Talking Urology and Raiders of the Lost CRPC featuring Neal Shore and Ben Tran

Joseph Ischia: Hello, I’m Joseph Ischia, and welcome to another Talking Urology podcast where we strive with great enthusiasm to help doctors develop a deeper understanding of the literature to ensure we apply the right evidence to the right patient. And in this case, it’s about the new androgen receptor target agents in non-metastatic castration-resistant prostate cancer. I’ve just listened to the latest Rewatchables podcast, which if you don’t know, do yourself a favor and listen to them talk about all your favorite movies. Well, their latest podcast was on Indiana Jones and Raiders of the Lost Ark, so in this spirit we’ll be trying to steal the idol of knowledge about non-metastatic CRPC from the Peruvian Temple of complex medical literature and escape with the idol before being crushed by the massive boulder of doubt that occurs when comparing PSMA PET to the conventional imaging standard used in these studies. Now I’ll humbly consider myself the producer in this case, George Lucas, but without the beard but all the fascination of classic space operas. And today, I’m being joined by the medical oncology equivalent of Steven Spielberg, Australia’s own director of excellence, Dr. Ben Tran, medical oncologist in Melbourne at the Peter McCallum Cancer Center, and Walter and Eliza Hall Institute of Medical Research. And then of course, we need a Harrison Ford character a swashbuckling, wide brim hat wearing, leather whip toting international man of adventure, a roll ably filled by Dr. Neal Shore. He is urologist and the Medical Director for the Carolina Urologic Research Center. He’s conducted more than 350 clinical trials focusing mainly on GU oncology and serves on the executive boards at the Society of Urologic Oncology, and the Bladder Cancer Advocacy Network. Welcome Neal and Ben and thank you for joining us.

Dr Ben Tran: Great to meet you. I love the Rewatchables, Joseph, and I love Indiana Jones. So, happy to be Steven Spielberg.

Joseph: Excellent.

Dr Neal Shore: I have no right to be even in the same sentence with Harrison Ford but thank you very much.

Joseph: Oh, it’s a pleasure to have you both. Now let’s talk non-metastatic and by that, we mean almost certainly metastatic castration-resistant prostate cancer. Ben, can you start us off with a good old definition like we used to do in the old debating days.

Ben: We can keep it simple, Joseph. We can say non-metastatic means you don’t have metastatic disease, right? But we know that when we have this large group of patients, there’s definitely some patients who are castrate-resistant non-metastatic disease with very low risk and will have excellent survival without early introduction of systemic therapy. But for the purposes of this discussion, we’re talking about the higher risk non-metastatic CRPC, those patients who will develop metastatic disease soon. You know, the definition we utilize are the definitions and the eligibility used for the clinical trials we’ll be talking about bit later. So, PSA doubling time less than 10 months and no metastatic disease on CT and bone scan, which is very interesting for kind of our practice here in Australia where PSMA PET kind of dominates. But that’s the group of patients we’re talking about.

Joseph: And what about a PSA level? Is there a certain PSA they need to get to?

Ben: Well in most of the studies it’s a PSA above— it used to be above 2, now it’s above 1, that’s kind of our arbitrary cutoff. We know there are patients with PSA less than 1 who very, very aggressive disease. That’s kind of the criteria for the trials.

Joseph: Okay. Neal, about advanced prostate cancer patients, we’ve got to be getting into the low single digit percentages here. I mean, something a Simpsons character could count on one hand. Why did three different drug companies get so excited about this relatively small space?

Neal: Yeah, it’s a very good question. I think primarily when we get to castration-resistant prostate cancer, metastatic, with imaging confirmation, a disproportionate number of those patients come from the newly-diagnosed metastatic castration-sensitive whether low volume or high volume or their recurrent metastatic. But another significant percentage comes from our patients who we perform radiation therapy to or radical prostatectomy, and they develop biochemical relapse or PSA relapse. At some point, they get started on testosterone suppression and if they get imaged, they by conventional imaging, they don’t have positive results. Conventional imaging – CT scan, technetium bone scan, the PSA goes down the testosterone castration level is confirmed. But lo and behold, after a period of months to years, the PSA level starts to go up. Conventional imaging is again obtained and there’s still no positive findings. So as Ben said, they technically don’t have metastatic CRPC, but we really always knew they had micrometastatic disease. So, it was sort of an artificial construct created by us as healthcare providers. Nonetheless, you asked the question, these three companies designed very well performed global trials to look at androgen receptor pathway inhibitor drugs to see if it would make a difference in the outcomes for these patients primarily metastasis-free survival and then ultimately, overall survival.

Joseph: And Ben just did give us the guts of those large papers, what sort of benefits were we seeing with regards to metastasis-free survival and overall survival?

Ben: Alright. So, three companies, three trials, three drugs, right? All are next generation AR inhibitors were the PROSPER trial which uses Enzalutamide versus placebo; SPARTAN trial which I was involved in, Apalutamide versus placebo; the ARAMIS study, Darolutamide versus placebo, all generally the same eligibility criteria, PSA doubling time less than 10 months. There were still some subtle differences, the SPARTAN study allowed some pelvic nodal disease, whereas PROSPER didn’t. All randomized 2:1, so you do the drug, one to placebo and all aim to improve metastasis-free survival and overall survival.

So, we go through the trials one by one, the PROSPER study using Enzalutamide, improved metastasis free survival from 15 months with placebo up to 36 months, and overall survival from 56 months up to 73 months. That’s a hazard ratio of 0.73, a 27% improvement in overall survival. And that’s despite about 64% of the placebo patients going on to receive life-prolonging therapy. That’s PROSPER.

Then we’ve got SPARTAN, which is Apalutamide. That improved, MFS metastasis-free survival from 16 to 40, overall survival from 60 to 73, hazard ratio 0.63 so that’s 37% improvement in overall survival despite 84% of placebo patients getting life-prolonging therapy at their subsequent line.

And the finally, the ARIMAS study, Darolutamide improving MFS from 18 to 40 months, OS are three years because it wasn’t as mature, hadn’t had as prolonged follow up as the other studies. At three years, the overall survival increased from 77 to 83% with a hazard ratio of 0.69 with 55% of the patients getting life-prolonging therapies.

So, when you summarize those three studies, all agents improved overall survival by around 30%. But there were some treatment-related kinds of toxicities that we can talk to kind of at a later date, which some of the differences between the studies.

Joseph: Okay, we’ll come back to that in just a moment Ben. And one thing I really like about the SPARTAN study in particular was with their progression-free survival 2 which really, you know, can make sense. You’re putting some patients on placebo and some on an active drug, so it’s a bit unfair to judge them at the end of the first period because you’re going to put them on, as you mentioned, the life-prolonging drugs. But the thing that I really took away from that was that if you delay treatment because I think a vast majority of people get the active drug, they crossed over after the four months, which was the first point of reassessment, that they never catch up in their overall survival, so you’ve really missed an opportunity to cure those patients. And I think that’s why as urologists if we are looking after these patients just on their first line, androgen deprivation therapy, we need to be prepared to step them up. And if you’re not going to do it yourself, then refer them onto a medical oncologist who will, but we’ll come back to that issue. I think these are drugs that urologists can be involved with if they choose to.

Neal, just back to those trials, you were involved in the ARAMIS trial, were you involved in any other trials? And what were sort of the major issues you faced or challenges while performing these trials?

Neal: So, yeah, I had the good fortune to be on the steering committee and an author of both PROSPER and ARAMIS. I’ve worked a lot with Apalutamide, not on the SPARTAN trial but with many others. So, these are really three highly effective drugs and undoubtedly urologists should be comfortable in using all three of them. Some of the trials in these NM CRPC studies was having a patient who, for the most part, is asymptomatic sans their use of chronic testosterone suppression, and tell them we’re going to start you on a medication, and it may have some side effects, and it’s designed to decrease the risk of radiographic progression-free survival and/or death which is essentially a composite endpoint of MFS, metastasis-free survival. Oh, and by the way, you had to have a PSA doubling time of less than or equal to 10 months. So, it wasn’t just anyone whose PSA was going up. So, I think for some of my colleagues, it was, “Why am I going to start someone on a drug that could have side effects and is MFS really going to be correlative with overall survival?” But first, what we saw was there was a near two-year delay in MFS in the three studies, and we also saw great declines in PSA, actually it is very reassuring to patients and to many clinicians, but also delays tumor burden and all of the associated therapies for MCRPC. It was a great positive secondary endpoint, finding that all three trials had overall survival as well. Those were some of the issues. I’m really glad we were able to overcome it. Remember, just a few years ago, when the AUA Guidelines first came out, they had those six index cases. The first case, index case one, was an M0 or an NM CRPC patient, there was no Level 1 evidence for any treatment whatsoever. So here we are, a few years later, we have a proverbial embarrassment of riches, we now have three therapeutics that we can have a discussion with patients and their families about.

Joseph: So, Neal, are there any patients that you’re concerned that the results of the studies would be extrapolated to that it’s not suitable for? Maybe say, apart from the prolonged PSA doubling time, any regarding comorbidities or other aspects of a prostate cancer patients’ sort of state that you’d be worried about?

Neal: Yeah, it’s a really important question, right? That all the trials had the PSA doubling time of less than or equal to 10 months, but in all of their product information labels, were not asked to calculate a doubling time. You know, I’m a devotee to trial inclusion criteria. It’s pretty uncommon for me to use one of these drugs if a doubling time is significantly above 10 months, maybe 11 or 12 months, I might consider it but north of that I would have a hard time using it. I would continue to monitor the PSA. As it relates to adverse events, both SPARTAN and PROSPER did not allow in patients who had a seizure history or had seizure-lowering type drugs. Now, that’s a very, very small percentage. So, that’s one difference. In ARAMIS, they did allow for patients who had history of seizure. All the other inclusion-exclusion criteria are relatively comparable, but there were some differences in the adverse event profiles. There’s some concern that, you know, there’s different penetrations of the blood brain barrier. Some of the earlier phase Darolutamide data suggests in preclinical models –preclinical, mind you, that there’s less blood brain barrier penetration, and that may be consistent with its adverse event and safety tolerability profile, which has been published. ARAMIS versus SPARTAN and PROSPER, we see some differences in the level of fatigue. We see some differences in falls and fracture risk. We see differences in rash. It’s not tremendous. But these are some of the things that I think one would want to have a full-throated conversation with patients and their families.

Joseph: Lets pick up on the issues of the adverse event rates that you see in the trials, it’s something that you’ve spoken about before, Neal, and this is this exposure-adjusted adverse events rate. This is something I reckon we can miss very easily. Can you tell us more about this exposure adjusted rate.

Neal: Yeah, essentially, without looking at—well, if one can look at adverse events as an absolute percentage recording as opposed to the amount of time patients are on drug, and interestingly, what’s beneficial to all three trials is patients who are on drug, have a remarkably much longer period than they were versus the control, and when you account for that the exposure adjusted adverse event rate becomes less impressive as it relates to adverse events.

Joseph: Yes. So, these drugs are actually very well tolerated. What was the discontinuation rate of treatment in the various trials due to their adverse effects? Were they similar?

Neal: There were slight differences. In ARAMIS the discontinuation rate was about 10% in both the control arm and in the treatment arm. It was slightly higher in both SPARTAN and PROSPER.

Joseph: Ben, so take it away. It really is the elephant in the room when we come to this particular space is the sensitivity of PSMA PET scan. We’ve certainly had PSMA pandemonium here in Australia. They’re a very common machine and we’re thinking of adding it to the Australian Coat of Arms. So, Ben—

Ben: It’s often easier organize a PSMA than it is to order a bone scan, right? It just happens.

Joseph: It is.

Ben: It’s quick. It’s great, great data. And Joseph, I think you’re probably in a better place to discuss the use of PSMA PET at diagnosis to look for metastases before undergoing primary treatment, perhaps where conventional treatment hasn’t found what it needs to find. In the CRPC setting, the data is much more scarce. I do a lot of PSMA PETs in my CRPC patients because they’ve been sent to me with PSMA PET already. And if I’m comparing apples, I’d prefer to compare apples and apples than apples and oranges. We don’t have much data. There’s some data from a registry and castrate resistant registry that kind of Arsha Anton and I kind of run, which shows that in this small cohort that we managed to put together of around 90 to 100 patients where they’ve had PSMA PET and CT together, no one’s had a PSMA PET and bone scan at the same time now. We’ve just accepted this method is better. You’ve either done one or the other, not both. But in that group, about 43% of patients had the PSMA PET to detect metastases that were not detected on the CT. And also, within that group, about 10% would have been classified M0 if it wasn’t for the PSMA PET.

So, there is definitely upstaging of these patients. It doesn’t really matter. I don’t know if it really matters, kind of for purposes, maybe does for the regulatory issues and the reimbursement issues, but high-risk patients are high-risk patients, whether you find a 2 mm node or you don’t right. We know that from the PSA doubling time data that’s been well described through the Zoledronic acid and Denosumab studies. Once your PSA is less than 10 months or less than 8 months, your risk of developing metastatic disease and dying from prostate cancer increases dramatically.

Joseph: Okay. I think it’s a really important point though, is the funding issue. Do we need to be concerned about the fact that we’ve detected a met on PSMA PET from a regulatory perspective if we want to start these drugs early?

Ben: I think we just want to start a drug, right? And whether we can, just depends on the criteria that it’s been set by our agencies. Do we want to start a drug in the non-metastatic space versus in the metastatic space? I don’t think it matters as long as we start a life-prolonging therapy and if we start it earlier, it seems to be better.

Joseph: I agree. They’ve worked though, they worked post-chemo, pre-chemo, non-metastatic, they work upfront. Neal, can I just ask you, in your experience, now that we’re going to start seeing these agents used upfront in Titan, Enzamet and the like, what do we do when they get to non-metastatic castration-resistant prostate cancer and they’ve either been on those agents for a short period or may even still beyond that, what does this mean now when they get to M0 CRPC?

Neal: Yeah, that’s a very important question. Interestingly, as you mentioned, Titan, ARCHERS, Enzamet, Latitude, the STAMPEDE arms have brilliantly demonstrated that patients who present with MCSPC, whether low volume or high volume, monotherapy ADT is no longer adequate. It is no longer acceptable, except in some maybe rare exceptions. It’s combination therapy, which is the way to go ADT plus an ARPI or ADT plus Docetaxel. And then, the point of your question, over time, we know that resistance mechanisms develop and patients will eventually stop responding, and they’ll invariably develop resistance or castration-resistance. And I think it’s at that point where we have to look at different mechanisms of action with different drug targets. As Ben says, the more life prolonging therapies you can administer to a patient, they clearly do better, they live longer, they stay out of hospital, they stay out of emergency departments. And it just has to be done in a way that’s judicious and efficient. That’s the challenge in front of all of us who treat advanced prostate cancer patients.

Joseph: And what are the triggers for changing treatments, say, that you’ve started them on one of these drugs in non-metastatic CRPC, when do you stop it? When have they progressed because it’s not just PSA, is it? What triggers do you use Neal?

Neal: So, what we’re starting to see looking at a lot of the data from all of these trials is that small increases from nadir is really a red flag to increase your imaging. And you’re going to see imaging positivity earlier with small increases from your nadir because the nadirs tend to be so powerful, the PSA 50s, 90s are so good with all three trials. Once you start to get some increase up from the nadir, is a very important time to image. So, imaging positivity has always been an issue for starting a new therapy, of course, any sort of symptomatic deterioration. Historically, we’ve always said just PSA alone increase based on PCWG criteria is not necessarily a reason to move to another line of therapy. But as we have more therapies, we do a better job of doing genomic profiling, having the availability of having PARP inhibitors, the very rare but occasional use of a checkpoint inhibitor if someone has MSI high, and of course, clinical trials. Clinical trials are really, they’re so important and of course in Australia, you do an amazing job of that. And then, we have the other well-accepted life-prolonging agents, whether it’s a radiopharmaceutical in the form of radium 223, whether or not it’s a Docetaxel or Cabazitaxel. And now, there are really exciting data from ASCO, the Landmark Phase 3 VISION trial. Of course, we already saw a glimpse of the effectiveness of antibody or radioisotope conjugates with the marvelous large phase two trial known as TheraP, which came from you know, Michael Hofman leading that effort in Australia.

Joseph: Absolutely. Shout out to the guys at Peter Mac. Ben is one of the inspiring lights there, so that’s some great work coming up. So, one final thing I want to chat about is, Ben, you’ve chatted passionately about the differences in the effect on the cyp enzymes of the various drugs, do they differentiate and how they may interact with other drugs? Is there a distinction?

Ben: They certainly do. This is an area that I love talking about. I don’t know why, but I do. So, drug-drug interactions is the key, right? So, these drugs they induce the liver’s CYP3A4 enzymes which by and large metabolize most of kind of many existing drugs. And so, these include proton pump inhibitors, the direct oral anticoagulants, some antiplatelet agents, cholesterol-lowering agents, it’s a long list. I remember, in the early days, one of your colleagues, Joseph, started a patient on Enzalutamide. He said, Ben Enzalutamide has made his reflux worse. Now, the Enzalutamide didn’t make his reflux worse, it made his Nexium less effective and therefore his reflux worsened, so these are things to be aware of.

Joseph: I’m just impressed that you noticed that his reflux was worse. Gee, good on you urologist.

Ben: The patient called you know, So, using these drugs, you might have less effective concomitant medications for these other issues, and therefore, maybe you get an increase in non-cancer related issues. And then therefore, maybe you get an increase in death from non-cancer causes. I’m thinking back and forth, I’m thinking, “Well, we didn’t see that in the late CRPC studies. But maybe that’s because patients don’t live long enough in that setting to die from non-prostate cancer causes.” We haven’t seen it so much in the hormone sensitive setting, but then I’m thinking maybe in that setting that patients haven’t been on ADT yet. They haven’t been on ADT to develop these ischemic heart diseases or other kind of comorbidities yet. And so, you’re not seeing this effect the non-cancer deaths, but in the non-metastatic space, they’ve been on ADT long enough to get some comorbidities, they’re needing those medications to keep them in good check. and if you’re reducing the effectiveness of those medications, maybe that’s going to cause some issues in a small minority of patients.

Ben: Neal, you might want to jump in here, that Darolutamide— of the three, of the Enzalutamide, Apalutamide and Darolutamide, Darolutamide might have the least effect on inducing these enzymes and probably therefore, the least effect on kind of reducing the effectiveness of these other medications. What do you think, Neal?

Neal: I agree with you completely with all of your points and keep in mind that the NM CRPC, the median age was about 74. I don’t know how it is for you, it’s probably similar. My patients show up and they’re on polypharmacy. I mean, they’re not on two or three medications, they’re on six, seven medications and I have to really rely very heavily on my pharmacist when I’m adding new therapies, because it can affect the bioavailability of an existing drug, as well as the ARPI that you choose. We did an indirect drug comparator analysis. Susan Halabi and myself, we presented that information at ASCO GU 2021 this year. Emphasis on that, it wasn’t a direct comparison but we looked at the published literature, and the DDI rate is decidedly lower with Darolutamide versus Apalutamide and Enzalutamide. But still, the three are excellent drugs, but I think that’s an important consideration when you have to look at a patient’s comorbidities and their medication list.

Joseph: Excellent. Well, thank you very much, guys, I really appreciate chatting about this topic. As I said, while it’s a small space, I think it’s it just goes to highlight how important optimizing treatment at every step of the way is. You can really miss an opportunity to improve the lives of men with prostate cancer. So, thank you and while we may not have been one of the great archaeological adventure movie productions of all time, I think we’ve explored one of the great wonders of the world in non-metastatic CRPC. So, thank you, Ben and Neal and I look forward to chatting again one day when we can leave our fare shores, catch planes and watch our international progress as red dots across an old-fashioned map. Until then and in the famous words of Indie himself, “If you want to be a good archaeologist, you got to get out of the library.” I’m Joseph Ischia. This has been Talking Urology podcast. See you later guys.

Outro: So that’s it for today folks. We hope you’ve enjoyed this Talking Urology Interview, we also hope that you’ve learned something new and will join us again next time. Take care and remember to send all feedback to joseph@talkingurology.com.au You can subscribe through Apple Podcast, or wherever you get your podcasts and check out the website at talkingurology.com.au. You can follow us Twitter at talking_urology where you’ll get all the latest news and notifications on past and upcoming podcasts.

You’ve been listening to Joseph Ischia, Neal Shore and Ben Tran. Produced by Joseph Ischia and Cara Webb thanks to an educational grant from Bayer.