think the latest version of the National Comprehensive Cancer Network (NCCN) guidelines really makes a good summary slide of what I’ve just talked about here. If you have atypia on a biopsy then it’s probably indicative that you should re-biopsy again. What about high-grade PIN? Well, if it’s multifocal, two or ore sites, probably you should be in this bin as well as the atypia. If it’s focal, probably should be down here with the benign. What do we do here? Do we just follow PSA, do we just do this again annually and follow into our PSA purgatory, or do we add some other things? And for the first time we’re starting to see recommendations in which you should use some of the tissue. We have the tissue in front of us. These other things I didn’t talk about today, 4Kscore, Phi, those other things that Dr. Crawford mentioned today, because they’re not really looking at the tissue level. And here you have the tissue with the negative biopsy, why don’t we glean as much information from that tissue as possible. And that’s where you can come into ConfirmMDx, that can then give you information about your risk and guide decisions on repeat biopsy.

So, to summarize this, trust guided biopsies may miss significant cancers. We know this, so there’s uncertainty as to cancer status, and a likelihood for repeat biopsy. But many repeat biopsies may be unnecessary, resulting in increased risk. Benign tissue may harbor malignancy associated changes that are not recognized under the microscope. So we can glean that information from a molecular biomarker such as the ConfirmMDx to help us improve patient selection of who needs repeat biopsy and reduce unnecessary biopsies. Thank you.

The “Who’s” of Genomic Markers: Who to Biopsy

So, my topic is talk about in genomic markers whom to biopsy. And I think this is probably one of the more critical areas here. This is where it all starts. This is where a lot of the controversy exists about too many biopsies and finding “benign” cancers and the complication of biopsies. So these are my disclosures. As many of you know, this whole thing about genomic markers is taking over the national press. It’s becoming a very timely topic at meetings, and rightfully so. I think it falls within what I consider the three biggest advancements in urology in the last decade. And the one I’m going to talk about, PCMs, or prostate cancer markers. The second one is next generation sequencing, which have opened up a lot of doors for us understanding genetics and genomics in prostate cancer. And finally, the arena of all these new drugs that are out there for advanced prostate cancer. They’re all different, and they’re all making major contributions in patient outcome and survival.

So I think that the needs out there starting in prostate cancer are many. But one is we need to start with family practice doctors, and we know why, because they’re the ones that see the patients first and order the most PSAs. Early detection, I think we have to redirect, refocus, and change this to this early detection of clinically significant cancers. We’ve got to stop doing biopsy, after biopsy, after biopsy on men and focus on biopsying men, again, who have a significant risk of cancer, or who have a significant risk of a cancer that was missed on our initial biopsies. We need to enhance risk stratification, having patients assigned to active surveillance or interventional therapy. And I think one of the newer exciting areas that we need to deal with is germline mutations in prostate cancer.

So what are PCMs? PCMs are something that is a molecule that can be found in blood, tissue, or body fluids that’s a sign of normal or abnormal process. And obviously, blood and urine are easy to access, tissue is a little bit more difficult. But some of these prostate cancer markers need tissue, at least at this point. So we like to compartmentalize this, and Neal Shore and I worked on this, and this has evolved. We started out with three buckets; whom to biopsy, whom to rebiopsy and who to treat. Now we’re up to five. The first bucket is identifying who should have an initial biopsy. And we’re going to talk about three of those tests, SelectMDx, Phi, and 4K score. And then negative biopsies; whom to rebiopsy. And there are a number of different ones of this bucket, primarily confirmMDx. Then whom to offer genetic testing, and those are certainly men who have metastatic prostate cancer, and men who have other risk factors; earlier disease, multiple family members, breast cancers, melanomas, all these things that go with the need for germline testing. And then who to offer active surveillance to. And we have some great tests here to help us to navigate this path. And then in men who have had a treatment, radical prostatectomy, that’s the last bucket, who to treat or not to treat with radiation, hormone therapy, and other things like that.

So with markers, they’re not all black and white. And I sort of like to think of them as relative risk. So here’s the bank and here’s the man. What’s his risk of being bank robber? Well, if he comes in with sunglasses, not a lot. It is a factor. If he comes in with a backpack, that raises it a little bit. If he comes in with a walkie-talkie that raises it a little bit. And if he’s carrying a gun that’s a big factor. And so that’s a big gene so to speak. But in all of these things, these genes that we’re looking at, these risk factors are important, but none of these things are 100%. He may actually be a police officer and that was the reason he was dressed the way he was. So we all know and have heard about the fallout from the US Services Preventative Task Force, giving this a D. And there’s a lot of discussion right now about what that means, what’s going to change and things like that. Many of us believe that a correction was needed. Not the correction that we had, but the pendulum needs to come back from swinging back and forth so far away.

There’s a saying that is what is good for the goose is good for the gander, and this is just less than a year old, the periodic physical exam of the President of the United States, Barrack Obama. And buried on the second page was the fact that he had a PSA, and it was 0.84 nanograms per milliliter. Was there informed decision here? We get US Service Preventive Task Force said there should have been. I don’t think there was, but I wasn’t there so I don’t know. But I do know that there are a lot of challenges that exist with early detection. PSA screening, as you well know, has poor specificity, too many negative biopsies, over-detection, overtreatment, false negative biopsies, risk stratification issues, and all of these things, which are the downside. The upside is we do think that there are men that benefit from finding the right prostate cancer.

So using PSA alone to guide prostate biopsy decisions for the most part should end. That is the first level, but it shouldn’t be the decision all the time to do a biopsy. Of course, unless somebody comes in, their PSA is 35 and they’ve got a nodule and things like that, but we’re talking about the average guy off the street we see with sort of a borderline PSA, normal rectal exam. We need tools to better use precision medicine to reduce unnecessary biopsies and reduce over detection of indolent cancers.

So precision medicine is a term that’s thrown a lot, around a lot. We’ve been using it in prostate cancer since the 40s with acid phosphatase, with specific treatments and things like that, estrogens and so forth, but it’s getting better. We’re being aided by genomic and proteomics, and other things that help us to drill down on the persons who would benefit from a specific action.

So for your iPads here and for the Array Technology we need you to vote on this. What percent of all PSAs in the US are ordered by urologists, 27%, 13%, 2%, 6%, or 19%? Got it?

So, the group thinks that—54% got it right, it’s 6%. All right, let’s go to the next slide. And in fact, this was a shocking data when I saw it first, because I thought urologists were a major contributor to PSAs. Actually, over 90% are ordered by family practice and internal medicine doctors. So where do you start? You start with them, obviously.

All right, here’s a problem, and we’ve confused family practice doctors. We have the US Service Preventive Task Force. And one of the reasons I think they’ve been so accepting is the fact that PSA screening has been sort of a quagmire for them. We tell them the PSA cutoff is 1.5, we say it’s 2.5, we talk about PSA velocity, density, age-specific PSA, percent-free PSA, complex PSA, Phi, PCA3, SelectMDx, 4K, it goes on, and they go help. They need a simple message, and that’s what the next part of it. And not something we did a number of years ago looking at the Henry Ford database. We wanted to find out, is there a PSA cutoff below which there’s relatively low risk that you can say to the family practice doctor, remember this one thing, above that it’s a danger zone. And in fact, what we showed, and this was actually something that we knew, I knew already from the PLCO data that we were involved in that, that trial, is that a PSA of less than 1.5, at least for 5 years, your relative risk of being diagnosed with prostate cancer is very low. It’s like 0.5%; whereas, if you’re in this group right here, above 1.5 to 4.0, not above 4.0, 1.5 to 4.0 you’re relative risk goes up.   That’s a danger zone. That’s a zone where we might have an opportunity to find prostate cancer earlier and find some significant disease is what we want to do. If you look at PSA of 1.5 and above, up to 4.0, most of the time the cause is BPH, not prostate cancer. So everybody, and where we got into trouble, we start biopsying these people, and we know that the autopsy incidence of prostate cancer in 50-year-old men is 25% to 30% or so, we were finding those. And that was a problem. So we have a PSA of 1.5 as an indicator for BPH, it’s also an indicator for progression. It’s precision medicine, focusing on those people. It’s associated with prostatic symptomology.

This is our publication, which came out a couple of months ago in October in Urology, and it dealt with that level of 1.5. And I must say, I’m very proud of all the people that contributed to this that are on this author list. And Alan Partin was one of the first to rank this and give it one of the top stories in Urology in prostate cancer for 2016, and using this approach of 1.5.

What percent of men have an initial PSA of greater than 1.5? That’s a question. And go ahead and guess, is it 18%, 27%, 14%, 22%?

So the issue is, is that are we going to be putting a lot of guys at risk of needing to be evaluated that we can’t handle? Okay, the answer, so most people got that correct. So let’s go and look at that. So we actually looked at that with data from BioReference Lab, and Matt Rosenberg did this. And what we found out was that in fact 73% of men had a PSA of less than 1.5. So that means 27% fall into that gray zone.

If we look at early detection ways forward I think we should treat PSA like everything else that the family practice does. They get informed decision when the test is abnormal. They don’t get informed decision, they check your blood pressure, they check your weight. They don’t tell you if I check your blood pressure and I put you on an antihypertensive you may pass out. They don’t tell you that before they check your blood pressure. They tell you afterwards. The same thing with cholesterol. They don’t tell you if I check your cholesterol and put you on a statin you might have rhabdomyolysis and have renal failure. They don’t tell you about all the outcomes. When they draw a blood sugar they don’t start to treat you for diabetes, they do an A1C. And when you have chest pain or you have an abnormal EKG they don’t do a bypass right away, they go to the next level of tests. When you have an abnormal PSA you go to the next level of tests, you just don’t biopsy somebody unless, again, it’s above 4.0 or whatever your threshold is. So it is a surrogate to go forward.

This sort of our diagram here of how we deal with this, PSA greater than 1.5. Urologists, and then this, we’re going to talk about these things right now to help define the next level of testing. Gleason 6, active surveillance, so we want to get rid of it. So this is our initial biopsy of who to do it. PSA is in an area where we think we should do it, SelectMDx, Phi and 4k. Phi is a good test. Detman Colter’s, as I mentioned earlier, Dr. Partin has done a lot of work with that in this whole group, Stacy Loeb, many others. There’s a nice reflection with the risk of prostate cancer, and they and others, including Lee, have done some work showing there is a risk stratification between Gleason 7 and 6s with the Phi score. PCA3 is a good test to detect prostate cancer, unfortunately, it doesn’t help us find prostate cancers that need to be treated. 4K test is another good test. It’s a blood test. It looks at four ingredients, one of the main ones is HK2. And then it couples with age, DRE and prior biopsy status, and gives you a relative risk of having prostate cancer. And you have to look at that and decide what you think is important, and you get a report back like this, it puts you at low risk, intermediate, high risk, and what your 4Kscore is. You discuss that with the patient, what are they willing accept? I mean some patients will accept 15%, 20% depending on things.

All right, the other one that I want to talk about is SelectMDx, which is the sort of second generation PCA3 test. It was developed by Jack Schalken, who also developed PCA3. It’s two genes which are associated with a higher risk of prostate cancer, pattern 3443 and above. And so these tests, it’s a urine test done after a gentle DRE. And what happens is it gives you a very low risk or it gives you a relative risk much like the 4K score. It will tell you what your chances are of having a prostate cancer. What I like in here is when we do this, the very low risk, and what we see and can tell a patient basically is you’ve got a 99% negative predictive value. You don’t have a Gleason 8 cancer and above, and a 98% chance for at least a Gleason 7. So this is the publication that’s out there, 98% negative predictive value, 99% for Gleason 8. If you look, those of you like ROC curves can see here that this ROC curve out performs the prostate cancer calculator and PCA3, and here on the right what we see is that there is a differentiation here with a 98% negative predictive value for higher grade cancers. So this is the report you get back for very low risk. It’s very reassuring to talk to patients about that, how you feel. And then this one on the left here shows a 50% chance that you have a higher grade cancer pattern 3443 and above, and it also gives you relative risk of having cancer. So it also can have a high-risk of having cancer, but a low risk of having higher grade cancer. But the real differentiation here is in the negative predictive value in a lot of patients that I’m seeing.

And so we’re going to be reporting some of this stuff at meetings coming up, association mapping biopsies and the sensitivity and specificity that are even not 99%, but 100%. Obviously, when we get more patients that’s probably going to down to the 99% or whatever, we’ll see. So PCMs are our friend right now. They help us navigate all this stuff. They help us to eliminate Gleason 6 cancers and eliminate active surveillance. This is the table in our publication that goes through these markers that we use as the next level, and I think we should become familiar with these. Thank you.

Impact of the USPSTF Recommendations on Screening

I’m going to talk about the impact of the Preventative Service recommendation in 2012 against screening for prostate cancer. And just to summarize it, I’m sure everybody in the room knows, it received a grade D recommendation, which means that the US Preventive Services Task Force has concluded that there is at least a moderate certainly that the harms of performing the intervention equal or outweigh the benefits in the target population. And here’s the actual paper that was published in the Annual in Internal Medicine. And by and large, the data that they used to come to that conclusion were derived from the PLCO cancer screening trial and the European randomized screening trial for prostate cancer, and collectively they showed that for men between the ages of 55 and 69 if they are screened annually or over an interval every four years that for a 1,000 men screened for a decade you’d save somewhere between zero and one lives at the cost of a certain number of false positive, unnecessary biopsies and so on and so forth.

So what happened in the spring of 2012 when this recommendation came out, well, like everything, there was an acute reaction. And then there’s been the medical community’s reaction at large over the last three to four years. So here’s the acute reaction by a prominent American academic urologist on Twitter saying that “I hope that Task Force member Tim Wilt knows in his heart of hearts that thousands of painful, slow, preventative deaths will be indisputably on his head.” That’s a pretty rough thing to say. Now, I guess he realized that, he tried to take it down but Declan Murphy and some others had re-Tweeted is, and once it was out there is was out there. And he wasn’t the only one sort of saying challenging things. Otis Brawley, who was at the NCI at the time and is now at the American Cancer Society, who wasn’t even part of the Task Force, is accused of having killed more men by giving them an excuse not to be treated. There was a reporter for USA Today who realized that when a screening guideline against breast cancer had come out a few years prior there was a very, very big uproar. So she kept track of what was going on in social media. And she characterized many of the acute reactions as depressing and ugly. One person, “One can only hope that all of those on this panel who made this decision, and Dr. Otis Brawley, all get cancer and find out too late.” “Could someone please tell me how it is that Virginia Moyer, a pediatrician and a woman is chair of a committee considering a man’s issue on cancer?” “This is a democratic war on men. They obviously want us all to die from prostate cancer.” “This is a prelude to the world of death panels where ignorant bureaucrats make your health decisions for you.” This one I like. This lady I think got it right. She says, “A scientist, especially one who disagrees with you, is the first one to tell you that the plural of antidotes is not evidence, but that seems to be the urologists only come back to the evidence examined by the Task Force.” Sure, every urologist would say, “Oh no, I just saw this guy. His PSA was 5,000. If he had only had his PSA a year or so prior, whatever, I would have been able to cure him.” Well, you don’t really know that that’s a fact.

So that was sort of the acute and ugly reaction. What has happened since? So I’m going to chronologically review a number of papers starting about two years ago that have showed what’s been going on. You can see here, and by the way, most of these papers look at different datasets, and each of the datasets has their strengths and weaknesses, but they’re telling pretty much the same story, that after the recommendation came out the incidents of newly diagnosed—wait, this is percent of men getting a PSA test has dropped in just a few years after the screening recommendation was made. The curious thing, and this is a real problem for the medical community at large, is that it’s much more likely that a man over the age of 75 gets a PSA test than the younger man. And that’s sort of part of the issue we’ve created as a medical community, we’ve probably been testing the wrong people overall. Otis Brawley and his people, again, about two years ago looked at what was happening in terms of the incidence of prostate cancer, and they showed that over the 1.5 years since the implementation that the rate of testing is only about 82% of what it had been in the index years prior to the institution of the guideline. And that this was true both for men between the ages of 50 and 74, and even for men over the age of 75.

These are data from the National Cancer Database, just looking at diagnoses of prostate cancer. And you can see low risk, intermediate risk, and high-risk disease is generally being diagnosed less commonly in the year or two after the guideline was issued. And you can see the fairly steep drop-off when you’re looking at even the target population of patients between the ages of 50 and 74.

These are data from the SEER dataset reported recently at the SUO meeting in San Antonio, that again, between 2008 and 2013 about a 9% reduction in diagnosis of low-risk cancer, 9% intermediate risk, and only a smaller 5% reduction in high-risk prostate cancer.

This was an interesting other way of looking at it. They looked at the case logs that young urologists were submitting to the American Board of Urology to sit for part 2 of the oral boards. And so in the years prior to the Task Force, 09 to 012, the average applicant said that he had done, or she had done 29 biopsies. In the post US Preventative Services that declined to 21. You can see there were differences. The average male candidate did 30 versus 11 for woman, 22 versus 10 in the post biopsy, in the post Preventative Task Force era. So overall, based on this, the total number of annual biopsies performed by candidates sitting for part 2 of the boards declined by 12.7%, the greatest decrease in biopsy volume was seen in those biopsies performed for an abnormal PSA. And remember, this was actually counteracted by the fact that biopsy volume for an indication of cancer surveillance had actually increased during that study period. So there are sort of two effects going on here.

Male urology sex was associated with higher biopsy volume; whereas, oncological specialty was associated with a lower biopsy volume. And I should say that this issue of gender differences by physicians might be sort of the next kind of big thing that we’re going to hear about, because this paper came out just a few weeks ago looking at over a million discharges by hospitalists in the United States. And what it showed was whereas there was just only a small absolute difference in mortality of patients treated by male physicians versus female physicians, it was statistically significantly better to be treated by a female than by a male physician. So I think gender differences in healthcare delivery is something that we’re going to be hearing more and more about.

But anyway, back to the candidate sitting for part 2 of the boards in urology, prior to the Task Force recommendation the average urologist candidates had done seven radical prostatectomies, that fell to six, and you can see the gender differences, and so forth. So after adjusting for physician and patient characteristics there remained a 16.2% decrease in radical prostatectomy following the Task Force guidelines.

This is a paper from the group at the American Cancer Society looking at the stage of disease. So this is locally advanced, and this metastatic, and you can see while the rate or the incidence of metastatic disease seems to be rising, it’s not yet statistically significant. And I think most people would agree that just a few years after stopping or reducing PSA screening it’s probably not enough time to see any increase in metastatic disease, at least on that analysis. And there are a number of different analyses looking at the datasets of older men versus younger men. You can see they’re actually fairly constant. In absolute terms the proportion of patients diagnosed with metastatic disease seems to be rising for men who are young, and even for men who are old, but the main criticism to this paper that was posted on Twitter is that when you curb over-diagnosis you leave behind a higher percentage of real cancer; therefore, this is a pointless study. The editorialists reviewing this paper said it is possible that the seemingly contradictory results of that study showing, or suggesting a slight increase in metastatic disease and the other studies are simply a statistical random variation of incidence that can change over time depending on a lot of different things. And furthermore, in the articles that analyze SEER data, for example, there are different ways of coding the stage of patients. So I think at this point just a few years after the guideline it’s not yet possible to say that the incidence of metastatic disease has risen.

This paper from Ted Shafer suggests that, but again, it’s criticized for the same reason. But the point I want to make is that the incidence of metastatic disease seem to be rising even before the Preventative Services Task Force guideline was issued. The American Cancer Society published the cancer statistics just maybe a week or two ago. And you can see the prostate cancer death rate looks like it was falling and continued to fall, at least according to their calculations as of 2014. And you can see the incidence of prostate cancer peaking in 1992ish or so, and then now coming back almost to the pre-PSA era level of prostate cancer, despite the fact that the population is now older than it was then.

Nice paper from the group at Michigan in Health Affairs that just came out a few weeks ago. A trend in the rate of curative prostate cancer treatments for all men eligible for screening, but notice this ended in 2012, their dataset, and the incidence of treating prostate cancer was actually falling prior to the Task Force guideline; however, if you are diagnosed with prostate cancer you’re nearly as likely in 2012 to be aggressively treated as you were in 2007. But we do know that very, very recently the rates of active surveillance have started to rise. And the curious thing about this paper, and again, this is something we should all pay attention to, that men in the highest quartile of ten year expected mortality still half of those patients were getting aggressively treated for prostate cancer.

So I think since the Task Force recommendation in 2012, which by the way, is going to be re-reviewed this year, and I’m told that a urologist, at least one urologist will be on the panel, so there’s apt to be—

MALE VOICE 1: Who is that?

ANDRIOLE: We don’t know yet. I think the AUA nominated a few different people, probably possibly people in this room. But that will be good to have a urologist at the table. I think it’s clear to say there’s been fewer PSA tests ordered. That there have been likely lower rates of biopsy, cancer detection, certainly radical prostatectomy, I don’t know about radiation therapy. I think there’s a possible increase in distant disease, but we don’t know that yet because it’s probably not been long enough to see that play out. My hope, we’ll hear about this a lot in this meeting is to make PSA great again. We need to test the men who need to be tested. We need to consider reflex tests if the PSA is abnormal. I think we need to do a quality biopsy. I don’t know if that’s MRI or transperineal, and we need to avoid overtreatment. So thanks very, very much.

Vascular Targeted Photodynamic Therapy for Prostate Tumors

I will be talking about another energy source if you will of providing ablation of prostate tissue. This is vascular targeted photodynamic therapy. I will start with one of two questions, so which of the following is true about focal therapy in general? Focal therapy for prostate cancer is FDA approved, and I will let you read the other three and you can vote.

Okay, so a smattering of things. Actually answer three is correct and we will go through that. Most folks getting focal therapy are continent and very few actually require surgical procedures, so three is correct. Let’s go to the next one please. And this is specifically for a vascular targeted photodynamic therapy and, again, you can read the responses and choose accordingly. Okay, so again a smattering of responses. Actually the correct answer is number two. So we will go through this and there is obviously a lot to learn about the new technologies so we will go through all of this.

So, vascular targeted photodynamic therapy basically uses a chroma-4, which is based on chlorophyll actually. It’s called padeliporfin. It’s called a drug from now on, and it’s specifically activated by a specific wave length of light, a laser delivered light, and that activates this compound locally. And it basically results in vascular occlusion, so this is not a strategy that generates heat or cold, and that is one of the proposed advantages of vascular targeted this that there is not collateral damage, and that basically you can destroy the lesion you are planning on destroying without having to worry about other surrounding tissues such as the neurovascular bundle or the urethra or other important structures from being damaged.

It’s basically done like any other brachytherapy template-based strategy, so there is a transrectal ultrasound probe placed in the rectum to visualize the prostate. There is a brachytherapy template that is utilized to guide cannula fibers into the prostate, and you map out an area that you wish to ablate. There are certainly guidance strategies, and depending upon the volume of tissue one wants to destroy and the location of that tissue, a computer algorithm will tell you where to place the fibers. The fibers do have different lengths in terms of how much light energy they will deliver, so you can set up a treatment plan to very specifically target an area within the prostate that will then be destroyed.

The light enhancing element, the padeliporfin or whatever it’s called, is the agent that is given about ten minutes before you place the light on, so it’s a relatively quick procedure in terms of getting the patient treated. These are the various types of fibers that can be used, and at least from a science standpoint you want what is called the light density index to be greater than one. And that is determined by the volume of the tissue that you want to ablate, and then the sum of the fibers in terms of the length of the energy that you will be delivering over that period of time. And, again, there is a software program that tells you where to place these fibers and the length of the individual fibers based on the treatment plan.

So this is a two dimensional image of the ultrasound, but basically it shows you where the fibers need to be placed, thus how many fibers, and then the length of those fibers. And that gives you a formula that allows you to calculate if you will destroy that tissue appropriately. This is flipped from the cartoon on the other image, but this was a left-sided ablation. And you can see that you can ablate large areas of the prostate with this technology. The resultant biopsies basically show necrosis of the tissue. The time lap studies of this demonstrate that it is a vascular generated necrosis.

There are really no heat changes that are associated with this technology. And as with all of these ablated strategies, whether it’s cryotherapy, electraperation, you can throw in radiation therapy, they all work in terms of destroying tissue. So some of the nuances of, well, do you use one versus the other versus the other, it depends on what you are trying to accomplish and what you have available to you, but they all kill tissue. That is for sure.

I am going to spend most of the time during this presentation talking about a recently published phase III study with Dr. Gammella [phonetic] if he is still in the audience. He actually commented on this article in Urology Times, but it was basically looking at the patients who we would otherwise consider candidates for active surveillance. So you can argue whether that is the best patient population to study, but this was the study that was performed that was done in Europe. It was led by Mark Emberton who is certainly a big proponent not only of MRI, but also MRI-guided treatment strategies.

Fairly low risk patients when you look at the patient population that was studied. So basically no one had any Gleason grade 4, certainly no Gleason grade 5 in their biopsy. It was small volumes of Gleason score 6 all with PSA’s under ten. Very few had actual palpable lesions, and then from a technical standpoint just a limit on the prostate size. The exclusion was basically anybody that didn’t meet the eligibility criteria, prior treatment for their prostate, whether it be a TURP, and no one could be on any type of hormonal type of therapy.

The primary endpoints, there were co-primary endpoints. The first was an absence of a positive biopsy at the 24 month mark, and the other was the time to treatment failure. The time to treatment failure is basically defining treatment failure based on all of these outcomes. So, again, at 24 months you wouldn’t expect much metastasis or death or progression to T3, but there is a PSA endpoint, and primarily a progression to a higher Gleason score. So those were the co-primary endpoints.

The secondary endpoints, they did do biopsies at 12 months. The patients that had a positive biopsy at 12 months that were in the original treatment arm could be retreated. It actually ended up only being about 5% of the patients, but retreatment was allowed. And then they looked at the PSA levels, MRI findings, etc. A well-balanced study, nothing dramatic, there were 200 or so patients in each arm, most were Caucasian, and body mass indexes were pretty much irrelevant.

But because this is a low risk patient population, so the patients that were otherwise candidates for active surveillance, the vast majority, 85+ percent were clinical T1C’s, and most had modest PSA elevations in the five to six range. the numbers of positive biopsies based on the eligibility criteria was only about two, and most had by definition a Gleason of six or less. There were a few that were still called Gleason grade two’s, but essentially all of therapy enrollment were Gleason 6. And three-quarters of them had a unilateral disease only. If the patients had bilateral disease, both lobes of the prostate were treated.

So the co-primary endpoints as I mentioned, the first was a negative biopsy at 24 months. And if one looks at the outcomes basically the TOOKAD is the treatment arm versus the surveillance arm, so there were far more patients in the treatment study. About half of them actually had a negative prostate biopsy compared to the surveillance group where only a small minority had a negative biopsy. And the second primary endpoint was this progression endpoint. Each of these were listed out. Most of the people that progressed were based on, of course, biopsy features, and very few were based on PSA or clinical score progression as I mentioned. None were going to develop metastasis or death within a two year time frame, but most had progression to a Gleason 3+4, and some had more than three biopsies positive.

But regardless of these individual characteristics, it all favored the patients that were treated with a photodynamic therapy. So basically fewer patients had either a positive biopsy at 24 months or met one of these definitions of patient progression. If one looks at, again, the other aspect of this was how long did it take these patients to progress, again, a delay in progression even in those patients who did progress based on treatment, whether they were just active surveillance versus the photodynamic therapy.

So in essence, setting the clock back if you will in those patients treated with the photodynamic therapy, even though this was a low risk patient population. This curve is a bit strange. It’s based on the biopsies at 12 and 24 months. That is why there are these steep drop-offs, but basically the patient population that received the photodynamic therapy were less likely to progress because they were less likely to meet either of the co-primary endpoints. This did reach statistical significance, of course, and far fewer patients as we will see.

And this developed higher risk disease, so in terms of the biopsy endpoint, if you looked at the patients who progressed to Gleason 7 it would be in many centers an indication that active surveillance had failed. About twice the number of patients that were just under active surveillance relative to the patients who had received treatment, very few patients went on to 4+3 rather than 3+4, but again it favored the treatment arm.

One criticism of this study is that there is this fairly high progression rate at just two years of active surveillance for what is a relatively low risk population. A single core of Gleason 6 that at two years had almost half of the population now having a Gleason score of 7, and that is a little bit quirky, but it was a randomized trial. The pathology was reviewed, so the numbers are the numbers, but relative to other active surveillance populations with similar low risk patients, that is a pretty high number again. I am just pointing that out.

If you look at the initiation of radical treatment, so the patients who again were active surveillance patients, some were treated with a standard active surveillance protocol, and the others treated with a photodynamic therapy, about 30% of the patients in just the active surveillance arm ended up being treated, and only about 6% of the photodynamic therapy patients, again, at two years. One can argue again that a 30% treatment rate after just two years of active surveillance in a relatively low risk population is a pretty high rate of treatment.

I think most would have a 5% to 10% treatment rate, but again a randomized population and their numbers are the numbers. If one looks at some functional outcomes, basically the patients did very well with what is a focal therapy and that is the advantage of doing a focal treatment rather than a whole gland treatment. If you look at the active surveillance population, they basically stated their baseline functionality throughout the two years of the study, there was a transient worsening of urinary function in those patients that were treated with the photodynamic therapy, but basically they then improved over time.

It was probably a reduction in gland volume as the result of the tissue being destroyed. If one looks at sexual function, there was a worsening of sexual function. Again, the active surveillance population had about a slight decline, age-related of course. They didn’t have any treatment. The patients that were treated with the photodynamic therapy had an initial decline. They had some improvement, but again relative to the active surveillance population, there is a little bit of decline, but not dramatically.

If one looks at the safety profile, certainly with the treatment as compared to active surveillance, the patients had more urinary dysfunction. These are the ones that reached essentially clinical significance, and then ejaculatory failure or erectile dysfunction, etc, again the active surveillance patients of course receiving nothing is not going to have a significant impact on your quality of life receiving something even if it’s a focal something does at least transiently have a negative effect.

If one looks at the more severe ─ compare these two columns ─ there is basically very little difference between the active surveillance arm and the treatment arm in terms of grade III or higher side effects. So, again, it’s a relatively safe treatment, some transient changes in the quality of life, more significant with erectile function than urinary function, and most importantly, an improvement in oncologic outcomes.

So the authors concluded from the study that basically it’s a first trial, of course. There was a substantial reduction in progression primarily by preventing higher grade cancers. Many more patients converted to a negative biopsy because they received treatment. There was a substantial reduction progressing to aggressive or whole gland therapy, 30% versus 6%. And then the safety and the quality of life profiles were at least acceptable.

So at least from the photodynamic therapy, you know whether this was the right treatment population, you know should we be focusing on active surveillance patients one could argue. But at least it is a randomized phase III study that at least will show in selected patients on active surveillance perhaps the higher volume patients that perhaps this type of treatment may be of some benefit.

Now just switching gears a little bit, this is just basic science laboratory. It comes out of Jonathan Coleman’s lab, who has done most, if not all, of the work on the photodynamic therapy at Memorial. What he did was he treated these LNCaP tumors, so these prostate cancer tumors generated in mice. And what he saw was that when they looked at the genetic stuff that goes on in these things that many of the androgen response elements were actually stimulated or increased with photodynamic therapy.

And what that resulted in is that one could hypothesize if some androgen deprivation therapy was utilized that that may improve outcome, and that since photodynamic therapy enhanced a survival pathway by blocking that survival pathway in these androgen regulated genes that perhaps the outcomes would be improved. And that is basically what he showed in a relatively small study with mice, but again looking at the control versus those who received hormonal therapy alone, those that received photodynamic therapy alone versus the combination, again, the combination arm of combining the androgen deprivation therapy utilized before the mice were treated with the photodynamic therapy, there was a much larger reduction in the tumor volume compared to either of the treatment arms than the control arms.

So, again, it suggests that the combination therapy in moving forward, short term hormonal therapy followed by the photodynamic therapy may actually be an enhancement of the overall treatment pathway. So there certainly is compensatory upregulation of androgen receptor signaling and that by blocking that pathway you actually improve outcomes.

So, in summary, I think focal therapy in general effectively ablates prostate tissue. It doesn’t matter what energy source you use. You can kill the tissue. I think how much tissue we kill, how we target it and how we follow these patients to have a meaningful outcome, then those are the questions that remain. Certainly focal therapy has a better quality of life outcome than whole gland strategies, and which patient population will best be served by focal therapy, what are the appropriate endpoints, I think that is what needs further discussion and has yet to be determined.

So with that, I will finish my presentation.

Cryotherapy: Update on the International COLD Registry

Thanks, James, and thanks, David, for inviting me to one of the best meetings in urology. I’ve been excited to be here for a long time and I’m pleased today to be able to share with you some work we’ve done on cryoablation. I went into practice in 1992, and at that point there was a flurry of interest in cryoablation. And that faded pretty quickly because the results frankly were not very good and there were significant complications and the science was worse than not very good.

And, unfortunately, what it did was it colored the word cryoablation or cryotherapy probably moving forward forever. And so what we have now is the opportunity to look at what has happened since that time. Now why is the COLD registry important? It’s because actually you know there is no significant funding in cryoablation. A number of people have completely shut off that it could be a possible modality, so there aren’t going to be large studies like some of those that you have seen in other modalities moving forward.

So the COLD registry is an opportunity for us to be able to share real world experience at a number of centers, both private and in academic settings. The disclosure on the COLD registry is actually an important part of this. It’s an online retrospective database sponsored by Endocare or Healthtronix [phonetic], and importantly what that means is that we have the ability to look at real world experience again. We do have funding from outside, which we go over the top to make sure and disclose. But I want to talk to you about how we separated that in a way that we believe brings the science better.

And the first is by having it run by an independent board of directors. I have had the ability to be the chair of that now for over a decade. Some of the people in this room have been a part of that, and it’s allowed us to actually be able to go into the data and do some quality work on it to bring the publications that you’ve seen. It’s currently housed by Watermark which is an independent data and center. That was done soon after I took over the COLD registry.

And the ability to take that completely away from the company having direct access to the data in a way that was able to protect it, and it is the largest dataset in existence. When they approached me now over a decade ago, there were several things that I asked for in agreement to run the registry. The first is that I chose to take no compensation for my work on the registry. And as I would always disclose, I do other work with the company over the years that I have been paid for. I want to, not by any means, pretend that that has been the case.

But all funds that have been related to work on the registry have been diverted to charity or other purposes, so I have not taken any money in that regard. And that was important to me. Second is that I would be the senior author on all of the manuscripts, and that was to assure that as the data came out that I had the ability to assure that what really came out was something that I felt we could stand behind. The independent board we talked about, and then we had a 100% decision on whether things got published or not. And the company immediately gave me permission and an endorsement to do that and they followed through on that.

So there have been publications that show a significant efficacy. I will share some of that with you. There have been publications that have shown actually places where cryoablation doesn’t work, and by the same token they have never exerted an influence to try to say anything other than we need the data to be out there. So there are a number of limitations to the registry that I think others can learn from moving forward.

It is a situation where the sites enter their own data, so it becomes a heterogeneous data set. It’s rare that I go to a meeting that someone doesn’t come up and say they want to be a part of the COLD registry and enroll their data. In the first couple of years I fell for that, and then after that we learned that what became clear was that people would often enter their data even for the first few months and it would fall off for a number of reasons, so we did get away from that.

And we are trying to now work specifically with centers that have an interest in continuing to assure that the data continued. In addition, it’s hard to get long term data. That is due to a number of things, including the fact that the investigators retire, they move to other places, they die. We had one investigator who lost their license, and once they’re there, the IRB approval says that we have to have licensed physicians. So we at that point have to take the data out of the registry and that will explain some changes in the registry that I will show you.

In addition we’ve got some fields that we feel very confident in. The PSA’s are obviously easy to do. We are very confident that if there is a fistula, it will show up in the registry. No one is going to miss that diagnosis. But in other fields like IEF’s and biopsy details, we just did not succeed in getting to the degree that we would be able to publish anything meaningful from that. But we have had 16 peer-reviewed publications coming from the registry.

The current data are a little bit different than I may have shown at any other point in time, again, because if someone retires or leaves, we can’t keep their data in the registry. We just can’t continue to analyze those data. so it is the largest dataset. We have other 4,000 patients who have primary whole gland ablation, salvage patients almost 1,000 similar to primary focal. We’ve got a small number of salvage focal patients that is a little bit lower than what we published recently because, again, some patients had to be pulled out.

And then we have a smattering of repeat biopsies. So now almost ten years ago we published the first group out of this, 1,200 patients that had undergone primary whole gland ablation. It’s a pretty typical population, but importantly only 136 of those had at least a five year follow-up. So we found a number of things. One is that only about a fourth of the patients actually underwent biopsy. Of those who underwent biopsy for cause, in other words, had a rising of PSA as we would have taken in any other setting, the positive biopsy rate was almost 40%, so and then if they had no cause, if it was done for protocol, it was a positive biopsy rate of about 15%.

And if you think in the acute setting, although it’s been quoted here earlier today that only 25% of the biopsies are positive, about 40% to 50% of all initial biopsies are positive in almost every study that has come forth in the past decade or more. And so what you see here is if you are suspicious of cancer and you do a biopsy, you have about a 40% chance of having cancer. And if you’re not suspicious of cancer, so if we went through everybody in the room here who had hair as gray as mine and did biopsies, we would find out that about 15% of those men have cancer.

So it’s really not any different than in that setting. Urinary retention rates were low, rectal fistula rate which is the area that originally ran cryoablation out 20-plus years ago, 0.4%. Incontinence was about 5% and 3% in PADS, and most patients who were sexually active did not return to intercourse, and frankly most patients who were sexually active don’t end up getting cryoablation in most of the practices. Now as far as determining whether there was a successful procedure, there is no standard yet as far as determining when cryoablation was successful other than if we did prostatectomies afterwards of course.

So you could look at Astro or Phoenix. You could look at undetectable PSA which one of the reviewers in the Journal of Urology required us to put in there, and it’s a meaningless study considering we know that we preserved tissue in cryoablation, and then a nadir PSA. So, as opposed to choosing one of those, we actually have pretty consistently reported both Astro and Phoenix with all of our outcomes. And basically you see the Kaplan Meier curves that are not anything different from other forms of accepted therapy.

We also, though, came back later with a group of patients, and over 1,000 patients had had a minimum of a five year follow-up, so some five year papers you see, the first patient had five years and everybody else had less than five. All of these patients had a minimum of a five year follow-up, and we saw again Kaplan Meier curves that are comparable to other forms of treatment based on low, intermediate, and high risk cancer.   What we found otherwise, though, is that the nadir, post-cryoablation, which was typically the six week read which we know now may not be the true nadir. We are working on some research on that.

But we see that the patients reach a nadir of less than 0.4, they have very good biochemical outcomes regardless of risk structure. And if the nadir doesn’t reach below less than 0.4 in that primary setting, in all likelihood we fail to cure the cancer. We subsequently have been able to look at a number of other scenarios including bulky disease, high risk patients in the elderly category many of which are now being diagnosed and the option is for surveillance. We have the salvage setting and the focal setting and I will go through those.

So with patients with high grade cancer one of the original hypotheses was you shouldn’t use cryoablation because maybe it wouldn’t be as good. What we see actually is high grade cancer will die like low grade cancer, but there are some caveats to that. So even in those patients with high grade cancer, if their PSA is higher, actually we do see separation in cure rates regarding the lower PSA. More importantly in my opinion is that if they have pure pattern 4, so if you have Gleason 8 cancers, we see that they actually do less well than patients who have any pattern 5 cancer. So there is probably some sensitivity issue there but in that setting we again get affirmation that post-treatment nadir is the determinant of whether they are likely to have a long term good outcome.

We have also published in patients who have had whole gland primary treatment in the elderly, and actually a number of patients have been treated as you see with the numbers there in that greater than 75-year old population who have mostly high risk disease. And I often have the question of should you treat a patient who is 76-years old, and if his father is there and he is in great health, as you know, and I recently saw a patient who had been treated with active surveillance with Gleason 9 disease because he was 85-years old, well, he had widespread metastatic disease at 91 and he was perfectly healthy other than having incurable metastatic disease at that point. So we have to rethink that.

In the salvage setting, our original studies again now almost a decade ago were 280 patients, so obviously fewer patients. And it was the same thing, a five year follow-up only in about 50 of those patients. In that setting we chose not to separate the high, low, and intermediate risk, and this has been an ongoing debate amongst some of the board is that I would regard anybody who has post-radiation recurrence as being high grade. Others would say we could segment them, and we started doing both.

But again what you see there is we would respect [phonetic] that depending on definition, a 50% to 60% chance at five years post-treatment that we would still have biochemical success in the post-radiation setting. In that setting we know that complications are a little bit higher with a fistula rate of 1.2% in that group, a retention rate of about twice as high, about 3% required TURP’s, and the incontinence rate which seems low to me considering our recent data, but at least in that setting the incontinence rate was actually only about 5% or 6%.

When we do stratify them, though, we see now in unpublished but subsequent data is that you do see some differences if you take the post-radiation setting and segment by high, low, and intermediate risk based on traditional definitions. You do see some separation of the curves and they are in the high risk patient. Less than 5% of those patients five year post-treatment will be biochemically free.

And in the salvage whole gland setting we also looked at patients who have had neoadjuvant treatment. And the important thing we find here is that although the hypothesis is in that setting that giving neoadjuvant treatment before cryoablation is done, some investigators clearly felt that that would be beneficial. That turns out to be absolutely the opposite. And the patients who had neoadjuvant treatment actually did worse, not better. My hypothesis on that would be that those patients may have had worse disease, but very clearly neoadjuvant treatment is not a panacea in the post-radiation cryoablation setting.

And then in that same setting we see continued the same separation on if the patients get a low nadir of less than 0.6, and actually subsequently our data would support less than 0.4, we know that that is the patient who is likely to have local disease or biochemical recurrence, and biopsy is probably not necessarily in follow-up barring some significant changes in PSA.

Here again we’ve done the same thing and shown that that will go across risk groups that in that salvage setting the nadir maintains across all risk groups. The final population is the focal treatment setting, and we have basically developed a series of nomenclature, or a definition of nomenclature. We have this in the registry such that when patients undergo focal ablation, the investigators can put which type of focal ablation they have.

And what I can tell you is that almost all of those are actually hemi-ablations in the series that we have reported. John Ward and I several years ago published that the growth on this was actually substantial and that focal therapy was taking off. Importantly in that group we found that focal therapy was not being done just on those patients who shouldn’t be treated, which are the low risk patients, but the majority of the patients were intermediate and high risk disease that were getting focal therapy at that point and subsequently as well.

And what we see in that focal setting is compared to whole gland at the bottom─ the bottom line is that we tend to see biochemical outcomes or Kaplan Meier curves with biochemical outcomes actually being similar in the focal group to the whole gland group meaning that most of the patients who are undergoing focal therapy appear to be doing that based on the right choices or the right patients are getting focal therapy.

The other issue with focal therapy, of course, though is why do we do it if we are doing organ-sparing. It is theoretically to protect some outcome. And so we do see in bold there compared to whole gland or salvage treatment, we see that the patients actually are going to be less likely to have incontinence, about half as likely. They are going to be less likely to have fistula. Only one patient in the entire 1,000, patients had a fistula, and urinary retention was less than 2%, so all of those are favorable.

What is not clearly favorable is protection of erectile dysfunction, so in those patients who underwent again mostly hemi-ablation, the bottom line is that is still about 40% of those patients that had direct erectile dysfunction afterwards. And so at least hemi-ablation clearly again is not a panacea for preserving erectile dysfunction.

Other issues we’ve looked at in the salvage setting I should say is that we developed a concept of a bifecta, so we’ve talked about the trifecta with thoratical prostatectomy, in the patient who has been radiated previously and undergoing cryoablation, whole gland cryoablation in this report here, we would not expect them to be sexually active. As we know many of them might not be sexually active because of their age or because of the prior radiation, but we felt that was not even something that was trying to be accomplished in the whole gland salvage setting.

But we did expect them to be continent and we did expect them to have a biochemical disease-free survival. And we found that about 75%─ 70% to 75% of those were able to accomplish those two goals. One of the other findings that we published is that salvage patients have poor outcomes if they have single vesicle involvement. And that actually is in my own experience, but I suspect that it’s why we also published it in the T3 setting, extra prostatic disease, that cryoablation does not tend to do as well as other modalities. So in a patient with extensive extra prostatic disease, our publication would suggest that that is not the patient to treat with cryoablation.

Then the last frontier would be the patient who could undergo focal salvage or partial gland treatment is again theoretically we could reduce the morbidity while still carrying the cancer in appropriately chosen patients. And for the biochemical disease free survival, we show that that turns out to be the case and that we actually have a high likelihood to have the disease controlled as we would with the whole gland setting or whole gland treatment. What we weren’t able to accomplish though was to have inadequate reduction in post-cryoablation complications, so again post-radiated patients who undergo focal ablation and that we actually had as high of a risk, if not higher, there were three patients out of slightly over 100 that had a fistula in that setting. Urinary retention certainly was not lower, and the 12 month incontinence was not lower as well.

So my initial enthusiasm for focal salvage cryoablation has waned some. I believe we could do this better, but at least in the first 100 cases it’s not uncommon for the first 100 cases of anything, did not turn out to provide the benefit that we had hoped for in the short term, and then again segmenting it by risk category. So the key take-away’s from that would be that the COLD registry is the largest source of cryoablation data and that it is the best data that we have got to be able to evaluate the role of cryoablation in any of these settings.

The primary and salvage therapy can be accomplished with either whole gland or focal therapy if the right treatment is given to the right patient, and I think that is the real key here to any form of ablation. And then finally, as we know, there are increasing numbers of men who have previously had radiation and that we believe that is highly likely to be a growth area in our practices for focal ablation. I appreciate it very much.

MRI Guided Biopsy and Ablation

First I wanted to thank Dr. Crawford for inviting me and including me. I appreciate it. My task is to talk about MRI of the prostate, and as Dr. Klotz mentioned earlier, there has been an absolute explosion of data, and it’s somewhat challenging to take all of the data and condense it into a talk. But I’ve done my best. There is a fair amount of data in here that we are going to move through quickly, but hopefully you will find it useful and practical.

So I have one relevant disclosure late in the talk about an upcoming trial that we are involved in. so of the six things that I wanted to talk to you about, sort of the MRI at different stages; MRI for screening, prior to initial biopsy, prior to a repeat biopsy, what is the data on using it in surveillance, what about staging patients and operative planning, and MR guided ablation which we have seen more of lately.

When I think of prostate cancer and take a step back, sort of the 10,000 foot view, I think of it as the good, the bad, and the ugly. The good news is that fewer men are dying of prostate cancer. The good news is that we have all of these novel tools, tests, and drugs that we have heard about. The bad news is there is a pandemic of overdiagnosis and overtreatment, which we are doing better at. And at the other end of the spectrum, we have often insufficient treatment for men with really advanced disease.

And then the ugly, which I think we need to shine on ourselves is screening the treatment patterns, the Preventive Services Task Force, and then the explosion of cost with all of these novel tools and tests. The bottom line in the United States is that smart prostate cancer screening can save lives. There are 50% fewer men dying of prostate cancer. I think this is underappreciated within the medical community. We should be shouting this from the rooftops and be incredibly proud of it.

But we can’t talk about that without talking about the elephant in the room which is overdiagnosis and overtreatment. And the reason I mention this as a lead-in, when I think of how to minimize over-detection and overtreatment, I think of the seven things on the slide there as real practical ways of minimizing over-detection and overtreatment. And of the bolded five, MRI can help play a role in. So I do think MRI is incredibly useful in helping to progress the care of men with prostate cancer.

So some basics on MRI and this can be a whole topic in itself, but just to download some information. Wait at least six to eight weeks after a biopsy to limit inflammation and hemorrhage that might obscure your pictures. There is a whole literature on what type of magnet, what type of coil do you use. In general, a 3 Tesla is better than a 1.5 Tesla. Some groups get away from an endorectal coil for patient comfort and logistics, but most of the data suggests that the quality of the pictures are better with an endorectal coil.

Everyone uses a phase array body coil, and then the sequences matter. The reason it’s called multiparametric is in general there are three different types of sequences. The most valuable is probably DWI, diffusion weighted imaging, which gets you an ADC map. The second best if T2, and that is more anatomic. It can also show some cancers. By far the last useful is DCE, which is dynamic contrast enhanced. The size matters. It makes sense that the larger something is, the more likely you are to see it. or equally important is that the location matters, so all of these anatomic zones, the way the radiologist can interpret a potential cancer is different depending on what part of the prostate they are looking at.

And then a key point which I would encourage you to do at your home center is not only does the experience of the radiologist matter, but the expertise does as well. Just because someone has read a lot of them doesn’t necessarily make them good. It’s kind of like surgery. Just because you do a lot of surgery doesn’t necessarily mean you are a good surgeon. And the feedback loop of data is incredibly valuable if you find a radiologist that can continue to look at MRI’s, get better, and you can learn how useful MRI is at your institution.

This is incredibly important, this last line. There is a bunch of data within this past year, mostly from UCLA and NYU that MRI underestimates the tumor volume most commonly rather than the opposite. This is incredibly important for a biopsy or potential ablation. I do think MRI is valuable, but I tell the patients all of the time that we can’t hang our hat on it. Depending on your institution, it is good or great, but it is far from perfect. It should be integrated into the decision-making.

The PI-RADS system which you probably heard of is an ordinal system of grading the likelihood of there being cancer. It’s sort of been strong armed through as the de facto way of measuring it. There are many other systems out there that are often useful, and just another point to look at your own data at your institution or your medical center if you can’t.

So now let’s go through every little stage on what the data shows. So MRI for screening, it’s being done at some places. I think it’s the cart before the horse. There is no compelling data that it should be used for screening. Hopefully we will get there. In essence with an MRI for screening, you want to know how reliable is a negative MRI. A clean MRI, what is the likelihood of a meaningful cancer? Four institutions here, mixed cohorts, the bottom line is Gleason 7 or higher on a biopsy is less than 10% and as low as 1%. So it’s not zero, and a negative MRI, if a guy doesn’t want to have a biopsy, I would tell him, here is our data at our institution, a 6% chance you are missing a Gleason 7 or higher, and some guys say I still want the biopsy and some say no.

The flip side of it is how reliable is a positive MRI. These are two institutions using two different types of MRI. The reference standard was different whether it was transperineal or radical prostatectomy, but the PI-RADS scoring system is useful as it gets higher, the higher the likelihood of getting cancer. And Larry Klotz’s data that he just presented is incredibly valuable because his PI-RADS numbers were very different than what was presented in the literature. And what is relevant for his patients are Canadian patients at those institutions, you can’t rely on this published data from two centers of excellence.

We will eventually have data relatively soon on the role of a screening MRI, so there is a big trial that we are involved with and it is the PRECISION trial. And I will just walk you through it. It’s biopsy-naïve men with an elevated PSA. They get an MRI done. If it’s negative, then no biopsy; but if it’s positive, they are targeted. And then the randomization to the other arm is just a standard 12-core TRUS biopsy. And the primary outcome is a Gleason 7 or higher. It is accruing ahead of schedule and there will be 460 men. This is the algorithm. Don’t biopsy PI-RADS one or two. You biopsy three’s, four’s, and five’s. And we will have very meaningful data on whether it’s worthwhile or worthless in this study.

What about routine MRI prior to an initial biopsy? It is done routinely at select centers. We have a big center in Chicago where, right before every biopsy, everyone gets an MRI. I do not routinely do it. The NCCN does not recommend it, though if you look at the guidelines they do say or sort of hint at it, that MRI could potentially be useful to find more aggressive cancers and keep your hands off of the Gleason 6’s. So I would not be surprised if at some point this gets integrated in, but on a population-based level in the U.S. where MRI is very expensive, it’s just hard to imagine that before every single biopsy everyone gets an MRI, but perhaps we’ll get there at some point.

In Europe and in other places, MRI is a lot more cost effective because it’s cheaper. Now there are a load of papers out there on the role of MRI before biopsy. This is probably the single best known for good reason at a center of excellent, and this is out of the NCI and it was published in JAMA. There were 1,000 men undergoing an MRI before a biopsy, and only about 20% of them was it their initial biopsy, and 80% was a repeat. And the take home message is it helps you find more higher Gleason grade lesions and helps you not to find the Gleason 6’s as frequently which I think is favorable.

The great news is we even have some randomized studies now on the use of MRI, and I am presenting a couple of them to you throughout this talk. This is a randomized study that is in press out of Italy, and this is 212 men with an elevated PSA and a normal DRE, and they are randomized to getting a biopsy 1.5 Tesla with an endorectal coil. If there are lesions there, they target the lesions. If there are no lesions, they get a standard 12 core. The other half of the study just gets your regular 12 core biopsy, no MRI. What does it show?

In this study, the MRI kicked butt. It basically found a lot more cancer, which I don’t think is necessarily an advantage, but most importantly, it found a lot more clinically significant cancer. And if you look at the third row there, 43% of clinically significant cancers in the MRI arm, there were only 18% in the control arm. That is meaningful information. And at this center or in this trial, a negative MRI was pretty powerful. So only basically 4% of the guys with the negative MRI had a Gleason 7 or higher. So that is good feedback data for that institution where maybe men with that technology at that institution with the people reading it don’t necessarily need a biopsy if they have a normal MRI.

This is a well-known study that was published at ASCO last year and it was just recently released in the past couple of weeks in Lancet Oncology spearheaded by the group out of the University College in London, but it was more of a population-based study. It took place at 11 centers in the UK and tried to make it as transferable as possible. So they did a 1.5 Tesla MRI without an endorectal coil. Guys with an elevated PSA and a normal DRE, and God bless these 576 men. They all had an MRI, then they all had a 12-core TRUS biopsy, and they all underwent transperineal mapping. So this is for the love of science, and I am selfishly glad they did it because it provided useful data.

The UCL group has really woven the flag on a primary endpoint of a meaningful cancer, primary pattern four or tumor length of more than 6 mm. That is a separate discussion on whether that is appropriate or not, but in this trial that is what they used. Here is their data. The red is a clinically significant cancer based on the PI-RADS score, so yet more evidence that some type of ordinal system, scoring system, helps you determine the likelihood of there being a meaningful cancer there.

Now the ideal test if you think about it, if you want high sensitivity and a high negative predictive value, do you want to identify all of the guys with meaningful cancer, that is a sensitivity that is high, and you want a high negative predictive value so that if you have a normal scan you don’t have to subject them to a biopsy. And the MRI basically destroyed transrectal ultrasound in sensitivity and in negative predictive value. And you can see the numbers there on the table.

Now what about the clinically significant cancers that were missed in this trial? Basically no matter what your definition of the significant cancer─ and the Gleason 6 there is more than 6 mm of Gleason 6. And the others are Gleason 7, but basically MRI was far less likely to miss a meaningful cancer compared to what most people do is a TRUS-guided biopsy. So the conclusion of this PROMIS trial, which I think is a landmark trial, is that a negative MRI as a triage test would avoid biopsies in about a quarter of men. And you basically diagnose the same amount of clinically significant cancers.

I think that is an advance. The only additional thing is the added cost and the logistics of the MRI. A positive MRI is the flip side of it with only targeting those lesions detects more cancers than if you just across the board did a TRUS biopsy. So, it’s a really well done study showing MRI is useful.

Now what about men with a previously negative biopsy? The NCCN guidelines show this is a very complex and muddy space. There are a whole bunch of biomarkers, urine, tissue, blood, and imaging that can contribute to this space. I essentially think of MRI as a biomarker. I think it’s an anatomic marker and a biologic marker. And it can be useful in this space just like many other things can be useful in this space.

Recently the AUA as well as the Society of Abdominal Radiology put some content experts together, and we put together some guidelines or recommendations for using MRI and then who had had a previously negative biopsy. And most of this is self-evident, but this is the take home point of the paper. Basically, higher PI-RADS lesions probably warrant a biopsy. There are many different ways of targeting these lesions; in-bore, cognitive, fusion technology, and at least two cores should be taken from each target.

And then a targeted biopsy alone, and I keep bringing up this point, should only be considered once you’ve looked at data at your big institution at your group to know whether that is a smart move for that individual patient going forward.

Another randomized trial, now this is a randomized trial using MRI for men with a previously negative biopsy. The PSA remains greater than four, they all undergo an MRI, and if there is a lesion on the MRI, they are randomized. And one arm is basically just targeting the MRI lesion, and the other arm is targeting the lesion plus your standard 12 core. And at the interim analysis this was halted because they were basically equivalent. Whether you wanted to define all of the cancers, just the Gleason 7’s or higher, the targeted MR biopsies basically got you all of the information that you needed and you didn’t have to do the 12 core.

Now remember these are guys with a previously negative biopsy. So it suggests that perhaps in this clinical state, maybe just targeting the MRI lesions is all we need to do. What about MRI for active surveillance? So it makes a lot of sense. There is a load of data out there on the MRI. I love this one out of the University of Toronto because it’s so simple and it makes sense and the data is so dramatic. Sixty guys with low risk cancer all getting restaged with an MRI and a repeat biopsy to look for higher grade cancers. They made their radiologists commit on the MRI to say it’s either normal, something less than 1 cm, or something greater than 1 cm, pretty clear cut. And look at the dramatic difference in upgrading, looking at that simple three-tiered system which speaks to the power of the MRI with restaging biopsies in guys with low volume cancers.

How do I do surveillance? Well, I get an MRI fusion restaging biopsy similar to what the women and men at Toronto did. I typically do it within six months. Some guys want to do it sooner and some guys want to wait a little bit longer. Not a huge deal. A PSA and DRE every six months; the NCCN guidelines and most experts say you don’t need to be checking it every three months. A surveillance biopsy every one to three years and it’s easy to risk stratify based on age, health, total millimeters of cancer at their initial diagnosis, and PSA density.

Those are your big ticket items. How much Gleason 6 cancer was there and what is their PSA density? I don’t think there is any convincing data yet for routine surveillance MRI. However, I am going to show you data to suggest that maybe we will be getting there at some point.

So what is the data on the use of MRI while a guy is on surveillance? Here is the data from Sloan Kettering. It’s a bit of a mixed bag in different types of MRI’s. About a third of their patients were found to have Gleason upgrading, but if you look to the right there on the figure, basically the higher the Likard [phonetic] score or PI-RADS score, the more likely you are to find a higher grade Gleason score. And the black there are the targeted biopsies.

So, most of the higher grade cancers were found from a targeting of the MRI lesions. It’s convincing data. the NCI also has a similar study where they took those low or intermediate risk men and they are looking for the worst cancers in using MRI. So 30% were upgraded. Their definition of MRI progression is not commonly used, but they basically gave points for each of the three things listed there. And you got either a zero, one, two, or three points. And, lo and behold, look, the more points you got on your MRI, the more likely you are to find those higher Gleason scores. It is encouraging data that MRI is useful.

The UCLA data is a similar study. The guys on active surveillance, they have a 3 Tesla MRI without an endorectal coil. Of the men who were upgraded, 32 of the 33 men that area that had upgraded, the upgrading was found within the lesion on MRI. So three centers of excellence, three well done studies suggesting that maybe MRI’s should be useful for guys that are on surveillance now. Should they get it how often, can you obviate the biopsy, and these are all questions worth asking that require a prospective analysis.

What about MRI for staging and operative planning? I think the two big ticket items that MRI is not as good as we had all hoped, the patients need to understand this. I mentioned one earlier. It tends to underestimate the tumor volume, and then the operating characteristics for looking for ECE, seminal vesicle invasion, not great. So if you are going to get an MRI before radical prostatectomy, do not hang your hat on the MRI suggests or don’t suggest ECE and make your nerve-sparing decision solely on that.

I do think the pictures can be useful, but integrated into all of the other information you have about that guy before you go to the operating room. This is a study out of UCLA where they did MRI’s before the prostatectomy. They whole mounted all of the pathology, and as you can see here the blue is basically identifying it or detecting an MRI, and the orange is missing it. So it doesn’t project great, but as the tumor diameter gets bigger, the more likely you are to see it on the MRI.

As the Gleason score gets higher, the more likely you are to see it. The index lesions are far more likely to be seen than non-index lesions. And what about predicting ECE? This is sort of a caution. A well done study at a center of excellence that had been pioneers in MRI of the prostate, so nearly 200 men that underwent a radical prostatectomy, they all had an MRI beforehand, 50% had ECE. And look at that sensitivity in the negative predictive value. So I would argue that you should not be making your nerve sparing decision solely on your MRI.

MRI actually does a decent job of picking up gross ECE, sort of macroscopic ECE. It does a really poor job of picking up microscopic ECE. So a UCLA study that was done on MRI’s and how it impacts nerve-sparing, the short summary of this is it changed the plan for nerve-sparing in about a quarter of the patients. But I would echo what was mentioned in an earlier session. You have no idea if that change was a good thing or a bad thing. So the MRI might have told me I am not nerve-sparing on that side, I am going wide, but you might have just resected a guy who was organ confined on that side and took his nerve with it.

So unfortunately without erectile function data as an outcome which wasn’t reported, you don’t know if that change in plan was ultimately good for the patient. Here is a well done study, a randomized controlled trial of using MRI before prostatectomy. Over 400 men getting a robotic prostatectomy randomized to no MRI versus a 1.5 Tesla MRI, and the positive margin rate was no different on whether they had an MRI or not.

Now, a subset analysis which was not the primary analysis suggested that amongst low stage patients, perhaps it was useful in decreasing the rate of positive margin. Kudos to these investigators for studying it, but again unfortunately there is no erectile function data. And just because you’ve lowered the positive margin rate doesn’t necessarily mean that was a good long term strategy for that man.

I’m running out of time and I want to be respectful of the others, so I am really going to whip through the rest of it. MRI is useful for predicting continence and basically the urethral width and the urethral volume can be useful. There is a bunch of studies that suggest that urethral length could help predict long term continence. I am not aware of anyone that gets an MRI that measures the urethral length and then says, oh, your rate of continence is going to be so low you shouldn’t have a prostatectomy.

And then lastly, but importantly, there is an MRI-guided treatment with many different ways of doing this. We are in the very early stages of developing it. We have participated in a couple of trials. We have done a phase I and a phase II of in the MRI machine putting lasers into regions of the prostate that have important cancer and MRI lesion, and the rest of their prostate looks healthy. The laser basically heats up and ablates that area. We have shown it is safe, we have shown that the early data, the primary endpoint is 96% of the guys no longer had cancer in that region of the prostate at three months when we biopsied it. I have no idea what the long term outcomes are going to be, but I’ll be happy to shout it out whether it’s worthwhile or worthless down the road.

It’s basically safe. We have proven that there is a very low rate of side effects from it, but from an oncologic standpoint, it’s unknown. There are people doing MRI TRUS-fusion focal cryo. There is not great data published. There are great PSA responses. This is a study where they didn’t do any follow-up biopsies, so you sort of shrug your shoulders as to what is going on within the prostate.

Here is a trial, a phase I study, and this is transurethral ultrasound ablation in the MRI machine. This was a safety study that basically showed it is safe. The median treatment time was about a half of an hour. That is just the time ablating the prostate. The total treatment time is significantly longer on the order of three to six hours of spending time in the early learning curve of trying to do this technology.

Now remember how long the first lap nephrectomy took, the first lap prostatectomy, and maybe we will get the times down. For most men, there is no impact on the quality of life; however, a beacon call in this phase I, and remember phase I’s aren’t meant to look at oncologic outcomes, but after this treatment, 30% of the men continued to have clinically significant cancers within their prostate. And this is whole gland treatment.

So in conclusion, hopefully you will agree with me based on the data I’ve showed you. I skipped ahead. The bottom line is that MRI can be helpful. There are significant limitations to it. Use it wisely, and get feedback within your own institution. We have dreamed for years about imaging prostate cancer. In the last 10 to 20 years we are now able to do it much better.

Updates in Brachytherapy

I want to do an update on brachytherapy very quickly. I have 20 minutes. This is one of the major options for treating prostate cancer. There is good data to show that brachytherapy is being chosen less frequently, and fewer of our residents are being trained to perform this procedure, and this is not just because lower risk disease is less common, although that is contributing to it.

We used to do a lot of cases and now we don’t do that many, but we still do them. And when it’s done, sometimes it’s not being done appropriately. And actually there is some evidence to suggest that this might be one of the best treatments, and it’s probably more effective than some of the other treatments. I’m not going to talk about some of the technical developments and future directions.

So this is one of the recent studies that basically shows the trends and the percentage of patients. So you can imagine that if the absolute number of low risk patients and favorable patients with prostate cancer being diagnosed, this is even having a bigger effect. But this is the decline in brachytherapy. That is that second curve there. And in addition to that, this is a study looking at residents in training programs and what has happened. And both academic and in non-academic centers have shown a significant reduction in the training of residents to do brachytherapy. So I anticipate that this trend will continue.

And then if you look at how it’s being used, you can see at the bottom of this curve down here, these are the high risk patients. They are patients with high risk disease who are getting brachytherapy as monotherapy which may not be a good idea and is not in compliance with the NCCN guidelines. So, again, it is becoming done less frequently and not always done in compliance with the guidelines. And then you have data like this. This is from a very sophisticated analysis performed by Steven Frank and an economist from Harvard, or actually somebody from the Harvard Business School.

And they looked at brachytherapy, proton beam radiation, and radical prostatectomy, and using a validated quality of life instrument, here they are looking at one year, at the one year time point. And you can see that for most things, vitality and so forth, there are some differences but they are relatively small. But when you look at the overall treatment costs and the brachytherapy, there is a trend for brachytherapy that you really could argue is the best treatment for the money.

So that is sort of the background and moving us into where we are with respect to what is relatively new. This is data from our phase III randomized trial. We were attempting to evaluate whether or not the patients with intermediate risk disease really needed to get external beam radiation in combination with their brachytherapy. So the patients were randomized with favorable intermediate risk disease to external beam radiation with brachy versus brachytherapy alone. They had to have either a PSA between 10 and 20 or a Gleason score of 7 with a PSA of less than 10, so these are pretty favorable intermediate risk patients.

And traditional treatment, as you would expect, these are the characteristics of the patients. And there were 443 patients that were evaluable for five years, and this slide just shows the so-called futility calculation to show that we should stop the study and that we weren’t going to find anything different than was suggested at this interim analysis. And this is about toxicity and efficacy. So if you looked at the freedom from progression, the brachytherapy alone versus brachytherapy plus external beam radiation suggesting that there is no difference between the two groups.

And you could use a Phoenix [phonetic], you could use the old astro [phonetic], you could look at the metastasis and overall survival, and there really wasn’t a difference. Again, this is biochemical failure using the Phoenix definition. Favorable results; and the if you look at toxicity, the toxicity tended to be a little bit higher although not dramatically so when you add the external beam to brachytherapy. So this data may establish brachytherapy as the appropriate treatment in favorable intermediate risk patients based on the data from the randomized trial.

And that was really what the conclusion was. A little bit more toxicity if you add the external beam and no improvement in the patient outcome. Now the next question is, well, how does brachytherapy compare to external beam radiation. And many of us were already convinced years ago that brachytherapy would be better than external beam radiation. This is from an old study that we did some ten years ago looking at favorable patients, and we did a matched comparison of patients with external beam radiation versus brachy.

And our primary endpoint was really the PSA nadir and the MR spectroscopy finding, so you know that cancer tends to have high choline and healthy prostate has high citrate. And if you have an ablation of cancer and normal tissue, you get metabolic atrophy after radiotherapy. And we looked at the degree of metabolic atrophy after external beam versus brachytherapy. And it was much more dramatic after brachytherapy, complete metabolic atrophy versus after external beam radiation. And if we looked at the PSA level, the PSA, the median PSA, and this is with a short follow-up at five years, our PSA is less than 0.1., the median PSA after brachytherapy.

So, brachytherapy is much more ablative, but that doesn’t prove that the outcome is going to be dramatically better, but we sort of thought it was going to be better. And, again, this is a match comparison with the people from the PROTON [phonetic] trial that was published in the New England Journal of Medicine, 79 gray protons versus a permanent implant. And if you look at the percentage of patients who had a PSA of less than 0.5, the one are greater than one, even with high dose protons, the ablative effective of the prostate were not as impressive as a permanent implant.

So now we have a randomized trial. This is a Canadian trial, the so-called ASCENT trial. This is now dose escalated external beam radiation combined with hormone therapy. So they got a total of a year of hormone therapy, and they either got dose escalated external beam or they received a brachytherapy at implant. And these patients had either unfavorable intermediate risk or high risk disease. You can see that 40% of them at least in scores of 8 or above, 69% of them were NCCN high risk, and about 20% had PSA’s over 20. So these are unfavorable patients by and large, and a multivariate analysis was clear that adding the brachytherapy improved the outcome relative to any of the other endpoints.

And if you look at the biochemical control rate which is the primary endpoint of the study, this is again high level evidence that in terms of biochemical control, adding brachytherapy improves the outcome. But we are doing less brachytherapy, and it’s going to be interesting to see how this data affects the practice patterns. The data are actually more impressive than they look just looking at that curve. That was by the so-called Phoenix definition, so if you look at the biochemical control if you use a nadir plus two definition which is the standard definition with radiation versus a surgical definition with a PSA of greater than 0.2 with radical prostatectomy, you can see that compared to external beam radiation, the brachy patients had a much more impressive degree of ablation of the gland suggesting that this is just more effective at destroying the prostate and potentially the cancer as well.

And although it did not reach statistical significance and that wasn’t the primary endpoint of the study, there is a trend that suggests that the brachytherapy patients might actually live long enough, and if the trial were much bigger it would be likely to improve the overall survival. Again, so this is the only problem that the toxicity was a bit higher in the brachytherapy group. The grade III toxicity was somewhat higher, and at six years a persistent rate grade III of about 6%. Now there are opportunities to improve the brachytherapy in terms of reducing toxicity.

So the take home points are that the brachytherapy is being chosen less frequently, and the trend is likely to worsen because we are not training the residents to do brachytherapy much anymore, and that the people that are using it are sometimes using it inappropriately, but brachytherapy as a monotherapy may be a treatment of choice in favorable patients, that it is favorable to intermediate risk patients, and if you look at those patients that were included on the ASCEND trial, unfavorable intermediate risk and the high risk patients, those results would compete favorably with any radical prostatectomy series.

And I think they are a good treatment option for those patients with more advanced disease. Thank you for your attention.

Current Findings on High Intensity Focused Ultrasound (HIFU)

I’d like to review the current findings on high intensity focused ultrasound. And I’ll start by speaking on selection and outcomes for whole gland treatment, and we will then go into focal ablation, and then a few comments with salvage HIFU.

Regarding general selection criteria, the ideal gland volume is less than 40 cc with minimal calcifications that would interfere with the transmission of sound waves. As noted in the whole gland HIFU series, larger glands can be downsized with the pre-procedural TURP or neoadjuvant ADT, particularly to reach anterior lesions. The anterior lesions can be particularly troublesome at HIFU because of the longer distance from the probe, and also energy absorption by intervening tissue as well as some of the progressive edema that one gets during treatment.

Also, HIFU is a time-dependent treatment, and it works quite well for focal because you are treating a smaller volume. Post-treatment includes interval PSA, MP or MRI, but treatment success is ultimately defined by negative biopsies of the post-ablation zone typically done 6 to 12 months after treatment. The publish experience of HIFU for whole gland primary treatment for prostate cancer is derived from retrospective reviews at several large, international centers. And here you see the five largest published series, each including over 500 treated patients with long term follow-up as long as 14 years.

The selection criteria that was reported in the whole gland series includes good life expectancy, and greater than 95% of the cases in each of these series are T2 or lower except for the most recent report by Dickinson et al, whereby 15% of the cases were T3 lesions, but none were metastatic. And up to 14% of the cases in each series were Gleason 8 or higher. All series’ used Abotherm except for the one by Dickinson which used Sonoblate. You can note here the differences in gland volume. And this also has to do with downsizing with ADT or TURP. Preoperative ADT was administered anywhere from 13% to 59% in each series, and there was a wide variability in the use of preoperative downsizing TURP.

Two centers performed TUR before most ablations while the other groups in general did not. Oncologic efficacy is measured with post-treatment biopsies. Biochemical recurrence, the need for salvage intervention and survival; the definition of biochemical disease free survival was based on the Phoenix criteria for most of these reports. Regarding biopsy, there was a wide variation in the number of patients undergoing post-treatment biopsy ranging from 32% in the Dickinson study up to 83% in the Uchida series.

The rate of positive biopsies in these five series ranged from 13% to 47%. Patients that required salvage therapy was typically less than 20%, although it was reported to be as high as 34% in men with high risk disease who were treated. Cancer-specific survival was greater than 97% in all series who reported on this outcome. And it’s worth noting that overall survival in the Munich series that comprised 78% of men with intermediate high risk disease features was comparable to the general male Bavarian population during the same study period.

So overall, as you can see here, we had a very favorable low PSA nadir. And in terms of functional outcomes, preservation of erectile function in preoperatively potent men ranged anywhere between 25% to 55%. Regarding continence, Dickinson et al reported that 88% of the patients free before treatment remained so in similar fashion after HIFU. Reports of grade II or higher incontinence was limited to less than 5%. The Sebastian and Crouzet and group reported the placement of an artificial urinary sphincter in 3% in a male sling [phonetic] in 2% of the patients.

Regarding complications, the most reported complication was bladder outlet obstruction, and including bladder neck contracture, urethral stenosis, and this occurred in up to 28% of the cases. Fistula occurred in less than 0.7%, and it was associated with early treatment here and also repeat procedures, and the need for secondary interventions endoscopically was as high as 24% to 30%.

Regarding primary focal ablation according to a recent consensus meeting published in 2015 on focal therapy, all risk categories can potentially be treated focally. However, in the case of low risk patients, it should really only be due to the patient refusing active surveillance or feeling uncomfortable with it, also perhaps the patients who drop out of active surveillance due to psychological factors. Focal therapy can be entertained if there is a lesion to be seen and ablated.

For high risk patients on the other side of the spectrum, metastases were to be ruled out, and the sweet spot is the intermediate risk patient who were considered the best candidates, particularly for a targetable lesion that is present. And one of the principles is that potentially if the Gleason 7 is ablated, this can recirculate the patient back into the active surveillance pool.

As we heard this morning, mpMRI is the ideal tool to characterize the localized lesions fit for focal therapy. It’s important for treatment planning, size, location, suspicion score, and the proximity to critical structures. All lesions should be mapped out in a three dimensional space, and all radiographically suspicious lesions should be biopsied and confirmed before being ablated.

The quality, as Scott told us this morning, is also paramount. 3T is ideal. At Duke we use a three heat plus an endorectal coil. You need a good reader, and I will show you a study we did in terms of over-reading MRI’s. For the patients with a positive biopsy but a non-suspicious MRI, we performed transperineal-mapping biopsies, and I know the UCLA group does as well. This is done through the 5 mm grid template; it has a very high fidelity for localizing clinically significant cancers.

There is still no consensus, though, if multiparametric MRI can substitute for TTMB, which is especially used for, again, if there is no visible radiographic lesion. Again, mpMRI at this point is considered the best imaging modality for planning and follow-up, but there are a few downsides to this as well that need to be kept in mind. And this is from the FDA. They had a panel the other year, but the sensitivity is low at only 47%. And as was mentioned this morning, it tends to underestimate the tumor volume by 0.5 cc. There was a study in the Journal of Urology this past month that talks about a good majority of the volume may be missing with multiparametric MRI, even in the centers of excellence reported by the UCLA group.

Contemporary outcomes of focal HIFU ablation are derived from studies, and typically performed in trial settings many of which utilize hemiablation, just like the cryotherapy trials. The cohorts include both Sonablate and Ablotherm for the most part with one trial reporting on the use of a new focal one machine. There are eight published series of patients treated in the last decade with focal HIFU totaling 357 patients. The largest group is 111 from Rischmann, which represents a multi-institutional registry initiated by the French Urological Association.

Most limit to localized disease and less than a Gleason 3+4. The recent index ablation case by Ahmed et al included two patients with T3a disease. All other series were limited to T2 tumors, and there is a small subset of patients with high-risk disease included in three of these studies. Most include staging mpMRI with or without template biopsy, and then mpMRI reevaluation after treatment with re-biopsy again between 6 and 12 months following HIFU.

One of the benefits of focal treatment is that neoadjuvant hormones where pretreatment TURP is typically not performed in contrast to whole gland therapy. Now most studies presented here are based on hemiablation just like Dr. Jones talked about for focal cryo. Post-treatment biopsy outcomes were reported in seven of these series. Feijoo et al noted 84% negative biopsy rate in the treatment zone at 12 months with an overall negative biopsy rate of 75% when including out of field positive biopsies.

Rischmann and co-workers on the negative biopsies were greater than 90% in both the treated and the untreated lobes, and 14 men went on to curative intent HIFU surgery or radiation. Only one study incorporated the use of HIFU to target the index lesions reported by Ahmed and co-workers. They noticed a high positive biopsy rate at 42% because they were doing a very coned down treatment. Ahmed et al noticed that 15% had residual clinically significant disease in the follow-up biopsy in the treated zone with an additional two patients outside of the treated zone.

In terms of functional parameters, these series reflect the advantage of a focal approach for preservation of erectile function and urinary continence. Almost all studies report on preserved erectile function of greater than 75% in preoperative potent patients, and the continence rate of over 95%. The complications, urinary tract infection, retention, self-resolving dysuria and hematuria were the most common. There was a single report of a fistula that was thought to be a fistula that was successfully managed in a conservative manner. Endoscopic intervention occurred in 5% in Ahmed’s index ablation series.

This is an interesting report coming from van Velthoven’s group reporting the results of their hemi HIFU ablation technique, and they matched that to unilateral cancer in the patients who underwent robotic prostatectomy. This was a mass peer analysis and they were matched for Gleason PSA clinical stage, and all unilateral cancer. And they looked at the outcome as salvage-free therapy survival. They said it wasn’t significantly different between surgery and hemiablation. But the HIFU group did have higher rates of preserved potency and urinary continence.

Switching gears to salvage HIFU; as a comparison, whole gland salvage HIFU for radio recurrent prostate cancer has demonstrated short term oncological outcomes comparable to other modalities, but with similarly high side effects. Murat et al reported a progression free survival at three years, and 53% for low risk patients; 42% for intermediate; and 25% for high risk. Urinary incontinence was noted in 48%, and 11% of those men required the artificial urinary sphincter.

In terms of focal salvage cryo, Ahmed et al tried to spare the apex to preserve the external sphincter to potentially reduce incontinence. He performed salvage hemi or quadrant ablation in 39 patients, and demonstrated three year biochemical disease free survival in 63% with 64% of the patients being pad free, and 87% overall pad free. One fistula was noted. Baco et al delivered hemi salvage HIFU to 48 men following radiation confined to one lobe MRI. The progression free survival at 24 months was 52% and overall 75% of the men were pad free. Four developed bilateral recurrence, four had recurrence in the untreated lobe, six had metastatic disease, and two had PSA only recurrence.

This is a recent multi-institutional retrospective study on post-radiation salvage HIFU comprising 418 men which demonstrated good short term oncologic control with a cancer specific survival of 82%, and post-treatment PSA nadir of 0.19. That was achieved after a mean of ten weeks. And you can see at the bottom at seven years 82% cancer specific survival and 81% metastasis free survival. In the same study, Sebastian Crouzet and co-workers looked at factors associated with salvage HIFU failure and recurrence. And they found that the ones that were noted were a history of ADT use, pre-salvage Gleason score, and the pre-salvage PSA level.

A study from Shaw et al, this is published in July 2016 on salvage HIFU, showed that post-HIFU PSA nadir was the best predictor of overall survival. And, for example, the progression free survival when including all of the patients was 72%. You can see that here at one year, but when you look at only the people who responded, i.e. those that had achieved a PSA nadir, the progression free survival improved to 86% at one year.

Another recent prospective series regarding salvage HIFU also identified PSA nadir of less than 0.5 as reported in the previous study by Shaw et al was a significant predictor of biochemical relapse and freedom of survival. The five year overall survival was 88%, and the cancer specific survival was 94%. From a functional point of view, the latest salvage HIFU series reporting continence ranges ranging from 3% to 31% because a high rate of bladder outlet obstruction with one series demonstrating the need for bladder neck incision in 54% of the men.

The fistula rates ranged between 0.6% to 9%, and erectile function in general was worse following treatment. So, in summary, for whole gland there is a good cancer specific survival, but a high─ post-HIFU positive biopsy rate. High rates of bladder neck contracture that require intervention, and for focal ablation MRI is necessary. Short and midterm outcomes look promising, but longer follow-up in prospective trials are necessary. And regarding salvage ablation, PSA nadir is associated with biochemical relapse free survival, and we need better techniques to minimize some of these side effects. Thank you.

New Horizons in Focal Therapy

POLASCIK: So I was asked to speak on some observations of what may be on the horizon and provide a few insights for the future or the near future for focal therapy. And I wanted to focus the observations on four main areas; patient selection, technology and technique, follow-up, and then long term outcomes. Now, of course there is contention with each of these categories; however, the ICUD, the International Consensus of Urologic Disease, in 2015 put together several panels to try to reach a consensus on these issues.

So in the absence of data and long term clinical trials, we have to look towards consensus in an attempt to drive the field forward, so let’s look at patient selection first step by step. In the top row here are four different consensus groups that met in 2010, 2012, 2015, and in 2016. And let’s see how things have evolved.

So, the first one is the goal. In 2010, eradicate all of the cancer. So now in 2016, we are just going after the clinically significant cancer. How do we determine cancer? Back then it was mapping biopsy. Now, it’s MRI and systematic biopsy. What about mpMRI? Back then, only at centers of excellence; now, it is used whenever possible. How about biopsy suspicious lesions? In 2017, yes. Biopsy of non-suspicious lesions, yes, at least 12 cores.

Disease factors; back in 2010 we were treating for the most part low risk and some low intermediate risk disease. Now we’ve pushed that into the intermediate risk with, I think, 4+3 as being one of the higher grade cancers that someone would tackle. There wasn’t really any guidance on maximum size. Again, most were doing hemiablation back then, so as long as you are bleeding, one-half of the prostate didn’t matter, but now since we can see these lesions and measure the volume we do have some guidance of lesion size.

And in residual disease back in 2010, we didn’t tolerate any residual disease. Now we are much more comfortable with active surveillance and we think it is okay to watch the Gleason 6, and maybe even a couple of millimeters of Gleason 7 in select cases. Now, life expectancy were found in the major guidelines. And sexual function, we think it’s important to preserve that, but that is not the only reason for doing focal therapy.

Now some of the pitfalls that we have today regarding patient selection is the 12 core biopsy. That used to be used to detect unilateral disease for hemiablation. The problem was the specificity was 34%. This then progressed to the transperineal template mapping biopsy, has a great detection rate. It is invasive and you need an operating room for the most part. So today this is all progressing again to the MRI and effusion biopsy. But it’s reader-dependent. Fusion has many moving parts. It has a high negative predictive value, but I think most people feel that you still need some systematic biopsies in addition.

Now this is a study that we did at Duke, and I know Scott Eggener made a few comments this morning about extra capsular extension. So the purpose of this study was to look at extra capsular extension for preoperative planning whether it be nerve-sparing surgery or focal or whatever you are going to do with that, and this shows ROC curves. And the first one down here looks at just clinical tables like the – – tables for prediction. And then what we did was we added on top of that, we layered on top of it, standard multiparametric MRI, standard read by a radiologist.

We gave a little bit of a modest improvement. We found when we have a really experienced leader who really looks for these things, looks at these with interest; we push the ROC curve above 0.91%. Fusion biopsy, again, is dependent on many moving parts, the quality of the reader, the fusion process, and also some patient factors. And this just gives you an idea of using the – – what needs to happen, so you can see the outline in magenta of the MRI with the lesion.

But the first step is to keep moving the surround, so the first step is you have to push this up, then you have to push it down distally, and then there is too much pressure with the probe on the right. You can see it’s being tented up here, so you have to drop the pressure off of this and then finally it’s not angled properly. So then we have to put a little angle on this just to fit this on. but you know there are a lot of moving parts to this and I think sometimes people get frustrated because they are not hitting the lesion and that has to do with the process.

But we have newer imaging modalities. The fusion process itself is fraught with many challenges, as many of you know. Not all lesions detected by MRI are cancers, but we are in need of better imaging modalities. Who wouldn’t want antibodies directed to the prostate cancer target, and here is one right here, a Gallium 68. It’s been shown to have an increased specificity when linked to PSMA and combined with multiparametric MRI.

These newer imaging agents will lead to substantial improvements to image-directed diagnostics and therapeutic interventions. And then as many of you know as well, urologists are very versatile when using real time ultrasound, so it would be nice if we could give that back to the urologist and devise what is called multiparametric ultrasound. Some of us have been working on this for some time. This would save substantial time. It would obviate the fusion process, and I think it would be much nicer.

So this is a schematic that shows an example of PSMA, PET MRI fusion in action. You can see here the top left, there is a dark area in the anterior fiber muscular stroma. There is increased vascularity in the middle one. And then you can see the very brisk wash-in, wash-out curves. You can see here in the fusion weighted it is very restricted. Then we do our PET image. You can see your target. We fuse it with the multiparametric MRI. I mean that’s beautiful, and I think that is where it’s headed, at least for fusion, okay.

Hybrid PET MRI scanners have enabled functional and molecular information to be combined. And the Gallium 68 PSMA PET signal combines with special resolution of mpMRI to create nice fusion biopsy platforms. Here is an example of a small study by Storz looking at histologically confirmed prostate cancers from seven suspicious cases. And they found cancer in six of them. And then in a separate study, Rowe et al looked at a different agent. This is a different tracer, 18F-DCFBC CT-PET combined with MRI fusion, so this gets a little more complicated.

But they reported sensitivity that was decreased compared to mpMRI, but the specificity improved for higher grade disease. And these are just two examples of newer types of marker agents that are soon to be incorporated with imaging and fusion biopsy. The other approach is to not use fusion.

And this is one of the items that we are working on in terms of multiparametric ultrasound. This is called ARFI, Acoustic Radiation Force Impulse imaging. It’s very similar to elastography, it looks for tissue stiffness changes. You can see that the lesion here in the ARFI mode, you can’t really see it in standard B-mode, and then you have the whole mount corroboration here.

But I think that this is a way of doing it real time in the clinic with ultrasound. You have a wand with several different buttons you can hit. You can put maybe flow on top of it, you can use ARFI to interrogate stiffness, and there is no fusion process so you don’t have that as a potential pitfall.

This is a study that we did, and we compared it to whole mount radical prostatectomy specimens. Each patient underwent ARFI and then underwent multiparametric MRI.   And you can see here, so for the patients that had a high PI-RADS score of 5, ARFI is quite good for big lesions, it is 100% detected, nine out of nine. MpMRI was 87%. PI-RADS was four, ARFI found 85% of the larger lesions, and mpMRI was 56.

So for both of these modalities as the index of suspicion drops where the size decreases, this also drops off. Focal ablation technology, there have been a number of them. For cryo there are eight cohort studies reported. Steve Jones talked about the COLD registry this morning. HIFU has four cohort studies. Laser has a phase I and II, and you’ve heard about phase III from VTP this morning. IRE is in phase I and II, and then there are other ones. There are new ones coming up almost every day, brachy, SBRT, and nanoparticles, etc.

The field is moving towards more focused treatments. Here are four schematics of the focal therapy. However, as you all know, cancer is a cellular disease and there are studies now that mpMRI cannot reliably determine the actual boundaries of the tumors. We talked about that earlier. And it cannot detect some of the smaller lesions. So for really target ablation like the top left, and this is how the laser therapists treat, they are having some issues with incomplete ablation rates because the treatment area is too tight.

Most focal therapists now, they have kind of migrated from hemiablation and they are doing some kind of a form of a quadrant ablation at this point in time. In the absence of comparative trials, we looked at outcomes between preoperatively potent men treated with focal versus whole gland cryotherapy. This is a matched population based upon the COLD database that Steve Jones talked about this morning.

Now this one has 634 men. These are all low risk patients. The bottom line is there was a comparable oncologic control between focal and whole gland treatment. But the patients who underwent focal had higher erectile function preservation at 24 months. Now with cryo, the continence, the retention rate, and the fistula rate made no difference whether it was focal or whole gland.

We took the same scheme and then used an intermediate risk matched pair analysis. This is 200 men and when comparing partial to whole, biochemical progression free survival was not significantly inferior for partial gland ablation, but the sexual function as nearly doubled.

I think this is one of the new treatment options that we have going forward for focal therapy. Due to the ability of MRI to see anterior lesions, we now have what is called anterior ablation. This shows cryotherapy probes, there are four of them placed here through a grid. You can see the placement of the probes here on ultrasound. The schematic is down here, and you can see our ice edges right here.

Now we are ablating this whole top part. Nowhere is this ice coming anywhere near the neurovascular boundary [phonetic]. So I think this is an ideal form of focal therapy going forward if we can recognize it due to the benefits of multiparametric MRI. I want to make a few comments on treatment adjuvants. Everyone is looking for the Holy Grail to find an adjuvant that improves the efficacy of ablation and perhaps minimizes the effect on the neurovascular bundles.

There are a number of categories as you see here of potential sensitizers. Now, for an example, adjuvants can take the form of a thermophysical one such as altering the cell’s microenvironment seeing that ice crystal formation. Or you can combine different agents. These are two different ways of killing strategies such as chemotherapy and cryoablation. There are four curves here, cryo alone, chemo alone, combination therapy, and the bottom line is the combination of cryo followed by chemo, which is shown in the lower curve, is the most efficacious.

Now what’s interesting is the chemo is given two weeks after the cryo because they’ve done some basic science studies showing that VEGF tends to peak at that point. You have increased micro vesicle density and oxygen in the tissues, and that is probably the best time to give your chemotherapy. Particularly useful for agents that are used in the apoptotic zone, these are agents that can help push the cells into the death pathway.

It is at the edge of the ablated therapy that cells are most at risk to recover and can’t have cancer persistence. So you see here that you have TRAIL and TNF alpha. Nutraceuticals; vitamin D has been shown to be a cryosensitizer. You have here LNCaP cells, androgen sensitive, over here on the right are androgen insensitive. Here is your control group. This is vitamin D alone, kind of a slow fall-off. Here is your cryo alone, and then finally the combination. You don’t see any repopulation.

So there are two interesting things, so that worked equally well in the androgen insensitive cell line. Typically it’s harder to kill with cryotherapy and salvage men who have failed radiation because you get more androgen dependent cancers. And, second, the temperatures that were needing to kill are much warmer. This is -15. Most of the time for cryo you have to get down to -40, so we changed the temperature for cell kill.

Switching gears to follow-up, there are several unaddressed issues that need to be discussed. How we obtain sufficient quality and imaging to admit systemic biopsies at follow-up, I would say no. What is the necessary frequency in follow-up schedule for MRI, fusion biopsies, systematic biopsy, and what is the role of PSA. We talked about definitions in failure in the treated and in the untreated zone. And regarding markers, we have a long way to go. Clinical trials are needed. PSA alone doesn’t seem to be the magic bullet.

We have spoken about MRI and biopsy already, and just a point about retreatment. If we are thinking about doing it with focal, the cause of cancer persistence or recurrence in the treated zone can be multifactorial, but before you consider salvaging with more focal therapy, you have to make sure you can identify the reasons for the initial failure and then correct them.

The long-term outcomes; the slide is still loading. There are none. We need them. We need randomized trials, we need multifocal and focal therapy registers that are done in a standardized manner, so there is a lot that needs to be done going forward. Thank you for your attention.

Highlights from the 9th International Symposium on Focal Therapy and Imaging

I was asked to speak on some of the highlights of the 9th International Symposium on Focal Therapy, which was held this past June at Duke. This is a two and a half day conference and it’s a real task to cover everything in five minutes. So if you’re invested in a technology─ okay, I will do my best to cover some of the highlights because there are a lot of things that we can’t mention just because of time. So my disclosure is I teach and do research with cryotherapy and Endocare, and I have an RO1 working on the development of acoustic radiation force impulse imaging, and hopefully one day on the commercialization of the products such as that.

There are a lot of key events. The first day we all felt that we needed a teaching course, so we brought in some of our top international radiologists, urologists, and we sat down with urologists who wanted to learn how to read the MRI’s. We did that for a couple of hours. And then we did a hands-on training with fusion biopsies using the – – machine. It was a great session. It lasted almost the whole day, and I think a lot of the people got much out of it.

We then had two consensus meetings. Again, every time we have an international symposium, we try to address some of the burning issues in focal therapy. One of the sessions was on patient selection for focal and the area of active surveillance. And if you want to read about that, it’s in press, PCPD, and the other one was the current utilization of mpMRI in clinical practice. And I think Scott talked a lot about that earlier, and that has been published in the World Journal of Urology.

Patient selection; we try to deal with some of the real contentious issues. What do you do with apical cancers? That is a tough one for anyone who does treatment whether it’s brachy, HIFU, cryo, etc. How do you deal with the salvage patient, and what do you do with the high risk prostate cancer patient, the Gleason 4+3 is the ace. We talked a little bit earlier today about high volume Gleason 6. It’s usually the harbinger for Gleason 7 disease.

We had a nice discussion point-counterpoint biopsy, a nice debate comparing transperineal mapping versus TRUS actually by people in this audience, and then we had a nice debate by Hash Ahmed and Art Rastinahad looking at can we just do targeted alone or do we have to combine that with a systematic 12 core biopsy. We then had a whole panel of experts discussing as the next step multiparametric ultrasound. Is this hype or hope? And the moderators included a urologist, a radiologist, and a biomedical engineer.

We talked about ultrasound contrast, what can be done in an office setting, personal experience, using ARFI, and then Sanji Guy presented his study on very high resolution, 29 megahertz, microultrasound. So I think things are getting better. We did reach some consensus with patient selection. In terms of disease factors we felt that low and intermediate risk groups were appropriate. The sweet spot was 3+4, localized, away from neurovascular bundles, a PSA of up to ten.

In terms of volume we thought that 1.5 cc was a good target. You can do up to 3 cc if you are bleeding a whole lobe in hemiablation. And considering life expectancy, trying to preserve erectile function, and gland size in general is not a contraindication to many detect technologies, and neither is mild to moderate TRUS.

So we like to stir things up because this is a good forum to do that. If you are going to start doing new things, you have to have a discussion. So we looked at the potential role for multiparametric MRI in screening. We had an expert from Europe, Canada, and the U.S.A. So the conclusion was in Europe, I think they were open to it was mentioned earlier that things are very inexpensive. They have a cheaper version of an MRI for about 300 euros that can be done. They are trying to do this. The issue right now is they are working on optimization. They have to get all of their readers up to speed and all of the rest.

In Canada it was felt that no one of the biopsy naïve men, but up to some discord information, it sounds like a good idea. The problem in Canada is one of resources. Right now they don’t have enough and they have excessive wait times. And then in the U.S. the problem is the cost. It’s very expensive, so we figure, well, what can we do? It was talked about earlier that the DCE is not the most informative part unless you’re looking at recurrence.

What about if we did a biopsy-parametric as was discussed earlier? That may be one way to slow down the cost. Anterior tumors, as was mentioned before, I think this is a new entity. This is a new disease entity that can potentially be treated with focal. We had a number of trial updates that talked about a number of these different technologies. And then one of the best parts of this is that we had videos. You can see new techniques. Wow, here are just a few of them, multiparametric ultrasound in an office setting. Dave Crawford talked about precision prostate tumor mapping for focal therapy.

Jack Tay did anterior gland ablation. Larry Klotz, MRI guided TULSA, we heard about that this morning. Arnauld Villers, he showed us how he does effusion biopsy in five minutes from start to finish. Interstitial vapor therapy for prostate cancer; we had a gentleman that says he does prostate cryotherapy in the office. I think these are really provocative. The videos I think were really the best part, and then finally Arnauld Villers showed his video on anterior partial prostatectomy using the robot.

So what is new; – – DaVinci from Hopkins talked about his experience with robotics. I think we’re moving towards robotics. Maybe the human hand is not precise enough to get to the same location every time. We talked about 3D mapping, biomarkers, epigenetic mapping, PSMA targeted markers. We talked about follow-up, how it should be done. We had radiologists define radiologic success. We had pathologists defining pathologic success and failure.

I wanted to state that if you wanted to look at the meeting, you can still access it under Focal Therapy 2016. It was filmed by the SIU, and it’s available on their website if you want to see any of the podcasts. And the next meeting, Focal Therapy 10, will be held in the Netherlands on June 18-20. You are all welcome to come if you’d like. Thank you for your attention.

EASTHAM: So you can submit questions if you’d like. I will start since Dr. Crawford is here, and actually one of the videos that was presented. David, you have presented a lot on transperineal mapping biopsies and how those are incredibly important for appropriately selecting patients for focal therapy and the like. What are your thoughts on that versus multiparametric MRI, and what is done at Duke in terms of patient selection for focal therapy? We can start with that one.

CRAWFORD: Thank you. Well, you know, that’s a very good question. And this morning when I was talking I said that in every cancer that we treat, we stage it. We do a PET scan, CT, bone scan, everything, and in prostate cancer we sort of make life and death decisions based on random transrectal biopsies. So the next step is the anterior gland, and there are the people that are the MRI folks. And depending on who you believe and how great it is, I think it’s the people that are good at it, are good at it. The average person isn’t so good at it, in my opinion.

We have been doing these transperineal mapping biopsies, and so has Tom and other people, and there are various ways for a decade now. And I think we’ve done 1,000 of them and we find that it is the way to interrogate the gland. I showed you this morning. It’s as accurate as a radical prostatectomy.

Not everybody does it the way we do it. They lump them together; they’ll do this quadrant and that quadrant. And in the study that – – did that was presented this morning, and Mark, they did mapping biopsies. But, they did not do them the way we do them. That was one of the problems with that study.

If you do that, you know where the cancer is. That’s the hard part; a blade in it’s the easy part. You can cryo, lasers, this, that, one thing after another.

I don’t think you have to limit yourself to Gleason 6 cancers. I mean, that was the argument. Well, you’re doing all this targeted therapy, and then you’re treating Gleason 6 cancers that don’t need to be treated, anyway. That’s okay; at least you don’t have to follow them so carefully.

Then we got into three fours, the four threes, and the eights. Gary Onik, the guy who started all this stuff a long time ago, and who has been at this meeting many times, he was treating Gleason 8s. People were laughing at him, “You’ve got to be out of your mind doing that.”

If you actually know where it is—and Gary and Winston Barzell actually pioneered a lot of this stuff—I think that mapping biopsies, are – -, but they’re a pain in the butt.

Tom, what do you think?

POLASCIK: I agree. I did mapping and MRI for everyone, and this is the problem. Patients came in and said, “I want focal.”

I said, “Okay. Well, how confident do you want to be that we’re locating the cancer and we’re getting it all? And they said, “I want to be very confident.”

Then we go to mapping biopsy. Then we start finding all this stuff. Then they want surgery. Sometimes when you start going down that focal path, then they want surgery, then you’re thinking, Maybe I shouldn’t have done all that, because – – out anyway.

I think now we do maybe a of that. I ask them how confident they want to be. I think you should have probably 12 cores in the untreated area, at least.

Most of these failures—we know that MRI is going to miss anywhere from 5%–15% of clinically significant tumors. We know that. Unless you’re supplementing by biopsy, they’re going to come back.

MALE VOICE 2: How confident do you want to be before you recommend focal therapy? Do you just need an MRI with a targeted biopsy plus 12 cores? Or do you want a transperineal quadrant biopsy?

What’s your—Mr. Smith comes in. He’s had an outside biopsy, shows unilateral disease, an MRI that looks relatively normal—PI-RADS 1, 2. Is that enough information for you to say, “We’re ready to go to the operating room, and we’ll use some energy source to ablate half your gland.”

I’m just throwing this out.

POLASCIK: On the one hand, I like to be very confident for the patient’s sake. On the other hand, we’re trying not to do more biopsies.

VOICE 2: Right.

POLASCIK: But, I think these things are going to come back and bite us in the foot, at some point. The reality is we’re seeing short-term studies now—couple years. I’m interested to see if those reports are going to extend out five and ten years, because I think if they do, we’re going to see more cancers coming back, just because the biopsy wasn’t thorough enough, the interrogation wasn’t thorough enough initially.

MALE VOICE 2: There’s at least a couple of questions. The first question was: When you’re doing the anterior freeze technique that you demonstrated, or showed slides of, do you use the temperature probes to monitor the temperature anteriorly? And that’s done hopefully to prevent penile . Or what kind of monitoring do you do intraoperatively, specifically for the anterior freeze?

POLASCIK: The answer is no. I haven’t really seen penile numbness. I’ve done over 500, 600, 700 cases. I’ve maybe seen it a couple times. It’s more common in the salvage setting.

This anterior gland ablation is no different than whole-gland cryo, and I don’t normally monitor the temperature there.

I do put a thermocouple at the rectal wall at the rectal wall and at the apex and monitor the sphincter. Then I may monitor one of the neurovascular bundles just to make sure that stays warm.

MALE VOICE 2: Then the following question, we touched on a little bit this morning, but it has to do with immunology. Do you think the release of neoantigens—when you ablate tissue, however you do it—they said HIFU in the question, but I’m sure it’s released by other energy sources, as well.

How much of a role, if any, do you think that plays?

POLASCIK: Again, I’m a believer. It’s not just HIFU, but with any of the ablative technologies that you’re releasing antigens and you can harvest the immune system. I’m just not aware of anyone who’s figured out a real good way to do it at this point in time.

One of the HIFU companies came by within the last year and wanted to know if we, or anyone that I know of, has figured out what that holy grail is. I’m not aware of anyone.

Like I said, for cryo, I think the best we have right now is vitamin D, which is very easy. You get a vitamin D level, you load it up, and you don’t need to hit those extremely cold temperatures to achieve cell death. But for HIFU, I’m not aware of anything at this point in time.

MALE VOICE 2: When you use cryotherapy, do you use vitamin D outside of a clinical trial at this point?

POLASCIK: I  recommend it; whether patients take it or not is another.

MALE VOICE 2: [Interposing] What do you recommend just for folks that do cryotherapy? What do you recommend? What kind of dosing, and for how long?

POLASCIK: Vitamin D2 would be 50,000 international units. Or for vitamin D3, I think 5,000 a day is reasonable, and for several weeks. Most people, by the time you go in the OR schedule, it’s four–six weeks, so I think that’s a good window.

Most Americans are very low in vitamin D anyway, especially in the winter months. You’re probably just trying to get their levels anywhere near normal. I don’t think they’re not going to become super therapeutic around here.

MALE VOICE 2: I may have misinterpreted it, but in one of the slides you showed for focal ablation, there was still about a 50% erectile dysfunction rate. That seems pretty high for a focal therapy.

Is there anything that can be done, other than completely missing the neurovascular bundle, to make that rate better? It just seems like a high rate for a focal therapy.

POLASCIK: Yeah. If you look at all the series—I’ll speak on cryo—the rate for potency ranges between 60% and 90%, overall. Half of those men who are considered potent are actually taking oral medication. That’s been seen in multiple single-center series.

The COLD Registry is a little bit lower; I think largely because there’s no set way of doing it. You have many, many people doing it, some of which don’t really have the volume or the expertise. It’s kind of a big picture.

I think we’ve also tried to put warming rods outside the prostate at the vicinity of the neurovascular bundle, but that didn’t really work, because then you have a cold-warm interface. That wasn’t very effective for a cancer-control point of view. And it didn’t really do very much for the potency issue.