Dr. Neal D. Shore presented “Updating the Concepts of Biosynthesis Inhibitors and Anti-Androgens” at the 27th annual International Prostate Cancer Update meeting on Thursday, January 26, 2017.

Keywords: prostate cancer, biosynthesis inhibitors, Abiraterone, Enzalutamide, anti-androgen, PSA

How to cite: Shore, Neal D. “Updating the Concepts of Biosynthesis Inhibitors and Anti-Androgens.” Grand Rounds in Urology. January 26, 2017. Accessed Jun 2019. https://grandroundsinurology.com/updating-concepts-biosynthesis-inhibitors-anti-androgens/.



Updating the Concepts of Biosynthesis Inhibitors and Anti-Androgens

Thank you very much Tom, and good morning everybody. Let me just make a comment about that whole notion that Tom brings up of getting everybody together and avoiding silos. I do want to thank David Crawford, because it’s amazing that we’re here now in our 27th meeting of the IPCU, and he really was incredibly forward thinking in bringing together urologist and medical oncologists, radiation oncologists, industry, patient advocacy groups. They’ve always been here, and it’s easy to forget that. And I think it took a lot of our larger organizations some time to catch up to his vision, but they have, but it was years later. And that includes Society of Urologic Oncology (SUO), AUA, and Large Urology Group Practice Association (LUGPA). And so now we’re doing better things and we’re working better together, including government as well. So it’s a great advancement, so David has been really at the forefront of a lot of that.

A lot of the stuff I have today is an opportunity to first just go through some concepts that may or may not be familiar to many of you. Just a show of hands, how many in the audience routinely prescribe the novel oral agents, abiraterone, enzalutamide for advanced prostate cancer patients? So it’s only really about I’d say a fifth of the group. So some of the stuff for you who are prescribing might be very obvious to you, but some of it is a review.

So I just recently came back from doing three courses with the AUA, and we went through the advanced prostate cancer treatments, and we’ve done similar courses with SUO, and similar courses with LUGPA. And it really does show an ongoing thirst and interest in developing advanced GU oncology clinics. We started saying advanced prostate cancer clinics because as has already been shown, in 2010 until now we’ve had all these incredible breakthroughs. I would argue that the advanced prostate cancer clinic in any good center classically the model is the academic center, it will be an advanced GU/oncology clinic, and that will now include bladder and renal, and again to David’s credit, on Tuesday we had the first international bladder cancer forum here. But my task today is to review this. I want to thank Chuck Ryan for the next few slides, which he let me borrow, and we used these at our AUA CRPC course. And what you see here is sort of that classic algorithm, or that developmental physiologic dependency of the endocrine pathway and the hypothalamic pituitary gonadal access. And as has been well documented. We saw in the 40s Huggins does bilateral orchiectomy in 66 he gets a Nobel Prize. And for many, many years that was pretty much it. And many of us who trained realized that we were really in a desert for treatment up until Dan Petrylak pioneering presentations in 2004, and the approval then of docetaxel, and the rest is all familiar to many of us. But along the way we looked at the BA cooperative group trials and estrogens, and the oral formulations, 1, 3, 5 mg had efficacy, but a very high risk of cardiovascular and thrombolic events.

Interestingly, there are trials undergoing now with transdermal estrogen. We were just involved in one, but unfortunately, they closed to some poor accrual, but it’s something to keep in the back of your thought process that transdermal estrogen probably does have efficacy, but estrogen is somewhat of an orphan drug, but may actually have a role in the future looking at value-based propositions and economics. But for now it still needs further trial development.

So the ADT strategies, as Tom has done a brilliant review, it was really quite remarkable, looking at the evolution of the LHRA agonist and the GnRH antagonist, the leuprolides and degarelix and their impact now in terms of achieving same ADT results, and getting rid of the typical psychological morbidity of undergoing testicle removal. But then again, we probably could talk about in the panel discussion the cost/benefit ratio of bilateral orchiectomy versus prolonged use of the ADT pharmacological strategies. And something we also may want to talk about too is other developments along the way, such as oral GnRH antagonists, and what would be the role for an oral.

So then we get to the newer concepts. So abiraterone, which I’m going to talk more about, as well as enzalutamide, highlighted in red. And what this slide really tells you if we’ve had the classic endocrine pathway, and it wasn’t until the last couple of years that we’ve really started to recognize that why do these patients fail. ADT in and of itself in metastatic disease is not curative, but fortunately for the majority, the overwhelming majority of patients it puts the disease into remission or stabilization. But then ultimately, what are the other pathways? And so we have the paracrine pathway, or the adrenal androgen biosynthesis, which further stimulates prostate cancer cellular proliferation. And then ultimately the androgen receptors. And we started off with the first generation anti-androgens, they’re familiar to everyone, bicalutamide, flutamide, nilutamide, which were partial antagonists and ultimately had a partial agonist effect. And then development of enzalutamide. We also have on the heels of enzalutamide, we have other phase 3 trials that are in development, include apalutamide and ODM201. These all both oral agents. Additionally on the abiraterone side, and – – commented as well, we have other selective lyase inhibitors looking at potential value in various mutational aberrations as well.

The good news about talking about oral agents, especially for urologists, is that they tend to be a little bit more user friendly, at least theoretically. But one thing that shouldn’t be lost is the fact that the AR, the androgen receptor is pretty remarkable in that, and fortunate for us, or for all of us that treat advanced prostate cancer, is the ubquitousness of the AR. And much like in metastatic renal cell, we have VEGF receptors, which also has been wonderful in terms of the development of advanced renal cell therapies. It’s a little bit of a challenge for our bladder patients. We don’t have that ubiquitous receptor or marker yet. So but that may be changing as well. But have to be thankful for the AR.

So this is some great work that was done years earlier by Bruce Montgomery in his lab and others. And what you can see here, and this is a complicated slide, but what you can see ultimately is the classic pathways where you see ultimately other examples of where we could be doing the work that we are doing today, looking at glucocorticoid, steroidogenic receptors, as well as the classic canonical pathways that we see changes or targets, drug-able targets in the AR. But then there are also the non-AR dependent pathways as well. So some of the excitement that we’ll be hearing more about in the future meetings are PARP inhibitors and PIK3 pathways as well, back to our pathways, which are very promising.

But for review and update, as for the title of the presentation, looking at abiraterone, which has really changed so much. The first oral agent approved in the CRPC space, CYP17 inhibitor. And one of the things I think is just a basic thing for many of us who maybe wanting to be getting into this space, and we learned this in our classic adrenal physiology is the three S’s, and where a selective coenzyme inhibitor at the C20 and C17 lyse and hydroxylase levels, where you could potentially have downstream effects. And so it’s really not so much the up, increase in aldosterone, but it’s the pre-mineralocorticoid effects. And so you can end up with sort of a pseudo con syndrome or primary aldosteronoma, and thus the reason for the physiological recommendation of a 5 mg BID prednisone, it helps avoid that effect.

Interestingly, we don’t see a dramatic change, but giving a physiologic dose of prednisone also prevents a hyperglycemic effect, and ultimately what we’re really trying to do is dramatically lower the androgens in this paracrine pathway, as we’ve already achieved it, and the endocrine pathway with traditional ADT choice. And thus, we can lower when a patients have T level of 50 nanogram or less getting them down to a virtually undetectable T level. So lowering those ligands that ultimately turn on the AR.

But what happens is, and this is really nice work done in a pre-clinical models. It’s been published by many others, and you can see the level of expression. Jim Mohler did some really work on this as well, looking at the over expression AR amplification. And so we really developed in a fairly short period of time the recognition that if you shut down the androgen biosynthesis pathway or the paracrine pathway on top of the endocrine pathway then you can get rather significant AR amplification and so that the receptor is still in play. And which goes back to what Tom was saying earlier, we had to change the nomenclature going from it’s not hormone refractory or androgen refractory, but it’s castration resistance.

So thus we have enzalutamide. And enzalutamide, you’ve probably seen this slide a zillion times but it’s actually pretty good, because we see where enzalutamide works as really a true more powerful complete antagonist, a drug-able target looking at the receptor within the cytoplasm and preventing the translocation to the nucleus, ultimately preventing the binding with the DNA, and subsequent transcription to the RNA, or translation to a PSA gene in protein, and thus ultimately regression of disease.

So I just put these up here. These are just really a nice summary of the enzalutamide as well as the abiraterone trial pathway. And we enjoyed participation in all of these trials. And what became abundantly clear is that this was going to really change the field significantly away from the historical concern about giving taxane-based therapy. And what’s interesting about that though is I could just leave it at that and say, okay, so great. But I’m going to show you some more data that actually things are turning around now, and as Dan pointed out, there’s now a renewed and vigorous appeal about giving taxane-based therapy after about 10 different large phase 3 couple of trials that all failed. So we went through presentations and – – year after year of all these failed couple of trials with docetaxel, but now we’re finding really great ways to use taxane-based therapy, whether it’s docetaxel or cabazitaxel in V7 variants and/or now in the androgen metastatic space. So just when we thought taxane-based therapy was though, it’s made a wonderful resurgence. And I think it’s great.

These are trials that just basically have been published previously, the phase 3 trials. And the COUGAR301, as well the AFFIRM, and what you see, it’s probably a little bit difficult to see from the back of the room, but on the left is the abiraterone trial looking at the RPFS, and the right is a little bit clearer, is the—and the RPFS and the OS, but they’re really both fairly comparable.

And this basically goes over the AFFIRM trial, the post chemotherapy. And we published this a little while back. And Howard Shure is the first author. It has now been said, there have been a lot of different analyses looking at Prentice criteria for updating PSA as a surrogate. We have some work that’s coming out in that as well. The problem with CRPC and PSA is PSA, as we all know, is a wonderful marker, post-prostatectomy. It’s particularly sensitive, even in post-radiation. But we do see a discordance often times in PSA elevation in the CRPC population and activity of drugs, so we might want to talk about that further in the panel.

This is the 301, which really was the first trial to come across using 1,000 mgs of abiraterone and 5 mg prednisone BID, which showed approximately 4 months survival of benefit. And as Tom pointed out earlier in the AFFIRM, which came out an interval earlier analysis, it was a shorter – -, at final analysis relatively comparable.

So you have these two vary active drugs, both given once daily. Abiraterone is given with prednisone twice a day by the label. Enzalutamide can be given with or without food. Abiraterone needs to be given in a non-fed state. And this is all according to label. So then the question was, okay, well we now have two oral agents, will there be great benefit to sequencing when one stops and will you just go to other one? How about combining them? And we’ll talk a little bit more about that and the trials that are going on in terms of this concept of combining these two orals and going with the theme of not just androgen deprivation, but with true androgen annihilation, as has been said by many others.

What this slide is really here to tell you, and the next one to follow, and this is just looking at abiraterone after enzalutamide. And one of the challenges with many of these studies is that the Ns in these are fairly small. But what you do see, and I’ll show you on the next slide as well, is that the PSA 50 or the PSA declination is rather timid, weak, and the median PFS is also rather short as well in these patients. And these are largely retrospective in a single institution. But they started to really get a flavor of what was going on. So is one better after the other, is enzalutamide better after abiraterone or abiraterone better after enzalutamide? My experience, it would be interesting to see what others think. But usually when you’re having the conversation with patients regarding going from one oral to another, they’re very happy to do that. The real question is, is it truly in their benefit, or are we just wasting time and would they be benefiting from another therapy, whether it’s a radiopharmaceutical or taxane-based therapy.

This is just some very, again, preliminary data, but again, the Ns in these studies are relatively small. Maybe a slightly better PSA 50 compared to going abiraterone to enzalutamide. And the thought process potentially here, although not clearly well defined, is that if you’ve completely, if you’ve really dramatically lowered all the circulating T from the paracrine adrenal pathway and the intratumoral pathway as well then you can hit the AR and essentially knock that out, and thus some of these studies suggesting that is a better pathway. But still, certainly not level one evidence to go with that recommendation.

So what about side effects and safety, and looking about picking your oral novel hormonal agent as opposed to the vintage agents? It’s still I think an area of great debate. And I’ll show you some thoughts on that in a second. With abiraterone and prednisone as opposed to prednisone alone in the COUGAR302, which also was the first oral drug approved in the pre-chemotherapy setting, that whole notion of pre-chemotherapy, post-chemotherapy has been recently somewhat turned on its ear by the PCWG3, seeing that we really need to think about lines of therapy and somehow move away from this artificial distinction of having had chemotherapy or not. And it speaks to the global concept of precision medicine. So CTC, LDH ratios, presence or not of V7, again, we need to get validated commercial assays in order to make these decisions.

But just looking at this and looking at some of all grades, versus the grade 3, 4, certainly with abiraterone because of the pre-mineralocorticoid elevations you can see hypertension. The drug is metabolized by the liver so you also can see a hypokalemic effects because of the pre-mineralocorticoid, hypertension and fluid retention. You have to use it with a certain amount of discrimination in patients who have significant heart failure issues. Here is the published presentation, the Lancet Oncology paper, Chuck Ryan first author, that all grades of fatigue. And we’ll talk more about that. But interestingly, abiraterone does not cross the blood/brain barrier. The AR signaling inhibitors do cross the blood/brain barrier, and so I’ll show you this data now, which many have been concerned about. This is the PREVAIL trial, which is the comparable trial the COUGAR302 in the pre-chemotherapy space.

The trial design is almost exactly the same, inclusion, exclusion criteria very, very similar. What you see here also is a level of hypertension, presumably it’s a mechanism of action that’s different. We do see this, not as profound as you’d see in abiraterone. There’s not a fluid retention, but it has a pathophysiology based on arterial development.

What was measured and noted was an increase in falls. And looking at the 32%, 35% again, not head-to-head trials. We are doing head-to-head trials looking at the fatigue issue. And I think this is something that sort of has come out in the real world experience of those us who are using the drug. Again, both of these orals are fantastic in terms of PSA declination when used in frontline. They both have delays in radiographic progression. They both have survival benefit. The real question is, how do we select the best option for patients?

So choosing abiraterone versus enzalutamide. No perfect answer to this. And so I think it’s a wonderful discussion. I offer in my clinic and when I’m not offering a clinical trial, which is 99% of the time I try to offer a clinical trial, but having said that, we’re looking at sometimes what’s the value of steroids? Keep in mind that in the abiraterone trials it was never against a pure control, they always used a 5 mg BID prednisone. If they have a rather significant baseline fatigue, it’s maybe perhaps the steroids are helping with that. Some concern regarding this mention of polypharmacy. Now one of the things is, and I’m not going to into a lot of detail, and for purposes of time, but there have been different drug-drug interactions between abiraterone and other drugs that have cytochrome P450 metabolism. You should be aware of that, as well is true of enzalutamide. So that there is a differential there. There’s also a little bit more data on abiraterone in its use in renal failure patients.   Neither is excluded for low-grade declinations in creatinine clearance, but still something to be concerned about. Again, for patients who have who have—who are perhaps elderly and have an increase, or you worry about their fall or the steadiness of their gait or other neurologic issues, perhaps abiraterone is a consideration. For enzalutamide, even though we’ve looked at work and we published this is European Urology, and I think Lenny Gomella is the first author on this, looking at prednisone, is that the incidence is actually pretty low, but nonetheless, it can occur. So maybe that for somebody who is a brittle diabetic enzalutamide might be a more advantage. And abiraterone, in the label you have to check potassium monthly, you have to check liver function tests every two weeks for the first three months. And so for somebody who lives further away that might be a challenge in terms of the lab monitoring. And again, for folks who have New York Heart Association risk for congestive heart failure.

So a little bit of a plug for this meeting, we had this two years ago in 2015 in St. Gallen. We have the second one is coming up in 2017 this year, and so we got together a whole bunch of folks to answer many of the unmet lack of level evidence one issues in advanced prostate cancer. So we published this paper literally two months afterwards thanks to the really enormous amount of work by Silka Gillison and Oralis Omalin, who is on here somewhere. This was about 57 physicians. It’s now been expanded this year to I think about 79 medical oncologists, urologists, radiation oncologists, pathologists, and we try to tackle and do a modified Delphi program to say what can we tell our colleagues out in the real world when we don’t have necessarily level one evidence yet and trials are pending. So I just have two of the questions that we asked two years ago. So I asked the panel, do you recommend abiraterone or enzalutamide as first-line therapy for otherwise healthy asymptomatic or minimally symptomatic CRPC patients in addition to ADT, prior to docetaxel, and this is, again, a global group. And you can see, 78% yes, and the majority. So that was rather overwhelming. But then the next question was, is it appropriate to extrapolate these pre-chemotherapy trials, the PREVAIL and the COUGAR302 to symptomatic patients which was not the inclusion criteria, and even back then 73% of the panel said yes.

There was another interesting question that’s on there is in the enzalutamide, in the PREVAIL trial they included patients with visceral metastasis and the 302 we didn’t. Similar question was asked to the group, do you feel it’s reasonable to extrapolate the results of abiraterone because in the 301 there was visceral metastases, and again, roughly 75% said it was fine to give it to patients with visceral metastases.

I forgot, they have it in here. My apologies. That’s exactly what, so I’ve just told you the basis here, so 79% said yes to extrapolating those results. That’s why this kind of conference is pretty good.

So complementary mechanisms of action enable the combination. There’s multiple large phase 3 trials that are ongoing now. Both sponsored by the companies that make either abiraterone or enzalutamide, looking at the combination to see if one is good if two is better. And there’s a lot of controversy about that, especially looking at the sequencing data. But we’re further looking at—so here’s the endocrine production issues, as well the paracrine polymorphisms, we talked about earlier, and ultimately whether or not there’s an opportunity to look at AR. So let me talk a little bit about that.

Here’s the ALLIANCE trial that Mike Morris. This is fully accrued. There’s a similar trial that has basically abiraterone in that arm A that’s the 3,001 that’s also now completed accrual, so these are interesting trials to see how they ultimately will pan out the combination results.

So it was already mentioned, we’ll talk more about it, is this notion of this ligand binding domain. And there’s a hinge here, as you can see that ultimately if this is really where all the action is taking place. But if this gets cleaved and you basically have this particular V7 variant, and there’s over 30 different variants that have been documented. You might think maybe it may even be higher than that now, upwards in the 50s, but the 7 and the 3 are the ones that have gotten the most publication, and the 7 for sure. It awaits potential commercialization this year. I think many of us are excited to see that, but ultimately we also have further work looking at the nitrogen binding domain which there’s some early phase trials going on this as well.

So I think Tom showed this a minute ago, is that when you—and Dan did as well, is that when you have these 7, and this great work by Emanuel Antonarakis at John Hopkins. This came out and was published in the New England Journal, that when you have the presence of V7 neither abiraterone or enzalutamide, these PSA waterfall plots that show you are likely to work. But there are exception, if you’ll notice. There are some exception, which is kind of cool. You might see some patients who are V7. You see these little exceptions in both sides. But by and large this is really moving towards precision medicine, and there’s really—time is not going to let me show this, but we have taxane-based data, both with docetaxel and cabazitaxel demonstrating that this is almost certainly the way to go for these patients.

And in this Hopkins study, which really—the print is sort of small. I hope you can see it in the back, but really what it shows is that when the presence of a V7 was there abiraterone and enzalutamide had a very unlikely success rate, both with measurement of PSA, PFS and response. So this interestingly led to a precision medicine trial that many of you are familiar with, it was a drug called galeterone, by Tokai Pharmaceuticals. And many of us in the room were involved in this. And so this was another oral agent that was somewhat of a combination of an abi/enza concept by having a CYP17 lyase inhibitor, direct AR antagonist, and then having some degradation of the receptor itself. So we we’re involved in two phase 2 trials. The drug is clearly active, very well tolerated, and so there was this 6 or 7 patients in the phase 2 studies that actually who had V7 based on the Qiangen Lab actually had a very good response. So on the basis of that the company went forward and did the ARMOR 3 trial as opposed to the earlier ARMOR 1 and 2 which showed its efficacy and tolerability. It was a 1:1 randomization. And they had to get V7 positive patients. So they had to basically look to screen like 1,300 patients to get roughly 120 patients. Unfortunately, the long and short of it is the data safety monitoring committee stopped the study about a two-thirds enrollment basically demonstrating a futility analysis.

So let me just kind of finish up here if I can spare a few extra minutes. Is on the TERRAIN trial which I’m proud to have PI’d on. We published this in Lancet Oncology. And we looked at for the first time, and we started this study literally at the same time the PREVAIL was started. And so we looked at the older generation bicalutamide in direct comparison to enzalutamide. Again, this was started, keep in mind historically, at the same time PREVAIL was started. And so you can see 375 men. A large phase 2 study, global trial. We looked at PSF as well as SRE and initiation of anti-neoplastic therapy, and secondary responses of PSA, and time to PSA, and safety.

The baseline characteristics very comparable between the enzalutamide and bicalutamide groups. The disease characteristics also very similar. I apologize for the upper line here on the KM not coming across, but what this tells you is knowing at the PFS is approximately a 10 month difference between the enzalutamide and the bicalutamide arm. And then looking at these factors of a proportion of patients with progression events, everything favoring the enzalutamide arm.

Additionally, look, here’s the RPFS. And then looking at the time to PSA progression, which is rather dramatic approximatively of greater than a year. Look at the PSA waterfall plots, on the far right is the enzalutamide, and on the left the bicalutamide. You can see some benefit in early use of bicalutamide, and I’ve had debates with folks saying well, let’s just use that first. And then let’s go to enzalutamide. Well, why go with—I guess my thought process is why would you go with an inferior mechanism of action drug? Well, the main reason is probably accessibility and cost.

So I’ll let you read through this, but we also look at our health-related quality of life, which is extremely important now, especially for payers, they want to see this in addition to our primary and secondary endpoints, and virtually everything favored the enzalutamide arm.

And thinking about AEs, we did see a little bit more of fatigue. You can see fatigue in bicalutamide. We didn’t see a dramatic increase in the grade 3 fatigue, but we did see more in the grade 1,2. And so the conclusions of TERRAIN trial, and it’s actually now gone into the—in for the label for enzalutamide is that the PFS was approximately 10 months greater. The PSA, you can see the marked differential there, the PSA 50, 82% to 21%. A little bit higher cardiac events at 5.5% versus 2.1%, so maybe some caution in patients who have baseline cardiovascular issues, but overall no new safety signals or concerns.

My final slide here is really just, and this is not exhaustive, but what makes me happy about this is that there are so many great things going on. This is an ATLAS trial looking at patients who had very high risk disease characteristics who are undergoing radiation and ADT, as well as apalutamide. And then ultimately, which is a new androgen receptor – – inhibitor. This is EMBARK trial for patients who have high-risk biochemical failure as well. We’re doing some immunotherapies in this area too that do not require ADT, which is interesting.

These are very hot trials right now in the M0 space. We could potentially talk about this and finding that window of the M0 patients, as you all know, there’s no approved therapy in M0 CRPC. The ARCHES, TITAN, and ARASENS, these should actually be placed back over here, which speaks to patients who have high-risk metastatic androgen-sensitive metastatic disease, looking at combination therapy with or without chemotherapy, depending upon specifics of the trial, and all three adding on you hear apalutamide, enzalutamide, and here ODM201. And some additional trials as well, so there’s a lot more to report in years to come. Thank you very much.