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.