Optimal integration of secondary hormonal therapy into the management of nonmetastatic castration-resistant and metastatic hormone-sensitive prostate cancer — Presentation

DR SAAD: So thanks for the opportunity to talk about integrating secondary hormonal therapy into the management of nonmetastatic castration-resistant and metastatic hormone-sensitive prostate cancer. So it gives me great pleasure to discuss this.

So prostate cancer really is now looked at more in terms of clinical states of the disease when we’re talking about the overview of prostate cancer. And really when we look at the states of prostate cancer the metastatic CRPC state is really the only state where men will suffer and actually die of prostate cancer rather than with prostate cancer. And the way we’re viewing this now is to try to delay, or even try to avoid, having patients enter this state of prostate cancer, which is metastatic CRPC.

And although we have made great strides in treating metastatic castration-resistant prostate cancer over the last 20 years or so we have to admit that the advantages in overall survival have been relatively modest from the time of chemotherapy, where we’ve significantly improved overall survival. This improvement was felt for many not to be enough to expose patients to chemotherapy.

So it was critically important to find alternatives to chemotherapy, and this is where the hormonally-based therapies with abiraterone and enzalutamide came in in the post-docetaxel setting. And following this it was clearly obvious that we needed to go before patients got docetaxel, given the fact that many patients will never get docetaxel in their lifetime, we needed something to delay it, or even more important for many patients, to replace chemotherapy-based treatment. And so this was welcome news, very beneficial, and has really changed the way we treat advanced prostate cancer today.

Now we talk about nonmetastatic castration-resistant prostate cancer because this is an entity in where men receive hormonal therapy, or androgen deprivation therapy, after they’ve failed local therapy or as primary therapy for locally-advanced disease. And these patients we know precede metastatic disease for quite some time. And the definition is really quite simple. These are patients that have rising PSA with castrate levels of testosterone and no evidence of metastasis on conventional imaging. And I stress the conventional imaging because that is still the definition today, even though we’ve had a lot of exciting news in terms of using novel imaging techniques, the definition remains the same. If we don’t find something on conventional imaging, these patients are nonmetastatic castration resistant.

And how these patients are going to evolve we learned several years ago, and Matthew Smith and myself have co-led many of trials in the natural history of this state of the disease, that we did not understand when we published the first paper in 2005, but really in the placebo arm of this pivotal study we learned that really the best predictor of how quickly patients will become metastatic or die of prostate cancer was PSA doubling time. And we realized that this is a heterogeneous state of the disease, where patients with doubling times of 6 months or less, the majority will be metastatic within a year. Whereas patients with doubling times of over 18 months could take more than 3 years to develop metastatic disease.

And we learned with the subsequent study, in the placebo arm, that again PSA doubling time was the best predictor of developing metastases and dying of prostate cancer. More recently we’ve seen that even PSA doubling time is very predictive of death from prostate cancer in this nonmetastatic CRPC state.

So this was the basis of developing therapeutics that would make a difference in these patients who are at high risk of becoming metastatic. And the definition of high risk for these very important studies was a PSA doubling time of less than 10 months. And we stratified against patients who had a doubling time of less than 6 months compared to patients between 6 and 10 months in all of these 3 trials because it was important to figure out whether a subgroup significantly benefitted more than another. So SPARTAN using apalutamide, PROSPER using enzalutamide, and ARAMIS using darolutamide all showed very significant improvements in delaying the time to first metastasis, in the range of about 2 years, which was beyond what we had expected when we designed these clinical trials.

When we first reported the overall survival results it was still too early to see a difference in overall survival mainly because these patients don’t die as quickly as when they’re metastatic, but also because the placebo arms of these 3 studies were very aggressively treated at first sign of metastasis. But we did see already a trend towards an improved survival.

But what we did learn early on, and this is very important in my opinion, is that the time to resistance, the time to PSA progression, is much longer than when we treat patients in the metastatic castration-resistant setting, in the range of about 3 years or more in these 3 trials. Whereas in the metastatic castration-resistant setting most patients will start having PSA progression within about a year. So clearly this was very important because it I think confirmed the importance that hormonally-based therapies are more effective and patients respond longer when they’re treated earlier with a lower tumor burden.

When we look at health-related quality of life, which is critically important because you have to remember these are nonmetastatic CRPC patients who are generally asymptomatic because they have no reason to be symptomatic, and we saw that we did not have a reduction in quality of life even though we’re imposing treatment on these patients who feel perfectly fine besides their PSA rising. And if anything as the trial progresses and the placebo arms develop metastasis, we actually see a reduction in quality of life in the placebo patients compared to the treated patients. So I think this is critically important when we’re trying to balance quality of life with delaying metastasis.

This year at ASCO it was really very rewarding to see that all 3 trials, at the same time, in the same session at ASCO, reported the longer-term outcomes of these studies, which allowed us to look at overall survival. And these overall survival results, I think, went beyond what any of us could have expected. Just by starting earlier in the CRPC setting, prior to clinical metastasis, we improved survival in SPARTAN and PROSPER in the range of about a year. This is about a 3-fold increased survival advantage than what we saw when we treat patients in the metastatic CRPC setting.

And these patients, we have to remember, in the placebo arms of all these trials, patients received therapy very early in the metastatic CRPC setting. So regardless of that we still see these improvements in overall survival, which I think is strikingly important in convincing ourselves and the patients we treat that earlier treatment really does make a big difference, and that if we delay treatment these patients unfortunately will not get as much of an advantage as patients who are treated earlier in their disease setting.

Now we talked about nonmetastatic CRPC, but another very important and probably a larger pool of patients worldwide are patients who are metastatic and still hormone sensitive. So these are patients who can present with up-front metastatic disease or patients who are treated for primary cancer in their prostate and who eventually had a recurrence and where we discover metastatic disease. And why these patients are important is that overall these patients will rapidly progress to the mCRPC setting and eventually die of prostate cancer.

And why I can claim that these patients progress quickly to metastatic CRPC is based on multiple trials. And the largest contemporary study is coming from STAMPEDE, where the control arm was ADT alone. And when you look at the results of this study you see that ADT alone, the median time to mCRPC was only 11 months. And this is consistently found in the multiple trials that have reported so far in the placebo arms of mHSPC studies.

And also very disappointing is when we treat with ADT alone up front the median survival, even though we have a contemporary series where patients did have access to docetaxel, had access to novel hormonals in a large proportion, patients only lived 3 1/2 years. So that’s extremely disappointing in this metastatic setting, that even today patients are living a short amount of time when they’re diagnosed with metastatic prostate cancer.

So the idea here is if we hit these patients harder up front with effective therapies that are useful in the CRPC setting, if we hit them while they’re still hormone sensitive, can we further delay the time to mCRPC and improve survival? And so the first proof of this concept came from the CHAARTED docetaxel study, where they were randomized to getting docetaxel or simply ADT alone in the mHSPC population. And what this study showed is that yes, we have a very significant improvement in overall survival in patients with high-volume metastatic hormone-sensitive disease. But on the flipside, in the low-volume patients, we did not see any difference in improving overall survival.    

Subsequent to the CHAARTED study there was the LATITUDE study in high-risk metastatic castration-naïve patients, all up-front diagnosed patients. And here the long-term follow up showed about a 17-month improvement in overall survival in patients treated with up-front abiraterone rather than delaying therapies when patients became mCRPC.

There are updated results now coming out of STAMPEDE that showed in patients who are getting abiraterone on top of ADT continued to have long-term benefit of the up-front novel hormonals given to patients who are diagnosed with metastatic prostate cancer, in the range of over 2 1/2 years improvement in overall survival. And what the STAMPEDE group showed in the UK is that when you look at the overall survivals in patients treated with docetaxel, you see that over time the curves are coming together with docetaxel, whereas patients treated with abiraterone the curves continue to separate even in the long term, showing that this impact early on is maintained long term. And what’s interesting with STAMPEDE is that they showed that whether you are low volume or high volume you do benefit with a hormonally-based therapy like abiraterone, and I would assume with any other hormonally-based therapy in combination with ADT.     

Also importantly is when they compared the results of docetaxel and abiraterone in terms of quality of life you see that the docetaxel patients, as expected early on because of the impact of chemotherapy, their quality of life was diminished. But even long term they never seemed to really catch up to their baseline or catch up to the abiraterone-treated patients who were treated in the same timeframe as the docetaxel patients in the STAMPEDE trial.

If we go onto more recent studies with ARCHES that compared enzalutamide to placebo plus ADT in patients with metastatic hormone-sensitive disease. And this was a radiographic progression-free survival primary endpoint that reported recently, showing a very significant improvement in delaying radiographic progression-free survival in men treated with up-front enzalutamide compared to placebo in patients treated with ADT. So a 61% reduction in progression of the disease radiographically.

Importantly in the ARCHES study is that you see that patients, whether they had low-volume or high-volume disease, benefitted to the same extent, and they also allowed patients who had had prior docetaxel when they were first diagnosed with metastatic disease, and whether they had prior docetaxel or not seemed to benefit to the same extent. Overall survival, given these patients were, again, very aggressively treated in the placebo arm, the first analysis really only had 25% of the deaths required to look at the overall survival endpoint. And we see that they did not show a difference in the first analysis, but we’re waiting for the long-term results.

In terms of quality of life, again, these patients are well when they started this clinical trial, and they maintained the same kind of quality of life, showing us that we don’t diminish quality of life when we intensify treatment in the metastatic hormone-sensitive setting.

So importantly with enzalutamide in mHSPC we have another large clinical trial, this is coming out of the ENZAMET trial, showing that patients who are randomized to hormonal therapy plus enzalutamide versus hormonal therapy plus first-generation antiandrogens had a significant improvement in their overall survival. A 33% reduction in the risk of death in an all-comer population. So they did not distinguish low versus high volume, low risk versus high risk, and they included patients that were diagnosed with primary prostate cancer treated locally and then became metastatic. So these patients all benefitted from the addition of enzalutamide, especially in the low-volume group, and even in the patients who had primary nonmetastatic disease at diagnosis.

In terms of secondary endpoints, again very significant improvements in progression-free survival. The only endpoint that didn’t reach significance was combining docetaxel with enzalutamide up front, and here this is not recommended, at least at the time of this analysis, but we’re waiting for longer-term results.

Another study using apalutamide, the TITAN trial, very similar to ENZAMET, included all comers with metastatic hormone-sensitive disease. And these patients were randomized to getting ADT plus apalutamide versus ADT plus placebo. And again, strikingly, and this is very important, the repeated positive results of these multiple trials using novel hormonals showing again a very significant radiographic progression-free survival in these patients. And again, exactly the same as ENZAMET, a 33% reduction in the risk of death in these patients treated with up-front apalutamide versus delaying therapy when patients become mCRPC.

And again, importantly, patients regardless of age, regardless of disease volume, regardless of whether they were metastatic at diagnosis or developed metastases later, all benefit from the addition of a novel hormonal like apalutamide.

So in summary, in today’s era patients become metastatic CRPC through different pathways. A patient can present with a rising PSA after primary treatment, be exposed to ADT to treat that rising PSA, and develop nonmetastatic CRPC. And that patient will be exposed, ideally if they’re high risk, to apalutamide, enzalutamide, or darolutamide, and then they will progress to the metastatic CRPC setting. So you see the pathway to mCRPC is totally different than what we were used to until recently. And what those patients will need as therapy at that point will be either docetaxel or radium, but in some patients a switch of novel hormonal therapy. But ideally these patients continue to need to be put on clinical trials to continue to understand the disease that we’re creating and how best to treat it.

On the other hand, patients can have metastatic CSPC (castration-sensitive prostate cancer), be exposed to ADT, and at that point they’ll have the options of going to docetaxel, and if they progress to mCRPC, then in that case they should get abiraterone or enzalutamide, or in some cases consider cabazitaxel or radium. If patients got a combination of ADT plus abiraterone, apalutamide, or enzalutamide and then become mCRPC, then here the next line with available therapies would be docetaxel or radium or considering a switch of novel hormonal therapy.

So in conclusion, patients with metastatic castration-resistant disease, unfortunately, if we haven’t given them anything until that point, will still live less than 3 years even with the best available treatments. And most will begin to fail therapy and progress within about 12 months. High-risk patients with nonmetastatic castration-resistant disease will rapidly progress to the metastatic CRPC setting. And we have here an ideal opportunity to delay the true lethal form of prostate cancer, which is mCRPC.

We now have multiple amounts of evidence that AR inhibition is extremely effective for all 3 states, mCRPC, mHSPC, and nmCRPC, and we now recognize that patients will respond better and live longer when they’re treated early. So the new standard of care for patients with prostate cancer that are at high risk of death from the disease should include early use of novel hormonal therapies.

The question of sequencing I think is still a research question, but for now sequencing basically follows the same logic as we’ve always used for mCRPC when patients eventually progress.

I’d like to thank you very much for your attention.

Results of the Phase III HERO trial evaluating relugolix, an oral GnRH receptor antagonist, versus leuprolide for advanced prostate cancer

DR LOVE: What’s this HERO trial?

DR SAAD: The HERO trial is, I co-led that with Neal Shore. So relugolix is the first oral antagonist. So it’s really an alternative form of therapy for ADT. So this is the basic ADT. And so I had helped with the Phase I, Neal and I for the Phase II. And so this is really the Phase III that FDA wanted to see, to see if it was noninferior to leuprolide. So the intent was to show that we were at least noninferior to a standard of care ADT. Since this is an oral antagonist, how it’s going to react, patient compliance, and all the rest.

And surprisingly it did not only show noninferiority, it actually showed superiority in terms of controlling testosterone levels throughout the whole 48 weeks. And this is mainly because of the up-front first month of therapy where it was significantly more effective than leuprolide in getting testosterone down very quickly and maintaining it throughout the whole 48 weeks. So what we saw here is that within the first week T levels were castrate in the vast majority of patients. So even orally it acts as quickly as the injectable antagonists. No flare in testosterone. Very rapid decline in PSA. So really in terms of testosterone clearly there’s something very interesting there.

But the reason it was accepted and published in the New England Journal is because we had wanted to look at cardiac adverse events. And quite unexpectedly, even for myself, is that we saw there was about a 50% reduction in cardiac events within as early as 1 year between these 2 forms of ADT, which was really not expected.

And we had started to see cardiac events early on, even in the first 3 months. So something is happening when we give ADT to patients, and the amount of cardiac events was less in the relugolix arm than in the leuprolide arm.

It’s in the process of being looked at by FDA.

I’m very confident it’s going to be approved based on those results.

DR LOVE: What you just described is really amazing actually. What do you think’s going on with the cardiac?

DR SAAD: We have cardiac experts. I’m not a cardiac expert. I’m a simple urologist that does a lot of cancer. But it was a surprise to me. I was always a little bit skeptical of this whole cardiac issue, so is it FSH? It’s hard to believe the FSH story would be that profound so quickly. There are cardiac experts that say that there’s something going on with sometimes a plaque, the change in hormonal therapy or maybe the surge in testosterone.

There’s a whole cardio-oncology specialty that’s being developed that are very interested in trying to figure out what is actually going on because we didn’t expect to see that many events. And these are patients that most patients had cardiac risk factors. But these patients didn’t have a major cardiac event within 6 months of coming in. So these patients were not like on the verge of having a heart attack. They were diabetic, hypertension, so the standard kind of issues.

But there were some patients that had a MACE event in the past. And those are the patients that had the most amount of benefit. So patients who had a major cardiac event more than 6 months before coming into the study are the ones that had the biggest advantage of this antagonist. But even the ones that didn’t have a MACE did have a reduction in the risk of cardiac events.

DR LOVE: I mean just from a quality of life and also COVID point of view you would think that just being oral would be enough to want to use it.

DR SAAD: Yeah.

DR LOVE: I mean would you like to use it?

DR SAAD: Well depending on my situation, definitely. I mean I think one of the main factors, and this is not minimal, patients have to be compliant, right? I mean this pill has to be taken every day.

DR LOVE: Absolutely. Yeah.

DR SAAD: So it acts very quickly, but it stops acting very quickly. And this was another advantage if you want testosterone to recuperate, the majority recuperated within 3 months.

DR LOVE: Wow.

DR SAAD: Whereas the minority recuperated within a year of stopping their leuprolide. So within 3 months almost no patients had recuperated their testosterone with leuprolide, whereas the majority had already recuperated with the oral. So if you want a fast recovery because you’re giving radiation or a short, fixed amount of ADT, there could be a big advantage for a young patient who wants to recover the fatigue issues and the sexual issues with ADT.

DR LOVE: I mean I can only imagine. Some of these drugs that cause dysgeusia in people stop it for the holidays, but maybe they stop their relugolix for a vacation or something.

But just a couple other follow ups just to what you said, one thing I wanted to clarify, in the hormone-sensitive metastatic trials of enzalutamide, the 2 trials, if I understood it correctly, would they allow the doc to decide whether to use docetaxel in both of those? And then they randomized after that? Both of them did that?

DR SAAD: Exactly. So there was a slight difference. In ARCHES they had to have finished their docetaxel, and then they were allowed to come into our ARCHES and be randomized to getting enzalutamide or a placebo. What ENZAMET did is that they allowed the physician to decide if they wanted to use docetaxel, but they were getting it at the same time, so in combination.

DR LOVE: Right.

DR SAAD: So they had to just decide, by the second cycle they have to decide if they’re going into the ENZAMET trial. So they were allowed to have started, but it was really in combination as opposed to having completed and then sequence with enzalutamide.

DR LOVE: So I don’t know whether either of these trials would inform on this question or whether there’re other trials, I think there are, that inform on the question of combining docetaxel and hormonal therapy versus say either one alone.

DR SAAD: Right. So there is the ARASENS trial is looking at ADT plus docetaxel versus ADT plus docetaxel plus darolutamide. So it’s really addressing the doublet versus the triplet approach in patients who need docetaxel. So it’s a bit different, and it’s powered to look at that question. In the ENZAMET trial it was left up to the investigator to decide whether to use docetaxel, so it wasn’t planned ahead of time, so it’s really a subgroup analysis of those patients getting docetaxel in the ENZAMET trial.

Perspective on the benefits of early initiation of secondary hormonal therapy for patients with prostate cancer

DR LOVE: I think first of all when I think about some of the global kind of macro points that you were making, I think the most important thing that really hit me, the way you presented it, on earlier versus later use of hormonal therapy.

So can you kind of go through that?

DR SAAD: So it’s my pleasure because it’s been my obsession over the last 10 years since I’ve been involved in these trials, is trying to convince myself before I try to convince anybody else that earlier is better. Because earlier is more expensive. So even though it’s a pleasing thought that anything you do earlier should lead to better outcome, we need to prove it.

So when we actually looked at the trial with abiraterone in the chemo-naïve setting, when we published the final analysis, we looked at the subgroups of patients, and you saw patients with no pain at all, patients with lower PSA, patients with lower alkaline phosphatase, all had better survival advantages than the other groups of patients with a little bit of pain, higher PSAs, or higher alk phos. So this was our first impression within the mCRPC state, that earlier was better.

But the kicker was really the nonmetastatic CRPC, where you’re getting that concept to an extreme. So they are CRPC. They are CRPC that are metastatic. I’m the first to admit if you have a rapidly PSA you have metastases somewhere. It’s just not enough to capture it on our conventional imaging. But it’s a concept of low volume versus high volume. And so that study that showed that you can delay metastases for so long that you delay PSA progression for so long. So we basically triple the amount of time that you stay sensitive to these drugs; went from 1-year PSA progression in the metastatic state to about 3 years in the nonmetastatic. And so you can ask me why.

DR LOVE: That was my next question.

DR SAAD: Well if we have less tumor burden biologically, we probably have less hormone insensitive clones to deal with. So if we hit those clones that are sensitive harder, and we get them to die or stay in quiescence, they should stay that way for much longer. And that’s what we saw. And we see it today. You take patients with widely metastatic disease and you give them hormonal therapy they don’t respond very long.

Whether it’s first-line hormonal or these novel hormonals, it’s just the fact the more you’re advance the less time you’re going to respond because if you let them progress too long, to a burden that’s impressive, you develop a lot of AR mutations. You develop a lot of disease that is more hormone insensitive, and you just don’t respond as long. Something that we don’t see with chemo. So chemo doesn’t look like it makes a difference whether you’re giving it earlier or later in terms of advantages.

And we did a subanalysis with the abiraterone metastatic setting, and patients who got it with lower PSA, with no pain, had a 1-year advantage in overall survival in that metastatic CRPC setting. Whereas the ones who started with a little bit of pain and a higher PSA only had a 3-month advantage. Both are statistically significant, but it’s much better to have a 1-year advantage than a 3-month advantage in overall survival. And so this concept of earlier being better, I think now is clearly shown, with the survival advantages that are tremendous. Even though the placebo arms did get very good treatment.

Role of immunotherapy for prostate cancer; optimal timing for the initiation of androgen deprivation therapy (ADT) for patients with M0 disease

DR LOVE: That model that you described with resistance, resistance mutations, et cetera, is kind of the one that’s out there, been out there in a lot of tumors. Where do you think the immune system fits in? Do you think it’s possible that the slower, lower burden is actually just a reflection of the immune system?

DR SAAD: It’s possible. It’s been a challenge. We’ve done a lot of clinical trials with immunotherapy in prostate cancer, and so far it’s been quite disappointing. The only positive one so for is with sipuleucel-T. It’s a complex process to get the sipuleucel-T. It’s really only approved in the States and used in the States because of all of the complexities. But I think we still have a lot to learn in the immune system in prostate cancer.

So when is the ideal time? I still don’t know. There are trials still ongoing to try and combine hormonal with immunotherapy because we might potentiate the role of immunotherapy, and there are trials going on right now in the metastatic setting. So you do need some tumor burden. I don’t think it’s going to be easy to show those advantages in the earlier setting.

DR LOVE: So let’s kind of focus in a little bit more on some of the data that’s come out related to these major questions, first looking at the management of M0 disease. Before we kind of get into the more recent work that’s been done on castrate-resistant M0 disease, any comments about the initiation of ADT? I guess traditionally people have used doubling times, for example 6 months, as a key factor. Do you still think that still falls into place that way? Is that the way you make decisions?

DR SAAD: Yeah, so those trials that came out of Hopkins years ago looking at the 3 components to help decide on whether or not to give early hormonal therapy are still very relevant. And I do use those — PSA doubling time is by far the most important to predict how quickly you’ll become metastatic in every state of the disease. So whether you’re still hormone sensitive, whether you’ve become castration resistant, it’s surprising just how powerful PSA doubling time is.

But in the hormone-sensitive state, in patients recurring after radiation or surgery, Gleason grade is still important. So I will use the Gleason grade, or at least a Gleason Score in combination with doubling time. So if it’s a very high Gleason Score, PSA, PSA doubling time I’ll use as an adjunct, but the Gleason Score is going to be very important.

Also how long after surgery or radiation patients start to show signs of recurrence remain important. Somebody who’s recurring within the first year of therapy gets me a lot more worried than someone who’s getting a slow PSA rise 5 years after surgery or after radiation. So I still use all 3 in combination, but by far the PSA doubling time is what’s going to trigger earlier use of ADT versus delaying ADT, especially in the elderly patient, where it’s not insignificant. And if they’re nonmetastatic we do a lot of intermittent ADT.

DR LOVE: I was going to ask you in the M0 situation where intermittent therapy fits in for you? How you do intermittent therapy? And do you do it, for example, in metastatic disease also?

DR SAAD: Okay. So let me address the second question first. In metastatic disease I still think the standard of care should be continuous ADT. So I will exceptionally stop ADT and do it intermittent in the metastatic setting because I think the risks of stopping the study that compared intermittent to continuous did show about a 6-month reduction in survival in the intermittent arm.

So I would be very cautious of doing it across the board. But there are select patients who tolerate ADT very poorly, that have an extremely good response, disappearance of metastases, PSA’s undetectable, that we can consider it. So I wouldn’t eliminate it, but de facto it’s continuous. And even now with the data that we have in the metastatic setting, we’re not only continuous but intensifying because of the high risk of death in these patients.

Now in the nonmetastatic hormone-sensitive setting recurrence after surgery or radiation my de facto approach is intermittent based on the PR.7 study that Canada led, helped with The States and Europe, showing that there was absolutely no difference in survival between continuous and intermittent. So except for the exceptional patient with a very high Gleason Score, where PSA’s totally unreliable, I will do intermittent and follow patients closely.

So how I would do it is very much like we did in the study, 6- to 9-month induction, and if PSA goes down very low, and when I say very low it has to go down to below 0.5, and then I will start again when the PSA rises to the baseline level. But if it’s rising slowly, I will usually wait for PSA to go to about 10 and then restart an induction. Once the off period starts to be anywhere in the range of 6 to 9 months it’s probably not worth continuing to do intermittent. We’re getting close to CRPC. It’s probably better to stay on continuous.

Phase III HERO study comparing relugolix to leuprolide for advanced prostate cancer

DR LOVE: Maybe this would be a good time to bring in the issue of relugolix, and the HERO study that you were involved with that was just presented at the ASCO meeting. Can you explain what this agent is and what was presented there, and what you see as its clinical implications potentially?

DR SAAD: Right, so relugolix is quite unique in the sense that it tries to combine 2 new concepts. One is an oral form of androgen deprivation, which until now doesn’t exist, and looking at the advantage of an antagonist, because we already have an antagonist. It’s an injectable. Unfortunately, it’s a monthly injectable that has its inconveniences in terms of injection sites reactions. So relugolix is based on very sound Phase I and Phase II data that showed that it looked to be very effective.

And so the Phase III was really to prove that it’s at least as good as what we use in daily practice, which is leuprolide, is one of the most commonly used forms of LHRH analog. And so this was almost a thousand-patient study randomized between relugolix or the leuprolide. The primary objective was to make sure that we were at least noninferior in keeping testosterone in the castrate range.

And surprisingly it was actually superior in keeping testosterone castrate over the whole 48 weeks of therapy. And we realized that in the first week testosterone plummets, even within 3 days of taking the pill. And so this was very informative because we couldn’t really predict whether an oral pill would be as good as the injectable that we know is very, very effective quickly. And it avoids the flare. And so that was the main reason for doing that randomized trial.

DR LOVE: And I guess the other thing we were chatting about before is what was seen, I guess unexpectedly, in terms of cardiovascular events. Can you comment on that?

DR SAAD: Sure. So there’s been a lot of excitement about the possible advantage of an antagonist in terms of having less cardiac adverse events related to castration, which we’ve known for some time could increase the risk of a cardiac event, especially in patients predisposed of having a cardiac event. So there was about a 50% reduction in cardiac adverse events in patients on relugolix compared to patients on leuprolide.

And this was surprising to us that these events happened so early. I think many of us expected this was a long-term effect of ADT, but very early on, even within 3 months, there was a separation of the curves. Which is still something that we’re trying to understand what is actually going on, especially in patients who have had a major cardiac event in their past. And so these patients are almost like a ticking timebomb, and it doesn’t take much to set things off.

DR LOVE: So if you put aside cost and reimbursement issues, if you could access this agent, would you use it? And in what situations?

DR SAAD: So would I use it? Absolutely, and I think it’s gotten a lot of excitement amongst urologists and radiation oncologists because of its speed of action, because of the advantages of an antagonist without the disadvantages of injections.

And as you mentioned earlier on, in this COVID era the less contact you have to have with either nurses, doctors, clinics the better. So definitely I would use it, especially if I want to do intermittent therapy because the speed of action is very quick, and the speed of elimination is extremely quick. So patients recuperated their testosterone, the majority, within only 3 months of stopping a year of therapy, which is unheard of with the analogs or the injectables.

So I think that’s a very strong advantage for somebody who doesn’t want to have the side effects for longer than they need to, and that’s everybody. And with radiation therapy there could be advantage in these short courses of ADT where you need it during the radiation, and you’d like to get rid of it as quickly as possible.

The only downside is that patients have to be reliable. I mean these patients need to take their pill regularly. But I think when we explain to patients the importance of what they’re taking they’re very compliant taking their pills, and the compliance rate was 99% with the oral agent in the clinical trial. So it can be done.

DR LOVE: Has relugolix been studied in the intermittent situation? Or have you used it, for example?

DR SAAD: Well the study was really intermittent. It was 1 year of exposure, and then patients came off study. You couldn’t continue. So then it was left up to the investigator to continue or not a standard analog. And so most patients that came onto the study were nonmetastatic. So many patients did stop. So that’s how we got the information of how quickly testosterone recuperates. And so yes, I have done intermittent with relugolix, and the nice thing that patients found was that they recuperated their testosterone really quite quickly compared to the patients who were on leuprolide.

Prevention and management of side effects associated with ADT

DR LOVE: When you begin a patient on ADT, regardless of the type of ADT, what are some of the complementary strategies that you employ, for example related to exercise, diet? What are some of the concerns you have in that regard in terms of prevention of problems, but also management of side effects. How do you prepare your patients, and what are some of the issues that come up?

DR SAAD: Okay, so that’s really a whole area that’s become very important, is quality of life in patients starting ADT. So I advise all the patients that fatigue is a major adverse event of ADT. So the best treatment we found so far for fatigue is exercise. So we give them an exercise program. We encourage them to be active. We encourage them to not succumb to this fatigue that sets in. We actually have clinical trials that we try to look at beyond just the fatigue issue; if we’re doing something to the cancer by giving them exercise programs.

The other aspects are bone health. So we will always give at least vitamin D and usually calcium to patients starting on ADT because we’re causing a profound type of menopause because of the bone loss due to ADT. And we’ll evaluate risk of fractures, and based on that we’ll give them either a bisphosphonate or denosumab to prevent. So if patients are at risk based on their BMD, or based on other factors that we can tabulate with a FRAX score, we’ll actively try to prevent them developing an osteoporotic fracture, especially if they’re going to be on long-term ADT. Not as concerned if patients are going to be taking only 6 months in combination with radiation therapy.

But what we’re realizing is that the fracture risk and rates are much higher than we expected because patients are living a lot longer on ADT, especially in the M0 population. And now that we’re giving them subsequent therapies, they’re staying nonmetastatic for so long that we’re seeing a high fracture rate that we have to work with to prevent these complications.

DR LOVE: Any thoughts about why exercise improves the fatigue in terms of the pathophysiology of the fatigue?

DR SAAD: I think any cause of fatigue is improved by exercise because it’s a vicious circle. If patients are slightly fatigued for any reason, and we see it postoperatively. I’m a surgeon. So if a patient stays in bed for just a few days, and we accept that, every day in bed in intensive care takes weeks to recover, when they’re completely immobile. So if they just start sitting around it really takes a big effort to overcome this fatigue. And I think we’ve shown — I think others that are much more experts in the field, muscular strength, respiratory capacity is all improved with activity. And if you’re becoming sedentary that fatigue just gets worse and worse and worse.

And this applies to enzalutamide, apalutamide, all the novel hormonals have a fatigue issue linked to them. And the best approach that we’ve found for that fatigue is exercise. And that’s been, I think, shown in very robust studies that have compared patients where you give them an exercise program versus patients that you leave them do what they want, and their level of activity, their level of fatigue, clearly gets better.

Impact of PSA doubling time on eligibility and outcomes of patients with nonmetastatic castration-resistant prostate cancer (CRPC) who received enzalutamide, apalutamide and darolutamide in the Phase III PROSPER, SPARTAN and ARAMIS trials, respectively

DR LOVE: So let’s talk about the M0 patient who has disease progression on ADT with a rising PSA. First of all, can you comment a little bit on — it’s interesting that the 3 key trials all use the doubling time of 10 months. Can you kind of go into, it looks like it really worked and made sense, though I kind of wonder whether they would have seen benefit even if it was higher, but kind of what went into the picking of that 10 months? And now that we have the data do you still feel that that should be what goes into clinical practice?

DR SAAD: Yeah. So the 10 months was not chosen out of a hat. It was worked with the FDA, and that’s why all 3 needed to use that. And it was largely based on the placebo arms of the clinical trials that Matthew Smith and myself had helped to run. So we learned a lot about the natural history. The first one was years before, that we realized that 6 months was clearly very, very bad.

So every trial showed that doubling time of less than 6 months was very bad. And then there was another trial that showed that really the inflection point was around 8 to 10 months. And so we had to find a number that was doable, and so 10 months was chosen, but then in every clinical trial, all those 3 trials, actually stratified between 0 and 6 months and 6 to 10. Because if only the 6-month and less group was benefitting, then we would have had to say you limit it to only doubling times of less than 6 months. But what as nice that all 3 trials showed that between 6 and 10 months you still get a benefit.

So your point is well taken. If we had gone up to a year, if we had gone up to higher, would we have still seen a benefit? We’ll never really know. The problem is if you wait for a doubling time too long it just takes longer to develop metastasis, and I think we have to honestly ask ourselves are we going to benefit patients to the same extent?

But what the FDA did not accept is an absolute PSA value. And this is where we get into trouble. If you wait for PSA to be at 20 to start thinking of looking at doubling time, and you’re looking for doubling time of less than 10 months, they’re all metastatic. And so that’s why if you look at the trials the absolute PSA values were in the range of 6 to 10 because if it starts going too high you won’t find the doubling time with nonmetastatic disease.

DR LOVE: So I would imagine age might factor in too. A patient in their 50s compared to in their 80s you might view it a little bit differently if they had a, I don’t know, 12- to 15-month doubling time, or would you hold off on therapy?

DR SAAD: Yeah. Yeah. And it applies even for the below 10-month doubling time. Somebody who’s frail — and in our Canadian guidelines that I’m responsible for, I actually put in that patients should have a survival expectancy of at least 5 years to really benefit. Because if you’re that frail maybe you should just be followed. But patients with anything more than a 5-year survival expectancy should probably be treated if they’re in the high-risk group.

Now if they’re not in a high-risk group, what we recommend is to maybe look for metastases with PSMA. And maybe those patients could have targeted therapy on a metastatic lesion or their local prostate, which could the reason why PSA is rising slowly. I don’t recommend PSA in a high-risk patient because I think it’s just a red herring starting to go after metastases that have bad biology. In those patients I really recommend the systemic approach plus or minus a targeted approach, but that needs to be in a clinical trial question.

Efficacy and tolerability of enzalutamide, apalutamide and darolutamide in the PROSPER, SPARTAN and ARAMIS trials for patients with nonmetastatic CRPC

DR LOVE: So could you talk a little bit about the follow up survival data that was presented this year at ASCO from the 3 trials and what your thoughts were when you saw that data for the first time?

DR SAAD: Yeah, so many people asked would we publish the trials of delaying metastasis to show us survival advantages. And personally my response was you’re asking for too much. These patients had a placebo arm that was treated at first sign of metastasis, which is not the real world. Who follows patients with imaging every 4 months and acts at the first metastasis to aggressively treat them?

In all the trials with metastatic disease they had a median of 10 metastases. Now we’re saying these are patients with 1 or 2 metastases, and you hit them with all you’ve got. So that placebo arm is an artificial placebo arm. It’s an aggressively-treated arm. So to expect an overall survival advantage I personally was not optimistic that we would see it. So when we saw that it actually was 3-fold better than when we treat metastatic CRPC patients all it did was confirm my impressions that earlier was better. And I think this was really the best example that treating earlier makes a huge difference and that by delaying therapy you don’t catch up to patients who are treated up front aggressively.

DR LOVE: I think it was also, I mean this is not the first time, but it was also an incredible endorsement of the way clinical trials are done, that all 3 of them had like the same hazard rate pretty much. You see this in a lot of PARP trials in ovary and stuff. It really shows you the way clinical research is being done, that you can get it that much.

What about the issue of the tolerability of these 3 agents, because it’s pretty hard to separate out? I can’t separate it out much in terms of efficacy at this point.

What about tolerability? I’ve heard actually different points of view. I’ve heard people say there are differences, although obviously it’s indirect comparison, and biology, clinical experience, and I’ve heard other people say I’m not so convinced of that. What are your thoughts about the relative tolerability of these 3 agents in this setting?

DR SAAD: Yeah, so we’ve all had good and bad experiences with every drug we’ve used. And it’s unfortunate if we blacklist any drug because we saw something happen. But when we look at the big picture, and that’s why we did, for both PROSPER and SPARTAN, we had separate specific patient-reported outcomes, papers in Lancet Oncology, for both. So I’m well placed because I was the first author on one and second on the other. So we spent a lot of time because this was an important point.

What are we doing to quality of life when we take very well patients and expose them to these therapies, for a much longer amount of time, because obviously they’re going to stay on drug for a longer amount of time? And it was very rewarding to see that we didn’t diminish, and if anything we improved quality of life as a whole because these patients on the placebo arm will develop metastasis earlier, will develop symptoms earlier. And so overall the quality of life were well maintained, and that was very reassuring because we did see more adverse events. That is undeniable. But these adverse events did not translate to diminished quality of life.

We have to remember, for people that are listening, what is an adverse event? It’s not a toxicity. It’s something my nurses pick up when they ask questions repeatedly. And in SPARTAN it was every month, in PROSPER and ARAMIS it was every 4 months. So they were constantly being asked how do you feel? Are you fatigued? And if they report once that something was going on, that’s carried over forever. And you have to remember that the placebo arms were only followed for about 11 months, whereas the treatment arms were followed for much longer, with a much greater opportunity to capture adverse events. And this people forget.

When you leave a study because you’ve met the endpoint, we don’t capture adverse events anymore. But if you’re on the active arm and you’re staying on 2 or 3 times longer, 2 or 3 years, well we’re going to capture adverse events. I have patients that are still on study for the past 5 years. They’re still seeing my nurse and capturing whatever adverse event they want to complain about.

Benefits and risks with enzalutamide, apalutamide and darolutamide

DR LOVE: I want to focus on the choice of these agents, putting reimbursement aside and just looking at the pure risk/benefit ratio, and particularly as it relates, again, to tolerability. Can you kind of contrast what you’ve observed and what we know about these 3 agents in terms of their side effect profile? And whether you, again putting aside reimbursement, you have a preference.

DR SAAD: Well I’ve worked quite a bit with all 3 agents, and I’m very comfortable with all 3. What I would recommend is that if somebody is comfortable with one, to continue with the one they’re comfortable with. Because I think the only time that I think we need to be maybe sometimes more concerned is in the very elderly patient, the very frail patient, where it doesn’t take much sometimes to unbalance the situation. And so in the elderly patient we’ll be more cautious because we’ve seen more fatigue, more falls in the elderly patient.

And when I talk about elderly, we’re talking about over 75, especially over 80. And patients were over 90 in these trials. So I think we need to just be cautious about when we introduce these therapies and to follow these patients after the first month. And not to worry about lowering the dose if they develop a side effect or an adverse event. Because patients who have more fatigue, my impression is that drug is probably a little bit too powerful and by lowering it from 4 pills to 3 often can help for the fatigue issues.

Now the only issue, and this is not a very frequent event, is somebody who’s at a risk of seizure. Somebody who’s had a seizure in the past or is at high risk of seizure, then clearly darolutamide allowed those patients in their clinical trial. So that would be the case where I would really choose one over the others, is in a patient who’s at a risk of a seizure that I want to start therapy in.

DR LOVE: Well I kind of heard another point of view expressed, and that’s kind of what I was trying to get to, which is, I’m sure you know what I’m getting at, which is the question of whether you get less falls, less fatigue, less CNS issues with darolutamide, and therefore there are people who feel it is preferable, how do you feel about that?

DR SAAD: Well like I said, I think all 3 are very well tolerated based on what we’ve done in the trials, based on what we’ve published, based on our personal experience. Yeah, and I have heard the same thing, that darolutamide might be better tolerated. It’s hard to really compare. We don’t have head-to-head comparisons, and I’m always cautious about saying that one is better tolerated than the other. It always depends also on how these adverse events were captured in the clinical trial. So I’m always cautious, but it’s true that at least what’s reported looks like maybe there are less adverse events with darolutamide.

But we have to remember, and I mentioned it up front, there’s a question of time of exposure. And the exposure time in the darolutamide studies are shorter than in the other studies. So I think the jury is still out, I’m very comfortable, and I will always repeat the same thing to whatever physician is asking about questions. Fortunately, for the vast majority of patients the 3 drugs are very well tolerated.

DR LOVE: So a couple questions about hormone-sensitive metastatic disease. Another surprise that I got, and again I’m sure I’ve seen it a hundred times but somehow it just hit me this time, if I saw correctly that in general the time to progression with just ADT is like less than a year, which I found shocking. When you think about starting somebody on ADT who’s never had ADT, you think years. It’s like 11 months. So again, your earlier versus later really smacks you in the face with that one.

DR SAAD: Yeah. And sometimes it sounds childish to repeat this, but what you’re saying is exactly — when I ask people how long does it take to become CRPC the response I get is 2 years. Those are historical data where we weren’t following patients the way we do today. But the fact is the majority of studies show, and this is even if you look at the TITAN data, if you look at the ENZAMET data, it’s in the range of a year. And the worst is the LATITUDE, where you’re taking all high-risk patients. It was actually 7 months to castration resistance.

So if you start enriching for higher-volume, higher-risk patients it’s even less than a year. If you take an all-comer population, it’s in the range of a year when PSA starts to go up and that you’ve become castration resistant. And so this is the reality. And when I wrote an editorial on the cost/benefit of treating these patients up front, you’re getting basically a year of extra survival by a year of extra therapy. That’s probably one of the best cost/benefit ratios I’ve ever seen in cancer. And it comes back again to the earlier. If you start earlier you might have the opportunity of hitting more hormone-sensitive clones and getting even more of a bang for your buck in terms of improving survival.

DR LOVE: And of course the toxicity’s way less than a lot of other therapies we have as well, particularly chemotherapy.

Outcomes with the addition of docetaxel versus abiraterone to ADT for metastatic hormone sensitive prostate cancer; impact of disease burden on therapeutic decision-making

DR LOVE: So another thing I think I heard you talk about, and again I hadn’t heard before, is I’ve always kind of been under the impression that in general in that situation, hormone-sensitive metastatic disease, that docetaxel was an equivalent choice in terms of benefit to hormonal therapy. And I thought I heard you question that in some ways. Did I hear that right?

DR SAAD: Well it’s hard to compare because we don’t have really head-to-head trials. The closest we have to head-to-head is in STAMPEDE, where they recruited about 500 patients in the same time period to docetaxel or abiraterone. And what we saw there is that clearly time to progression was better with abiraterone. Survival looked to be pretty similar. Except that when you’re looking long term, they’re realizing that the survival curves with abiraterone continued to separate over time, and this was just presented at ESMO. Whereas in the docetaxel the curves come together. And so the survival benefit looks like it diminishes over time. The hazard ratios are clearly better with abi than with docetaxel, so really the thought of hormonal therapy up front seems to maintain over time.

The patients that came into STAMPEDE, randomized to the docetaxel arm, are not reflective of the real world, where we looked at the Canadian statistics, and many patients don’t get their 6 cycles. So if you’re not getting your 6 cycles, you’re not even going to get to those kind of advantages that we saw in CHAARTED and in STAMPEDE in the real world. And so these things have to be considered.

And I do my own chemotherapy, so I’m very comfortable with chemotherapy. But I’m realizing that it looks like as time progresses that the hormonal approach looks like it’s at least as good, but probably better, than the chemotherapeutic approach. I still do chemotherapy for subsets of patients though. Patients that worry me in terms of AR activity. So patients who have large visceral metastasis, especially liver. Patients who have lower PSAs than I would expect, I think they need an aggressive approach, and I will give them chemo up front. And I will, when I can, immediately switch to ARAT after, very much like the TITAN or the ARCHES approach, especially if a patient doesn’t have undetectable PSA after he finishes his chemo.

DR LOVE: So I think it was in the CHAARTED trial when it first came out there was the issue of high- versus low-volume metastatic disease. Do you think that that is still a relevant factor in treatment decision-making? Do you consider it? And how does that affect what you recommend?

DR SAAD: Yeah. So when deciding on chemotherapy, clearly that is the driving factor. So any patient who does not have high-volume disease is not a candidate for chemotherapy in our center. So it’s within the high volume deciding chemo versus a novel hormonal therapy. And until the data came out with LATITUDE and now with ENZAMET and TITAN, the data is very, very convincing that all patients do benefit, and not only the high-volume patients.

High-volume patients, high-risk patients, I think in 2020 it’s almost unethical not to at least offer intensification of therapy. Giving ADT alone to a high-volume, high-risk patient I think is inadequate. In the low volume, low risk there are some patients that will be discussed, age, life expectancy, not giving them all systemic therapy. But in the high volume, high risk, clearly those patients need something. And for now I think ARAT is becoming the preferred choice in those patients except for a small subset.

DR LOVE: What about local therapy to the prostate in men with hormone-sensitive metastatic disease? Does volume matter there in that decision?

DR SAAD: Even more than the systemic therapy. So clearly patients that have high-volume disease, there is no evidence that they benefit from local therapy. Patients with low-volume disease, especially if they’ve got 4 metastases or less on conventional imaging, clearly look like they benefit, based on what was reported from the STAMPEDE trial again. That they had significant improvement in progression-free survival, but importantly they had significant improvement in overall survival.

The question that remains is, is it worth treating the metastatic disease with focal therapy, and should we be combining radiation to the prostate plus systemic therapy in those low-volume patients. My personal impression is yes, especially in a patient with a good life expectancy, but there we’re still trying to figure out what the best approach is.

DR LOVE: I’m assuming you wouldn’t propose surgery in a patient who’d had primary radiation therapy.

DR SAAD: Surgery rather than radiation therapy is not our approach at our center. We don’t have the data supporting surgery. The risks outweigh the risks from radiation to the prostate in a metastatic patient. We will do it in clinical trials, but outside of clinical trials I don’t propose doing radical prostatectomies in metastatic patients. I know there are some countries that are offering it to a lot of metastatic patients, and we’re trying to collaborate with them to capture their data. But I think in North America most would not operate on a metastatic patient outside of a clinical trial.

DR LOVE: What about the patient who’s had prior local therapy? So for example someone’s had surgery, now they have metastatic low-volume disease. Well there’s nothing to radiate I guess, right?

DR SAAD: Well there could be. Hopefully they would have gotten the salvage radiation before they were metastatic. But if they’re metastatic following surgery I would go with systemic. I wouldn’t really irradiate unless it was an oligo site. So if it was an oligo site in the prostate region picked up on PSMA with 1 other lesion, there could be a tumor board discussion about trying to hit those 1 or 2 sites. But outside of that I think it’s really systemic therapy is going to be the most appropriate.

Novel agents and approaches under investigation for patients with prostate cancer

DR LOVE: Just a couple other follow up questions. Anything that you’re anticipating in general, at ASCO GU this year? Any big things that you know might be presented?

DR SAAD: Well, there’s going to be data presented on combining abiraterone with apalutamide looking at the combined approach versus the monotherapeutic approach. So I think we’re all looking forward to hearing about that. Obviously, the other big area of excitement is PARP inhibitors in patients with homologous repair defects, or mutations. And so that’s very exciting, where now we have opportunities, and we’re starting to really get into I think personalized medicine where we’re basing our therapeutic decision on a prespecified biomarker. And I think we’re going in that direction. So I think those are the things that are probably most exciting. But at ASCO GU hopefully we’re going to consolidate more and more what we’re doing today.

I’m not sure we’re going to have much in terms of results with immunotherapy. That’s still being worked on. But I think what we’ve seen is extraordinary in prostate if you look at the last few years. I mean we’ve overtaken ESMO, ASCO —

DR LOVE: Absolutely.

DR SAAD: — in terms of prostate.

DR LOVE: It kind of reminds me, there was that other flare, I think it was about 5 years ago, with sip-T, enzalutamide, all that. Everything came in at once, and then it was quiet, and now it’s exploding again.

Anything in terms of PSMA-directed therapy or imaging that’s going to be coming up?

DR SAAD: Well, definitely in imaging there was a lot of stuff that came out over the last year. I think the imaging is being consolidated. We’re obviously all looking forward to the large Phase III study with PSMA ligand therapy with the lutetium PSMA. So hopefully the data will be mature enough to be presented in 2021.

I think we’re all very hopeful because the results so far that the Australians have shown in the third-line setting compared to cabazitaxel. It was presented showing improved results over a chemotherapeutic. I think it’s very, very exciting. And there are a lot of trials bringing this lutetium-based, or PSMA-ligand therapy, earlier rather than waiting until we’ve reached the end of the road, which makes biological sense. And so in Canada we’re running a randomized trial of PSMA-based therapy versus docetaxel head-to-head post novel hormonal, and then switch to the other when they progress, to be able to figure out what is the best approach and also the tolerability of going from PSMA-based therapy to chemotherapy and vice versa. So we’re going really in the second-line setting, which I think is where more patients are going to benefit.

DR LOVE: Are there any tolerability/toxicity issues there?

DR SAAD: Well, in well-selected patients it’s really well tolerated. But obviously if they’re limited in terms of bone marrow, if their renal function are limited, the toxicity that’s been reported so far, and that I haven’t seen personally so far in the treatments is the salivary gland issues. But that’s more with the actinium than with the radioligands with PSMA based. So there’s a lot of excitement in ligand therapy, and I think we’re going to keep hearing more and more about it.

DR LOVE: So one more question. You said there’s going to be data on abi plus apa?

DR SAAD: Yes.

DR LOVE: I’ve never even thought about that. What do we know about adding an antiandrogen to abiraterone?

DR SAAD: Well there was an Alliance trial that was reported about a year and something ago showing that combining abi and enza didn’t look like it was more effective than enza alone in terms of survival. So this trial completely recruited a long time ago in terms of combining abiraterone to apalutamide, so really hitting the production of androgens and the AR receptor. So the idea here is can we delay progression of the disease significantly? And that’s going to be very exciting to see the results of that trial.

Optimal management of metastatic CRPC (mCRPC); promising agents and strategies under investigation — Presentation

DR LOVE: I next met with Dr Kantoff and to begin he gave a presentation on the optimal management of metastatic castration-resistant prostate cancer and promising strategies under investigation

DR KANTOFF: Today we’re going to talk about metastatic castration-resistant prostate cancer, promising agents, and strategies under investigation. This the states model of prostate cancer, from clinically-localized disease all the way out to metastatic castration-resistant prostate cancer with multiple lines of therapy.

What you can see in this slide is that most of the drugs that we now use have been introduced in the metastatic castration-resistant prostate cancer state. However, over the past few years there have been clinical trials that have permitted the use of some of these agents in either the nonmetastatic castration-resistant prostate cancer space or the castration-sensitive metastatic prostate cancer space.

These are the classes of agents that I’ll be talking about today. I’ll be talking about the so-called hormonal agents, cytotoxic drugs. I’ll be talking about DNA damaging agents, talking about immunotherapeutic agents, and finally talk about a targeted agent.

So what are the factors that determine how we sequence these agents in metastatic castration-resistant prostate cancer? So there are generally 2 big categories, one are the clinical characteristics, and the second are biological factors. And I’m going to turn back to these biological factors many times and just now touch on the clinical factors.

So the clinical factors really speak to how aggressive the disease is. So one factor is how the patient got to metastatic castration-resistant prostate cancer. If the patient progressed from nonmetastatic castration-resistant prostate cancer to metastatic castration-resistant prostate cancer it’s more likely to be an indolent form of disease. If the patient progressed from metastatic hormone-sensitive prostate cancer to metastatic castration-resistant prostate cancer, more likely to be aggressive.

Another factor is when ADT was initially administered was another agent administered with it? Chemotherapy, an androgen receptor signaling inhibitor. That will modify the way we treat patients. Is the patient asymptomatic or mildly symptomatic or very symptomatic? Does the patient have visceral, specifically liver, metastases versus nonvisceral disease? Is the patient pre or post docetaxel? And of course comorbidities.

The biological factors that I’ll be talking about today include the presence of BRCA2 mutations, other DNA repair abnormalities, either germline or somatic, MSI high, tumor mutation burden high, the state of RB mutation, p53 mutation, or PTEN loss, and AR markers such as AR amplification or AR-V7.

So it’s almost 10 years ago since we’ve put together a consortium of institutions to look at the landscape of metastatic castration-resistant prostate cancer. This was the Stand Up To Cancer prostate cancer foundation effort, in which we sequenced about 450 tumors that were biopsied from patients with metastatic castration-resistant prostate cancer. And this is the results of the initial paper that was published in 2015 in Cell, and what you can see in these 450 or so patients is that the common mutations are in the androgen receptor, usually amplification, p53, PTEN, and the TMPRSS2-ERG fusions. I’ll come back to this slide over and over again during my talk.

So let’s talk about the hormonal agents. These agents have been tested in metastatic castration-resistant prostate cancer post chemo, pre chemo, in the nonmetastatic castration-resistant state, as well as in the castration-sensitive metastatic state. And suffice it to say, in my estimation, in the absence of comparative data, these agents all look about the same with regard to efficacy. There are differences that appear to emerge with regard to toxicity. Abiraterone, mineralocorticoid excess; enzalutamide, some CNS issues related to change in mentation of likelihood of falls, seizures; apalutamide the rash; darolutamide, which seems to have fewer side effects.

Now we just recently published this paper looking at the large clinical trials of these agents and did an analysis to determine if one could come to any conclusion regarding the comparative toxicity. And because the toxicities were collected in different fashions in each of the trials, we concluded that you could not make cross-trial comparisons regarding toxicity. So it’s hard to make a statement right now about one drug being safer or less toxic than another.

Let’s move to cytotoxic agents. Docetaxel, of course, being the mainstay since the early 2000s. The standard of care is every 3-week docetaxel with or without prednisone as first-line therapy. I think it’s perfectly reasonable to consider using every 2-week docetaxel at 50 mg/m2 plus prednisone based on a Phase II study that showed that it was better tolerated, and there was a long time to treatment failure.

Let’s move to cabazitaxel, which is a semi-synthetic taxane. In preclinical data it was active in docetaxel-treated cell lines. Its activity is against tumor cells and tumor models that are resistant to or not sensitive to the available taxanes. Phase I trials, DLT was neutropenia. Phase I trials showed activity, and the Phase III trial, which compared cabazitaxel at 25 mg/m2 compared to mitoxantrone, which had been a standard chemotherapy many years ago, demonstrated a survival advantage for cabazitaxel.

The CARD trial, which was published last year, took patients who had been treated with an androgen receptor signaling inhibitor and docetaxel and compared the use of cabazitaxel at 25 mg/m2 versus either abiraterone or enzalutamide as secondary hormonal agents after use of, in all likelihood, the other agent. And what was found was a survival advantage in favor of cabazitaxel compared to the androgen-signaling inhibitor, a median survival difference of about 2 1/2 months, with a hazard ratio of 0.64.

Surprising to me was that cabazitaxel, in this context, in the second-line chemotherapy setting, was very well tolerated. Similar AEs, similar Grade 3 AEs. There were more discontinuations with the cabazitaxel, but there were more AEs leading to death associated with the secondary androgen-signaling inhibitor.

Let’s move to DNA-damaging agents and start with radium-223. There was a randomized study of radium compared to standard of care in patients either pre or post docetaxel treatment, and it demonstrated that there was a prolongation in survival. There was a prolongation in the median time to the first skeletal-related event by 5.5 months. The benefit was seen pre and post chemotherapy, and it has, unfortunately, not been widely used.

Now radium is a bone-seeking alpha particle. It delivers very powerful radiation in a limited span of distance. So it was very promising, and it proved to be effective, but it has not been used very widely. And the reasons are you rarely see declines in PSA, it has to be given over a 6-month period of time. We still don’t know that the optimal timing is, whether it’s prechemotherapy, postchemotherapy. Can it be used earlier? Is it safe to give an alpha particle earlier in disease? Can it be successfully combined with other agents? And that’s a key point because one would like to be able to give it with other agents that cause a more rapid response as opposed to radium-223.

Unfortunately, in the ERA 223 trial, which asked the question whether abiraterone could be added to radium-223, the combination proved to be more toxic. There were 29% fractures in the combination arm as opposed to 11 in the abiraterone-alone arm. So that trial was discontinued. Other combinations are being explored right now, but I would not recommend the use of an androgen-signaling inhibitor in addition to radium-223.

This is one of the more exciting areas in the prostate cancer field, and that is targeting PSMA. It’s not a new idea. It’s been around for a while. There have been agents that have coupled antibodies to toxins that are directed at PSMA. They have not proven to be successful to date.

PSMA is a membrane antigen. It’s a protease. Much of the protein, as you can see, is extracellular, so it’s a good target. The catalytic site is seen at the bottom over here, and there’s a transmembrane domain, as well as a cytoplasmic domain.

So the most popular way of attacking PSMA right now is either through using a small molecule ligand that binds to the enzymatic pocket of PSMA, and these come in a couple flavors, PSMA-617 or PSMA I&T. You can also attack it with an antibody, which can attach to any part of the molecule. And J591 is such an antibody that does bind to PSMA.

You can also target PSMA using alpha particles or beta particles. Now beta particles are smaller. They have less intensity. And alpha particles are much bigger, and they travel shorter distances.

So this was, I think, landmark study of a small molecule ligand, that is 617, that attaches to PSMA and also is attached to Lutetium-177, which is a beta particle. And the endpoint in this study was PSA decline of greater than 50%. These were heavily pretreated patients. They were selected based on PSMA positivity by PET scan, and you can see that the majority of patients had a PSA decline of greater than 50%, so very active.

And this has led to the VISION trial, which is a randomized Phase III trial of men with metastatic castration-resistant prostate cancer who had received a prior novel hormonal agent plus a taxane, needed to be PET positive, randomized to best supportive care or best supportive care plus lutetium PSMA 617. The results are soon to be released. The trial is fully accrued.

Are alpha particles better than betas? And a few years ago we in the prostate cancer field saw this image of a patient who had a PSA of almost 3,000, widespread metastatic disease, who was treated with a small molecule PSMA alpha particle, actinium-225. He got 3 doses, had a complete response, got 1 more dose, complete response, PSA undetectable. This was a very dramatic finding, strongly suggesting that alpha particles are going to be important agents.

And there has been a trial of the antibody coupled to, the antibody being J591, coupled to the alpha particle targeting PSMA. And in this Phase I trial you can see once again the majority of patients had a response — or nearly half the patients had a response. And a lot of these patients, about 48% of the patients, had already received a PSMA-targeted agent, that is 617 lutetium. So alpha particles directed at PSMA, as well as beta particles directed at PSMA, small molecules, antibodies, all very promising with regard to treatment of prostate cancer.

So let’s move onto DNA repair. And this was one of the big revelations from the study that I mentioned before, the Stand Up To Cancer study, that we found that about 25% of patients with metastatic castration-resistant prostate cancer had DNA repair abnormalities, most common of which was BRCA2, about 11% of which were germline. The others were somatic.

Soon thereafter we realized that the PARP inhibitor olaparib was effective in patients with DNA repair abnormalities. This was a study published in 2015, relatively small study, but basically demonstrated that people with DNA repair abnormalities, most notably BRCA2, were responsive to olaparib, the PARP inhibitor.

More recently, the PROfound trial was published,

And this was an interesting study that involved patients with metastatic castration-resistant prostate cancer who had progressed after an androgen receptor signaling agent, like abiraterone or enzalutamide. And there were 2 cohorts in this study. Cohort A were patients who had BRCA1, BRCA2, or ATM mutations, and Cohort B were those with other DNA repair abnormalities that are mentioned at the bottom of this slide and on the next slide.

And in both of these cohorts patients were randomized to physician’s choice or alternatively olaparib at 300 mg twice a day. And the primary endpoint was radiographic progression-free survival for Cohort A, that is for the patients who had BRCA1, BRCA2, or ATM mutations. And the secondary endpoints included the combination of both cohorts, and radiographic response, time to pain progression, and ultimately overall survival.

So once again, these were the DNA repair abnormalities that were included in this study, and this is the overall population and the radiographic progression-free survival. And there was dramatic difference in outcome overall, with a 50% reduction in progression with olaparib in this patient population.

Interestingly, if you look at Cohort A alone, which only included BRCA1, BRCA2, and ATM mutations, the curves separate even more, which implies to me that the majority of the action here is happening in BRCA2, BRCA1, and ATM patients.

If you look at survival, this is only for Cohort A once again, that’s the patients with BRCA1, BRCA2, and ATM mutations, there is a survival advantage as well, hazard ratio of 0.64, p-value of 0.02.

So this has led to the approval of olaparib in patients who have progressed following treatment with enzalutamide or abiraterone and have an HRR, or homologous recombination repair, gene mutation.

In parallel, rucaparib, which is another PARP inhibitor, has been studied in the TRITON2 study. And here are the results. This only included BRCA1-, BRCA2-, and ATM-mutation patients, and you can see that the vast majority of patients in this trial responded to rucaparib. Now these were patients who had been previously treated with an androgen receptor signaling inhibitor, as well as docetaxel. But as a result of this trial rucaparib was approved for patients who have been previously treated with an androgen receptor-directed therapy plus a taxane chemotherapy.

Now there are a whole bunch of other trials going on to try to improve upon the results of PARP inhibitors in DNA damage repair patients with the addition of agents like radium, the addition of PD-1 or PD-L1 agents, and AR-targeted therapies.

So my conclusions with regard to PARP inhibitors are that PARP inhibition is effective in patients with DNA repair abnormalities, particularly the BRCA mutations. PARP inhibition appears to be less effective in those patients who have ATM mutations.

Olaparib is FDA approved in patients with metastatic castration-resistant prostate cancer with HRR gene mutations who have been previously treated with enzalutamide or abiraterone. And rucaparib, similarly, the patients have to have received docetaxel chemotherapy.

There were 2 interesting trials, that were not shown on the previous slide, the PROpel trial, which looks at abiraterone plus or minus olaparib in patients, as first-line therapy, for metastatic castration-resistant prostate cancer. And the CASPAR trial, which is enzalutamide plus or minus rucaparib as first-line therapy for metastatic castration-resistant prostate cancer.

Now let’s move onto immunotherapeutic agents. I’m not going to talk about sipuleucel-T. It was approved 10 years ago. It, like radium-223, is not used as much as many of the other agents that we have talked about for a variety of reasons, but I will talk about other agents in this space.

So one of the things I failed to mention in the first slide of this landscape of metastatic castration-resistant prostate cancer is that there is a small proportion of patients who have a high tumor mutational burden.

And this was a landmark paper published in Science 3 years ago by one of my colleagues, Luis Diaz, who is a senior author, demonstrating that people with mismatch repair deficiency predicted response to PD-1 blockade. And it turns out that a small proportion of patients with prostate cancer have DNA repair deficiency. And we conducted a trial of patients with microsatellite instability, mismatch repair, and we treated 11 such patients with a PD-1 inhibitor of one type or another, and 5 of the patients not only had responses but had durable responses. So we look for these abnormalities in patients because of this phenomena of extreme responders to PD-1 inhibition.

Now what about the PD-1 inhibitors which have been, obviously, very active in other diseases, like melanoma, lung cancer, bladder cancer, kidney cancer. This is pembrolizumab alone in metastatic castration-resistant prostate cancer. The response rate for

PD-L1 positive patients was only 8%, 5% in people who were PD-L1 negative and 1% in bone predominant. There seemed to be an indication that patients with BRCA1, BRCA2, or ATM mutations had a higher response rate. And obviously patients who had MSI high also seemed to respond. So my conclusion is that single agent PD-1 inhibitors are not very effective alone in metastatic castration-resistant prostate cancer.

This happens to be the Duke experience, which is a little bit better, 16% overall response in 51 patients who were treated. They did enrich for patients with MSH2 loss, MSI high, and patients with LRP1b mutations, which are known to sensitize to PD-1 inhibition. But the results, similarly, are not all that impressive. This is generally a cold tumor.

So there’s a large effort underway to try to combine PD-1 inhibition with other agents, including docetaxel, PARP inhibitors, androgen receptor signaling inhibitors, other combinations. There is a trial of cabozantinib and PD-1 inhibitor versus abiraterone as well. And there are a whole bunch of efforts in CAR T cells, as well as bispecific antibodies underway, as well.

So the final thing I’m going to talk about are targeted agents, and I’m really going to focus on 1 targeted agent. And I go back to this landscape curve in which we see that there are a large number of patients with PTEN abnormalities, about 40.7 with PTEN loss, for the most part, in metastatic castration-resistant prostate cancer. And a number of patients with PI3-kinase abnormalities.

So there was a randomized Phase II study evaluating AKT blockade with the drug ipatasertib in combination with abiraterone. So the study was abiraterone plus or minus ipatasertib. And the results were very encouraging, particularly in patients with PTEN loss, which one would expect. PTEN activates AKT, and in turn you’d expect an AKT inhibitor to be effective, particularly in patients with PTEN loss.

So this study was very promising and led to the IPATential150 Phase III clinical trial, which took patients with metastatic castration-resistant prostate cancer and a known PTEN mutation and randomized them to receive either abiraterone alone, plus placebo, or abiraterone plus ipatasertib. And the coprimary endpoints were radiographic progression-free survival, as well as overall survival.

And a press release came out in June that said that it had met its coprimary endpoint of radiographic progression free survival in patients with metastatic castration-resistant prostate cancer whose tumors had PTEN loss.

So I anticipate, based on this trial, that ipatasertib will be approved for this genetic subset of patients with PTEN loss.

Management of de novo metastatic prostate cancer; recommendations for screening and implications for clinical presentation

DR LOVE: So why don’t we just start out and have you talk a little bit about this kind of scenario and how you would think through.

DR KANTOFF: So the first case is a 55-year-old man who presented to his local doc with back pain and radicular pain down his leg. And he gets an MRI, which shows multiple spine mets and mild cord compression at L1-L2. And his primary care doc gets a PSA, and it’s 357, refers him to a urologist, and the urologist finds that his Gleason score is high grade, high volume, Gleason 5 + 4. So a standard bone scan shows widespread high-volume metastatic disease, and he’s referred to me for evaluation.

DR LOVE: I’m just kind of curious, in the past a lot of men presented with metastatic, not the majority, but it was not uncommon, and then it kind of seemed like there was a period of time when it was very uncommon. Do you think we’re seeing more of these kinds of cases? And what’s going on right now with PSA screening?

DR KANTOFF: Yeah, I think you’re right, Neil. I think that we are seeing more patients presenting with metastatic disease. I was kind of surprised when Chris Sweeney, who is a colleague of mine, did the CHAARTED study, and I said where are you going to find these patients with de novo metastatic disease? And they backed up a little bit and included patients who were treated locally, who progressed onto metastatic disease. And those patients are generally a little more indolent than patients who present with metastatic disease. But they did do the trial, and the STAMPEDE trial was conducted. So those patients are out there. They represent probably 5% to 10% of the population.

Now your sense and my sense is that there’s more of those patients now than there had been say 10, 15 years ago. And I think that we were going through a phase that lasted a long time of over-screening. And when you do a lot of over-screening you find indolent cases, but you do find disease that may be very aggressive, but you find it earlier. So we were finding these cases, but they were found as localized disease more frequently, and then progressed onto metastatic disease.

And then around 2012, the task force recommended no screening. And while medical oncologists and urologists were very much in disagreement with that decision, I think primary care docs and internists really took that to heart, and the rates for screening for prostate cancer significantly decreased. And I do think that that contributed to a recrudescence of this form of disease of de novo presentation of metastatic castration-sensitive disease.

So whether it’s that, there’s a change in the biology of the disease, I don’t see anything that suggests that or environmental factors. I doubt that the environmental factors have really changed that significantly over that span of time. But I do think that the natural history of the disease has changed in the past 10 to 15 years, probably the result of the decreased screening in the United States.

DR LOVE: It’s interesting. I’m curious whether you have any impressions about how people are presenting in the last year. You’re in New York, one of the early places that COVID was an issue. Is it your sense that men are coming in with more advanced disease this year than in the past because of — I’ve heard about cases like that, but I don’t know if we have any data that that’s really occurring. Because they don’t want to go to the doctor because of concerns about just getting out of the house, to start with.

DR KANTOFF: Right. So the data on screening in general, not only in prostate cancer, is that screening across all cancers has gone down dramatically. Prostate is probably one of the diseases where the immediacy of screening plays less of a role. There have been studies that suggested only in the highest of risk prostate cancer patients would it make a difference, and the lag would have to be greater than 6 months.

So I don’t think, in my opinion without real data, that it’s had a huge impact on the presentation of disease in the COVID world.

DR LOVE: It’s a lot different to get your blood drawn than to come in for a mammogram as well.

Benefit with the addition of chemotherapy or secondary hormonal therapy to ADT for patients with metastatic prostate cancer

DR LOVE: So I guess in the past these men who presented with metastatic prostate cancer or developed prostate cancer after having been treated previously but have never had endocrine therapy in the past, these men would get treated with androgen deprivation. They almost all responded. And even when the idea came up of adding to it, I think people are saying how much better can you get. And it turns out, quite a bit.

Maybe you can summarize what we’ve learned over the last I guess decade about adding onto ADT in this situation.

DR KANTOFF: Yeah. I remember when Chris Sweeney, who joined my group when I was at Dana-Farber, telling me that he initiated the CHAARTED trial, which was combining ADT with docetaxel. And I said, “Chris, you’re such a smart guy. Couldn’t you think of a more imaginative trial than that?” And then about a year and a half later he came into my office and said, “See, I told you so.” And it was a dramatic difference in hormone-sensitive disease, the addition of docetaxel, than in metastatic castration-resistant disease, where the median survival benefits, for whatever that’s worth, I mean it is a statement on biology, the median survival differences were 2 to 3 months as opposed to almost 2 years.

So one of the things that we’ve been studying, with Chris and with others, is why? Why should docetaxel be more effective in hormone-sensitive disease than in castration-resistant disease? Very important question. I don’t have an answer. I have hypothesis for you.

And soon to follow suit have been all the other androgen receptor-signaling inhibitors. And they all have shown pretty much the same thing, and that is the same margin of benefit as had been seen with docetaxel, much more profound than in the metastatic castration-resistant prostate cancer setting. And once again, as I said earlier, I don’t see real differences in those agents from one another. So the decision is pick your androgen receptor-signaling inhibitor or pick docetaxel or maybe in some cases, of the most indolent of patients, just use ADT alone, which is still not the most unreasonable thing, and wait and see.

I tend to use some combination because I think the results are pretty compelling. And where I stand, Neil, is in the more robust patient with high-volume disease, where there has been shown more convincingly to be a benefit of docetaxel, I’ll lean in the direction of docetaxel. In the less aggressive kind of patient with lower-volume disease, non-de novo disease, I’ll tend to use an androgen receptor-signaling inhibitor. And I think any one is fine. I’m a traditionalist, and I’ve stuck with abiraterone in that context as the alternative to docetaxel.

DR LOVE: So another thing that I personally was pretty surprised at is the work that they did on treating the primary in metastatic disease. And I’m wondering what you think about that and whether that is something you bring into your practice.

DR KANTOFF: Yeah. I had been doing that before the STAMPEDE study showed that. I don’t go as far as removing the prostate as some people advocate, but in high-volume localized prostate cancer, particularly with oligometastatic disease, I will include treatment to the prostate. When I do it, I usually wait months. I get the systemic therapy started first, and then after some period of time of regression of tumor I will add the localized radiation.

It’s convincing. The hazard ratios of localized radiation really look like some of the agents that we use. So what is going on there is the question. Is it repeated metastases from the primary that you’re preventing, or is it some immunological phenomena that you’re setting up, where you’re stimulating the immune system against the tumor? I don’t know. But it does seem to work.

DR LOVE: Do you think it could be as simple as debulking? I mean I wouldn’t think there’s that much, bulk there, but could that be it?

DR KANTOFF: I’ve seen in my career, I can count on 1 hand the number of patients that died of localized disease. So I don’t think that’s it. I think it has to do with metastases and whether it’s preventing subsequent metastases or some immunological phenomena is higher on my list.

Choice of androgen receptor inhibitor for patients with metastatic prostate cancer; impact of COVID-19 on therapeutic decision-making

DR LOVE: What about the choice of antiandrogen in this situation? What are the ones that have been studied that you think are reasonable to consider?

DR KANTOFF: Enzalutamide and abiraterone, abiraterone being the first, and there are apalutamide and darolutamide to follow. I think they’re all reasonable. It’s just, once again, I think they’re all efficacy wise in the same ballpark, and it’s a toxicity issue. And as I said early on, we were very interested because the claims of darolutamide being less toxic. And it may be true, but based on the studies one can’t come to the conclusion because when you look at the control arms, Neil, of each of these studies, the rates of toxicity are so different from one another. So it’s hard to make cross-trial comparisons of toxicity.

So efficacy being the same, toxicity different but hard to make comparisons. I just tend to go with the things that I’m most familiar with. Obviously, abiraterone, would stay away from it with somebody with diabetes, problems with hypertension. Enzalutamide, I would be hesitant to use in somebody who’s frailer, older, susceptible to falls, that sort of stuff. So there is some individualization, but I think any of the above would be fine.

DR LOVE: I wasn’t aware there were data, at least at this point, for darolutamide in the metastatic disease.

DR KANTOFF: There isn’t. It’s only in nonmetastatic castrate —

DR LOVE: So from your point of view, is it a reasonable, I don’t even know if you can get it paid for, is it a reasonable consideration to use in metastatic endocrine-sensitive metastatic disease?

DR KANTOFF: In the absence of data I would say no. I don’t know if people are using it. But in the absence of data, I wouldn’t be surprised if it’s equally effective when the study is done. But you’re right, Neil, that data’s not in yet.

DR LOVE: And the other thing I noticed in your CV, the work that you had done looking at the comparative toxicity of these agents. And I thought it was really interesting because I’ve definitely heard, I mean I think for example about your former colleague, Matt Smith, who I find a pretty conservative person, who for a while now has been pointing to falls and other CNS-related things as being clearly lower. Understanding totally it’s indirect comparison. So you don’t really find that when you look into it?

DR KANTOFF: No. It’s not that you don’t see it, it’s that if you really dig deep into the data and say can you conclusively say, based on the data that’s been presented, that there is a difference, you can’t. I’m taking the most academic point of view right now.

DR LOVE: Got it. Okay.

DR KANTOFF: On a practical level, it doesn’t cross the blood-brain barrier, and it probably has fewer CNS — if you’re talking about darolutamide, it probably has fewer CNS side effects than say enzalutamide does, or apalutamide does. So there probably is something there, it’s just that the point we were trying to make in that study that was published in the JNCI was we’ve got to do a better job at standardizing the way we report toxicity across these randomized clinical trials so that we cannot have a discussion like this, and we can say look here, look there, and we can conclusively say, or almost conclusively say, that darolutamide is less toxic.

DR LOVE: So is that your experience clinically or it’s kind of hard to say?

DR KANTOFF: I have had less trouble with abiraterone and enzalutamide. I’m not saying that in large populations darolutamide is not somewhat safer, but if you select the patients carefully, those drugs are still reasonable.

DR LOVE: I’m curious how you see patients and physicians processing this decision, and also whether or not the way people are processing is different nowadays with COVID. It’s interesting where you have an alternative between oral and IV therapy. That doesn’t happen too often in oncology, but you have it here. And initially I was hearing people — before, a lot of people were saying hey, there’re patients out there who prefer docetaxel, get it over with, then when COVID came along it felt like maybe things were shifting away from docetaxel. What’s your perception about how the decision in general has been made before COVID and whether it’s being changed now?

DR KANTOFF: Well, I think before COVID it was the high-volume de novo decision. During COVID, in the early days of COVID, I don’t know what the early days are, but like what we experienced here in March and April, we were trying very hard to keep people out of the hospital and keep people out of clinics. And probably, I don’t have the data in front of me at Memorial Sloan Kettering, but we probably tended to use oral agents more. But that’s returned back to normal right now, whether it changes again with the relapse of the first wave or the beginning of the second way, depending on what it is, we will find out.

I think we are a little more prepared now for COVID than we were in March and April. And I think that backing down from what we think are the best treatment plans for patients will probably prevail.

Molecular profiling for patients with prostate cancer; spectrum of related genetic alterations

DR LOVE: So why don’t we continue with this case scenario, and you were saying that the patient gets docetaxel, the PSA goes down to 1 by 6 months, but then after 12 months his PSA starts climbing again. Can you talk through kind of how you would think though this kind of situation?

DR KANTOFF: Well, I did want to mention before that that this was a patient with mild cord compression, and I tend to treat that person with local therapy urgently in conjunction with giving systemic therapy. So this patient gets the chemo and the ADT, and the PSA has declined to 1 by 6 months. And then the ADT is continued, but the chemo is discontinued. But after 12 months the PSA begins to climb, so by definition the testosterone is castrate. He started on abiraterone and prednisone. But his PSA continues to climb.

The impression that I have is that these patients who receive this combination therapy at the beginning, who relapse, really do poorly. And they tend to be a little less hormone sensitive, a little less sensitive to other agents. But I think it was well worth trying abiraterone in this patient since he had not seen an androgen receptor signaling inhibitor.

But he unfortunately was resistant. Now he may harbor let’s say an RBp53 mutation, which is notorious for rendering people resistant to abiraterone or enzalutamide. It’s a little bit early for this patient to have AR-V7 mutation. He’s only received primary ADT, and you rarely seen AR-V7 in that context. So I’m thinking that this patient has some bad mutations, like RBp53, and is less responsive to abiraterone.

So then we move to, since he got docetaxel before, we move onto cabazitaxel. And I’ve moved over to using 20 mg/m2 of cabazitaxel. And the patient responded to this. So that’s where we are with it.

DR LOVE: Maybe to just pick up on a few points related to the case. I’m curious where along the line in this kind of case scenario do you think it would be optimal to start looking for mutations? What kind of germline and somatic testing you’d recommend?

DR KANTOFF: Well as you know, we routinely, at Memorial Sloan Kettering, get germline testing and tumor testing on patients with certainly metastatic disease, and many patients with high-risk localized disease. So I failed to mention this in this case that germline here was negative for any BRCA, say, mutation. This is panel testing now. And tumor testing did reveal the p53 RB mutation in this patient.

So I encourage this because of the DNA repair abnormalities, the rare MSI high, Lynch syndrome patients, and perhaps looking for PTEN and certain PI3-kinase abnormalities, which are actionable.

DR LOVE: Can you talk a little bit about the profile that you see with patients with prostate cancer genomically? You had a fantastic effort where you looked at this in hundreds of patients. Globally what did you see? And more specifically, related to some of the abnormalities you just talked about, how often did you see them?

DR KANTOFF: Right. We specifically looked at DNA repair abnormalities, and this is Colin Pritchard’s work at the Hutch soon after the initial landscape paper that we published in Cell in 2015. And BRCA2 is a dominant germline abnormality, but there are other lesser ones that we should be looking for, including BRCA1 and PALB1 and others, because these are at the moment potentially actionable with regard to PARP inhibitors.

Activity of the AKT inhibitor ipatasertib in patients with mCRPC

DR LOVE: You mentioned PTEN. Can you talk a little bit about where we are today in trying to target that? And also PI3-kinase.

DR KANTOFF: Well, PTEN at the moment is not actionable. It’s a tumor suppressor gene, and they’re hard to target. But PTEN loss leads to PI3-kinase activation and in turn AKT activation. So AKT is really the downstream target of PTEN that’s most actionable. PI3-kinase inhibitors in the context of prostate cancer so far have been not extremely active, for whatever reason. I think it’s the AKT story that seems to be the most exciting one at the moment.

DR LOVE: Any comments about ipatasertib? How that works and whether or not that has a possibility of coming into practice.

DR KANTOFF: Right. I think the early returns on the study are very interesting. The randomized Phase II study comparing abiraterone versus abiraterone plus ipatasertib was very promising, particularly for PTEN-loss patients, which represent 40% to 50% of patients, and that led to the Phase III trial. The press release was very promising. Right now, I await seeing the published data to determine how effective it is and whether the risk/benefit is worth it. But it’s very exciting to have another targeted therapy in the context of metastatic prostate cancer.

Role of immune checkpoint inhibitors alone and in combination with targeted therapy for mCRPC

DR LOVE: What about immunotherapy in metastatic prostate cancer, particularly checkpoint inhibitors?

DR KANTOFF: I think so far disappointing as single agent PD-1. I think the combination of PD-1 plus ipilimumab is a little bit better, with response rates in the low 20s. And there are certain subsets of patients that may respond better. Toxicity pretty high in this elderly population. So I think we have a ways to go before checkpoint inhibitors become part of the armamentarium.

I was particularly struck with the early results of the cabozantinib/PD-1 trial. It was not a big trial, but using cabozantinib, which we were all struck by, I don’t know, it was 7 years ago when it was used in men with metastatic prostate cancer to the bone, and we saw bone scans completely clear. And then we did randomized studies of cabozantinib in men with metastatic castration-resistant prostate cancer, which turned out to be negative. How much of those bone scan changes were real metabolic changes or even artefactual? I don’t know. But there was no survival advantage in those patients.

But cabozantinib is a drug that has many targets, and some of the targets affect myeloid-derived suppressor cells, which those cells are involved in suppressing the immune system. So cabozantinib may suppress or overcome the suppression of those cells in an immunological response when combined with PD-1. And the results of the combination of cabozantinib and PD-1 inhibition were actually very promising.

Akash Patnaik presented some early data at ASCO last year, I believe it was, and that led to a Phase III trial, which is now underway, comparing PD-1 inhibition versus PD-1 plus cabozantinib.

DR LOVE: Well certainly the combination of a checkpoint inhibitor and a TKI is something in renal cell that’s obviously been very successful. And actually there was a cabo plus nivo trial of renal presented at ESMO that looked pretty cool.

So in general has that strategy, beyond what you just said, been looked at in prostate? Combining a VEGF-TKI, lenvatinib for example, with an IO?

DR KANTOFF: Yeah, I think there is 1 trial with cediranib and a TKI, but that’s the only one that I know of.

DR LOVE: We were talking about checkpoint inhibitors. What about the issue of MSI-high prostate cancer? How often does it occur? Is it worth looking for? I don’t know if you have any clinical experience using checkpoint inhibitors in patients like that.

DR KANTOFF: Right. So Luis Diaz’s study showed that MSI high, the rates of it differ from cancer to cancer. The rate of it in prostate cancer is about 2% to 3%. There are some studies as high as 5%. And in our study, which was not a prospective study, but a retrospective study, the patients treated with PD-1 inhibition, we treated 11 such patients with PD-1 inhibition, and out of the 11, 5 of them responded and responded quite durably. It is definitely worth looking for these patients. And it comes along with tumor sequencing. You get the data in terms of tumor mutational burden. And so I think it’s important to look for. It may only represent 2%, 3% of your patients, but it’s worth looking for because these patients can — their tumors can disappear.

DR LOVE: You mentioned tumor mutation burden. Of course, we had, not too long ago, an approval for pembrolizumab in those patients, I think over 10. Do you ever see that in prostate cancer? And again, have you used a checkpoint inhibitor in that situation?

DR KANTOFF: Well that’s the study I just mentioned, Neil. We used pembro or nivo in patients with MSI-high tumors.

Efficacy and tolerability of radium-223 in patients with CRPC and bone metastases

DR LOVE: Why don’t we go onto your next case, the patient who got radium-223?

DR KANTOFF: Okay. So this is a 70-year-old man who presents with a PSA of 8.3, obviously high, normal DRE. Prostate biopsy reveals high-volume Gleason 4 + 3. Bone scan and MRI showed no evidence of metastasis. So the patient’s treated with, at the age of 70, with external beam radiation plus 6 months of ADT. And the PSA declines to 0.3 after 6 months. Everything is stopped. And 2 years later the testosterone returns to normal, and his PSA begins to climb.

So given that this is a man in his 70s, we wait until his PSA reaches 10, and he has known metastases at that time, and he’s restarted on ADT and continues on intermittent ADT, which can go on for many years in patients. But in his case, after 4 years, while his testosterone is at castrate levels, his PSA begins to climb, which is heralding, obviously, the emergence of castration resistance.

So he’s then maintained on continuous ADT, and despite that his PSA begins to climb and reaches a PSA of 5. His PSA doubling time is about 12 months. And this is now the first time that his bone scan shows several metastases in his spine and pelvis, although he’s still asymptomatic, and a CT scan shows no evidence of soft tissue disease.

So this is a man who’s now 75 years old. He’s relatively asymptomatic. He has relatively indolent disease, so I’m thinking about the options of radium-223, bone-only disease. I’m thinking about sipuleucel-T. I’m thinking about these agents that I would only institute in relatively indolent disease, particularly in older patients. So we treated him with radium-223.

DR LOVE: What about endocrine therapy, enza, abiraterone?

DR KANTOFF: I think they would be fine. It’s just that it’s always, in oncology and in prostate cancer, the balance between risk/benefit. And radium-223 is a pretty well-tolerated drug. It is associated with a survival advantage.

And no matter how effective the androgen receptor-signaling agents are, they have some toxicity. They take the wind out of the sails of men, who are particularly older, even when their T levels are castrate. It still has an effect on them. So I try to minimize the burden of therapy on patients as much as I possibly can.

DR LOVE: Are there situations where you would combine radium-223 with endocrine therapy, such as enzalutamide or abiraterone? There was a trial out there that showed some potentially deleterious effect. But as I’ve been talking to people, my understanding was that really it was an issue about bone protection, and that if you do use bone-sparing or protecting agent it maybe is safe to combine with endocrine therapy, radium-223. Any thoughts about that?

DR KANTOFF: Yeah. The desire to combine it is based on the fact that, as I mentioned before, radium-223 does not cause a lot of PSA declines. Patients don’t feel very different, for the most part, and it’s sometimes hard to manage a patient when you’re treating them with something, and the PSA is not going down. So the inclination is to combine it with something that makes the PSA go down, although that’s more psycho-oncology than it is medically sound.

Now I guess the ERA-223 study did scare me a bit. And it is possible that better bone protection might mitigate some of the bone fractures that were seen in that study. But I don’t see any, in this man, any compelling reason at this point in time to add another agent. We can wait until a later time or a time that he’s clearly progressing to institute another therapy.

We’re always trying to balance, once again, the quality of life and quantity of life thing. And we do have a lot of things that work, they work to a limited extent. Sometimes they work fairly miraculously. But we have do a number of things that we can string along and try to maintain the best quality of life for the longest period of time.

Activity of PARP inhibitors in patients with mCRPC

DR LOVE: So why don’t we go onto your third case and get into the issue of PARP inhibitors.

DR KANTOFF: Okay. So the next patient’s a 60-year-old man with a strong family history of prostate cancer who presents with a rapidly rising PSA. I’m not giving the PSA values here, but you get the point. His biopsy reveals high-grade prostate cancer. A bone scan reveals oligometastatic disease. CT scan reveals extensive nodal disease in his pelvis and retroperitoneum. And the patient’s started on ADT and abiraterone and prednisone.

So in this case I made the choice of abiraterone/prednisone in this man with a new presentation of metastatic castration-sensitive prostate cancer. He had oligometastatic disease, so he did not have high-volume disease, so I was more inclined to treat with abiraterone than with docetaxel in this case. So this is obviously a guy that would get, in our hands, germline testing and a tumor biopsy to look for genomic abnormalities. And with the therapy his PSA declines to 0.2 after 6 months, and fortunately his bone scan and CT scan improved as well. And his germline testing reveals a BRCA2 mutation.

So BRCA2 mutations just, as a rule, not, I wouldn’t say proven at this point, but pretty strong evidence that they’re associated with a poor prognosis. These are generally heterozygous mutations in the germline, and the tumors acquire either a second mutation or a deletion. Interestingly, that spans BRCA2 and RB, because BRCA2 and RB are adjacent to each other on chromosome 13. And they are associated with, even that deletional event, is even associated with a poorer prognosis than a second mutation in BRCA2.

So right here we know that we have a PARP inhibitor ahead of us if we need to. But at the moment he’s still hormone sensitive, so he’s maintained on intermittent hormonal therapy for about 3 years before he becomes resistant, as evidenced by a castrate testosterone and a rising PSA.

So with a rising PSA in the context of a castrate testosterone, a bone scan and CT scan that’s worsening, I started him on olaparib at 300 mg b.i.d.

DR LOVE: So can you talk a little bit about the research that we have available right now on PARP inhibitor in prostate cancer?

DR KANTOFF: So PARP inhibitors create synthetic lethality with patients who have BRCA mutations and cause double-strand breaks, and presumably as a result of double-strand breaks, kill the cells. The problem with PARP inhibition is that resistance occurs soon after, variable, but soon after. So if you look at the trials in prostate and many other diseases, the duration of response is brief. And while the mechanisms of resistance are not clear there are mutations that occur that restore a normal BRCA so that there’s no longer synthetic lethality.

In our hands, we see changes in BCL2, a rise in BCL2. We see other changes that may instruct us to combine PARP inhibitors with other agents. And there are a number of trials, that I mentioned before, combining PARP inhibitors with other agents, including androgen synthesis inhibitors or androgen receptor-signaling inhibitors, and combining them with PD-1 inhibitors. So there’s a real effort to try to improve upon the efficacy of PARP inhibitors right now.

CARD trial results: Improvement in overall survival with cabazitaxel versus enzalutamide or abiraterone for patients with mCRPC previously treated with docetaxel who experienced rapid disease progression on a prior androgen receptor-targeted agent

DR LOVE: I guess the one thing I was thinking about is the CARD trial and the whole issue of cabazitaxel. Can you talk a little bit about that study, and I think there was an update recently, and where we are today in terms of management of patients who progress on the first endocrine therapy for metastatic disease?

DR KANTOFF: Well the CARD trial included patients who had received an androgen receptor-signaling inhibitor and also received docetaxel. So they have been heavily pretreated. We know that if a person has failed a first-line androgen receptor-signaling inhibitor that they’re extremely unlikely to respond to a second one.

So it’s not surprising that cabazitaxel, which was proven to be effective after docetaxel in the era before androgen receptor inhibitors came along, that it’s still effective and better than using a second-line agent. So it doesn’t come with a lot of surprise to me, Neil, that that trial showed what it showed. It’s sort of the same trial that was done 10 years ago 10 years later. A slightly more advanced population because they received the androgen receptor-signaling agents.

DR LOVE: One other thing I wanted to ask you about is the issue of oligometastatic disease and whether there’re situations where you treat people locally with oligometastatic prostate cancer.

DR KANTOFF: So there is data from randomized studies showing that in patients, prior to hormonal therapy with oligometastatic disease, if you treat them with SBRT you can delay the time of initiation of ADT. And from a quality of life standpoint I think that is a good thing to do, and I have done that. So I’ve treated patients with 2 or 3 metastases with spot radiation, and maybe given patients 6 to 12 months, maybe longer time, before they have to start an ADT, which has its side effects.

The question that remains is whether the treatment of oligometastatic disease is going to change the natural history of the disease. Is it going to change survival? And for that to happen you have to imagine that there are metastases from metastases, and number 2 that there’s a long time before the emergence of the other non-imaged metastases. And that by treating these larger metastases with spot radiation you’re prolonging survival. And I just don’t know that we have an answer at this time. We need a randomized study.