Introduction

DR LOVE: Good evening, everyone. I’m Neil Love from Research to Practice and welcome to Second Opinion, as tonight we have our investigator faculty discussing cases from their colleagues that we’re going to be presenting here this evening. We do have a great faculty today. From the far side here, Dr Alicia Morgans from the Dana-Farber Cancer Institute, Professor Karim Fizazi from the University of Paris Saclay, Dr Rana McKay from the University of La Jolla, California, Dr Emmanuel Antonarakis, University of Minnesota, and Dr Oliver Sartor from the Mayo Clinic in Rochester.

We’re going to be presenting cases that we produced over the last couple of weeks.

So let’s jump right into that. As I mentioned, we have 3 docs who’ve worked with me over the last couple of weeks to put together some cases. Dr Neeraj Agarwal from the Huntsman Cancer Institute at the University of Utah, a medical oncologist. Dr David Morris from the Urology Associates in Nashville, Tennessee. He’s a urologist. And Dr Sandy Srinivas, a medical oncologist from Stanford.

Here are the modules that we’re going to be covering tonight. Each one of these we’re going to have a short presentation from the faculty, but we’ll precede that with some case discussions.

Case: A man in his early 70s diagnosed with localized prostate cancer who underwent a radical prostatectomy in 2010 experiences rising PSA from 0.18 to 0.4; PSA doubling time 7 months; PSMA PET-negative for other sites of disease — David S Morris, MD

DR LOVE: And we’re going to start out with this first case from Dr Morris. And Rana, I’m going to ask after you watch this case to respond to it. This is a 71-year-old man — I was really interested to see what Dr Morris as a urologist thought about the EMBARK study that was presented here in Chicago just about a month ago. So he pulled this case from his practice that I thought would be a good opportunity to really dive into it.

Here's the case.

DR MORRIS: This is a case of a 71-year-old man who had undergone a prostatectomy over 10 years ago and just over the last year or so he has had a PSA rise 0.18 and then 0.4. PSA doubling time estimated there just over 6 months. And a PSMA PET scan which was negative for uptake anywhere.

DR LOVE: So, would you consider this an EMBARK-like situation?

DR MORRIS: This would certainly be somebody whose PSA doubling time under 9 months, he hasn’t reached the threshold that EMBARK used, which was a PSA of 1 for postsurgical patients. But obviously with just a few more months, he’d be a candidate for combination therapy or monotherapy and potential withdrawal of therapy after duration of induction.

DR LOVE: For a patient like this, putting aside reimbursement, FDA, all that, for a patient like this, would you offer intermittent enzalutamide monotherapy without ADT as an option in addition to the option of ADT plus enzalutamide?

DR MORRIS: I would with the appropriate risk counseling. I do think it’s reasonable to try enzalutamide.

And I would pitch it to a patient as, we still may need to use ADT therapy down the road with all of its concomitant side effects.

DR LOVE: So Rana, I was very excited when I saw that presentation. We actually had Dr Shore the next day in a satellite meeting. We’re waiting for the patient-recorded outcomes, and you’re going to talk about the study. But can you just brief the audience a little bit on what they looked at in the study and what your take-away was of it.

DR MCKAY: Really, a landmark study actually. So EMBARK was a large, Phase III trial looking at patients who had biochemically recurrent disease that was nonmetastatic. They didn’t incorporate PSMA-PET imaging into the context of EMBARK; they enrolled patients that had a rapid PSA doubling time that was less than 9 months. And patients were actually randomized to 1 of 3 arms, either leuprolide with enzalutamide, enzalutamide monotherapy, or leuprolide monotherapy.

The primary endpoint of the study was MFS and OS. And the intentions for comparisons, the 3 arms were all intended to be compared to one another, but rather the primary endpoint was really designed around the combination of ADT plus enzalutamide being compared to leuprolide alone.

And I think this was really a practice-changing study that demonstrated that those patients that have a rapid PSA doubling time really seem to benefit from therapy escalation in the biochemically recurrent setting. We don’t have data comparing leuprolide plus enzalutamide versus enzalutamide, the trial was not designed to compare those subsets. But I think the trial demonstrated that there was a statistically significant improvement in MFS and OS actually, with combination therapy.

Now the enzalutamide monotherapy was not – the evaluation of the enzalutamide monotherapy cohort was not the primary endpoint of the study, but it did provide prospective modern-day evidence of what enzalutamide monotherapy were to look like. I think when we look at the AE profiles we don’t have the quality-reported outcomes, the patient-reported outcomes, but when we look at the AE profiles of enzalutamide monotherapy, they’re not actually all that different — we were chatting about this a little bit earlier — they’re not all that different from leuprolide alone, barring the exception of the hot flashes which were significantly reduced in the enzalutamide monotherapy arm.

DR LOVE: And you would expect sexual function, although I don’t know if they’ve reported that yet. But normal testosterone levels. So let’s just take a couple of parts of this. First, Emmanuel, you were at Hopkins before, and one thing, just to put in context, we know a lot of people are sort of new to oncology, maybe a quarter of the people here are within the first 5 or 8 years of being in oncology. And the major issue here, which is just doing a randomized trial in M0 disease, I don’t think it was done before. We always look to the Hopkins historic data, trying to figure out what to do, oh, we can never do a study like that. And then, all of a sudden, industry comes along after powering through hormone-sensitive disease, M0 castrate-sensitive. And then this incredible Phase III study.

So can you put that in context a little bit Emmanuel? And also, the trend that we’re seeing in general of endocrine therapy intensification going all the way down the line.

DR ANTONARAKIS: Neil, not every patient with a biochemical recurrence needs therapy. So the main Hopkins contribution was that the PSA doubling time, the rate of PSA rise after definitive local therapy, that is very strongly prognostic. And PSA doubling time of less than 9 months is pretty bad. Those patients, their natural history is that they’ll develop a metastasis within 2 to 4 years. Whereas someone who has a PSA doubling time more than 2 years, they might not develop a metastasis for 8 to 10 years.

So the EMBARK study did not answer the question when should we start ADT, but it did answer the question if a patient warrants the initiation of ADT, does the addition of enzalutamide provide a benefit beyond ADT alone. And I think that was the question. And to select for high-risk patients, it still took 6 years to reach the primary endpoint, even with the high-risk patients. They said, okay, we’ll pick those guys that have a PSA doubling time less than 9 months.

So if this becomes FDA-approved, it’s important to mention that this moment in time enzalutamide does not have an FDA approval, either as a monotherapy in the M0 biochemical recurrent patients, or in combination with leuprolide, but it might in the near future. And if it does, I think the main lesson from this study is, if you have a rapid doubling time less than 9 moths, definitely less than 6 months, and your patient’s longevity is otherwise long enough from other health issues, that it’s reasonable to add enzalutamide.

The monotherapy question, I’m not convinced myself, that the benefits, in terms of AE reduction, are enough.

DR LOVE: Yeah, so we had a big argument about this. Of course, I’m completely naïve. They’re the ones with all the — but I was all excited when I saw that not only with enzalutamide — intermittent enzalutamide therapy, which, personally, although you all have done it, I never even heard of it — but was actually better than ADT. A hazard rate, 0.63 or something like that. And the other thing, before Oliver comments, can you see yourself if you decide that a patient needs ADT for M0 disease, do you think it’s justifiable to use an LHRH agonist alone when you see a hazard rate of 0.4-something when you add in enzalutamide? Emmanuel.

DR ANTONARAKIS: Are you asking about enza alone?

DR LOVE: No, I’m asking about can you see yourself using LHRH agonists alone?

DR ANTONARAKIS: Less likely now. Less likely.

DR LOVE: So of course, the big issue, and this is what we were arguing about, I was all excited that intermittent enzalutamide monotherapy sounded really exciting to me. Actually, maybe before you comment, Karim, we were talking also about high-dose bicalutamide has been studied in the past. Again, for those of you new to oncology, there was actually a 9,000-patient study, adjuvant trial, done in like 2000, right, Karim, looking a bicalutamide. So a lot of people got experience, although I don’t think it was intermittent at that point.

Can you comment on what we knew Karim before about, let’s say androgen receptor signaling, whether it’s bicalutamide or enzalutamide, by itself without ADT?

PROF FIZAZI: Right. I mean theoretically at least, the beauty of AR targeting alone without ADT is that testosterone level will be preserved and actually will even increase. So, potentially you can protect part of the sexual life of these patients and also avoid some side effects from androgen deprivation therapy.

Having said that, gynecomastia is a clear side effect of this treatment when used a single agent. And it can be painful. It can socially an issue. I mean many of these patients are telling me I cannot go anymore to the beach or to the pool or with my little children. I feel uncomfortable. All these things.

So one way to prevent that when really you have to, or you make the decision to use an AR inhibitor, or an AR inhibitor actually alone, is to irrigate the breast as a prophylactic treatment with very low dose, not at all radiation therapy for breast cancer obviously, it’s very low dose, just 1 fraction. It actually works. So this is something that people can consider.

I’m not using bicalutamide alone very often, I have to say. I’m doing that probably in 2 situations. One is a situation where I’m facing someone at very high risk for cardiovascular complications of ADT, but still he has a bad prostate cancer so I want to treat him. And the adverse situation, which is actually rare, is also someone who’s telling me, no, no, no for ADT for sexual reasons. So those are my probably 2 indications. And probably I’m prescribing bicalutamide alone once every year or something like that, no more than that.

DR LOVE: So you were saying, though, that also when you’ve used enzalutamide alone, sometimes you use half dose?

PROF FIZAZI: Oh, enzalutamide, that’s more for the elderly. I think we all agree that enzalutamide has cognitive side effects like fatigue. And that could really be an issue clinically in many patients, especially in the elderly. It’s actually associated also with falls, in again, mostly in the elderly. And I suspect that the dose that was historically chosen a decade ago is probably just too high. And this is also because at that time we were doing Phase I and trying to reach the highest tolerated dose, which may or may not be the right strategy for hormonal therapy.

So, my policy is that if I’m using enzalutamide in a man, say more than 70 years old, I tend to use half a dose, and maybe we’ll dose increase, or maybe not. Because I know it works. I don’t have Phase III obviously, but I know it typically works. And the side effect appear to be lower with these doses.

DR LOVE: So I want to go onto to the second case and we could spend the entire time easily talking about this topic, and we probably should. Just a couple of other points though. So again, Oliver, I was all excited about the possibility of at least offering to the patient the possibility of avoiding ADT and at least trying enzalutamide alone. I thought, well, hey, maybe they’ll have better sexual function, less hot flashes, et cetera, yet you still have concerns.

DR SARTOR: Well, just very briefly, because I know we need to move on, but I want to be a contrarian, that patient could have been treated with radiation and potentially cured. So, salvage radiation therapy, is with the SPORT trial, published in Lancet, 1,500 patients, 3 arms, radiation to the fossa, fossa radiation in combination with 4 to 6 months of ADT, or a large field of radiation, so 3 arms. Bottom line is, at 7 years, the probability of progression was only around 15% with 4 to 6 months of hormonal therapy and salvage radiation. That patient could have been cured. So I’m not even sure I would use the intermittent hormones. I’ll try to cure them first.

DR LOVE: Hmm. Alicia, any thoughts about, again a quality of life in this situation? We were waiting for the data. We’re going to see the data. Dr Shore, who was actually in the satellite we had the next day, was talking about that. But what do you expect? I don’t know how much experience you already have with intermittent enzalutamide monotherapy.

DR MORGANS: Sure. But just before I get to that, I want to emphasize what Oliver said, because I think that we should really think about the EMBARK data in the context of a maximally treated pelvis and prostate area.

DR LOVE: Sure. Of course. Yes.

DR MORGANS: So, just to emphasize that.

DR LOVE: Yes.

DR MORGANS: I have not personally used intermittent enzalutamide. I’ve used intermittent other AR-signaling inhibitors. And I think, at least from a patient’s perspective, there can be those patients, as Karim said, that want to emphasize this ability to maybe increase testosterone, which is what we see with the AR antagonists given as single agents, because they do have some quality-of-life benefits. They may have retention of muscle mass, maybe less weight gain. But the gynecomastia, from my perspective, is probably the most limiting effect. And if we have strategies to mitigate that, I think that this can be really, potentially, very patient-friendly alternative. And when the patient-reported outcomes from EMBARK are available, I think we’re all going to be really curious to see how our considerations and concerns, when it comes to CT-CAE, which is doctors and the clinicians as we rate our concerning side effects, really stack up against what the patients say in terms of their fatigue, their sexual function, and their overall quality of life. There may be a disconnect, and they may feel better, be happier. We don’t know. We’ll have to see.

DR LOVE: I mean from the point of view of clinical medicine, quality of life, patient care, to me this study is epic. And I mean in oncology, not just in prostate cancer. It just took my breath away.

Case: A man in his early 70s with M0 hormone-sensitive prostate cancer (HSPC) with PSA persistence after radical prostatectomy received androgen deprivation therapy (ADT) intensification with abiraterone/prednisone and went to the ER with hypertension, palpitations, headache and abnormal liver function tests — Sandy Srinivas, MD

DR LOVE: All right, real quick case for you, Rana. This is from Sandy Srinivas.

DR SRINIVAS: 73-year-old male. Gleason 4 + 4. Pathologic T3a, had N1 disease.

Unfortunately, postoperatively he had PSA persistence, and it was confirmed with a rise a month later. He gets a PSMA scan that’s negative. The plan is for him to have radiation along with ADT intensification.

So the patient gets abiraterone, and within a month he’s in the emergency room with hypertension, palpitations, headache, and he has a T bili of 12.0.

Clearly has drug-induced liver enzyme abnormality. The abi was discontinued and fortunately showed resolution. So the question that I have for the panel: who can get rechallenged with abi? Are there alternates to abiraterone? Like could enzalutamide be substituted in this case?

It would also be nice to know how frequently do you monitor liver enzymes?

DR LOVE: Any thoughts, Rana?

DR MCKAY: No, I think this is a situation that we encounter not infrequently in clinical practice. And quite honestly, we don’t really have Level I evidence to guide just exactly what to do for those patients that have persistently positive PSAs post-RP, or have pathologically positive nodes at the time of radical prostatectomy. What is the right therapy for these individuals?

I think there are clinical trials that are being conducted through the NRG, that are looking at actually addressing what is the role of therapy escalation in this context? But we don’t actually have prospective data at the present time.

I think we try to extrapolate from the STAMPEDE data, try to extrapolate from what we’re doing in the metastatic hormone-sensitive disease setting, understanding that this is a pretty high-risk patient population where we want to kind of escalate those individuals with the addition of abiraterone.

I think, with regard to monitoring for abiraterone toxicity, technically on label, patients should be undergoing q2wk LFT and potassium check, making sure that they’re actually taking their medications appropriately. Making sure they’re actually taking the prednisone appropriately to limit the amount of mineralocorticoid excess that is seen. Sometimes a lot of patients, especially our older individuals — they’re on statins, they’re on other medications. They may have a little bit of alcohol, a little bit of acetaminophen for either arthritis — and all of that can potentially come into play with regard to the liver toxicity.

So I think education is really important, informing patients about these potential side effects and guarding against them. Making sure patients have a blood pressure cuff; they’re checking their pressures at home. And trying to identify those high-risk individuals up-front, like that may already be on 1 or 2 BP medications when you go ahead and start them on the abiraterone.

DR LOVE: What about her question of putting in an AR blocker at this point?

DR MCKAY: I think the data are really quite limited for just exactly what to do in this setting. I think the most data that we have comes from STAMPEDE with the use of abiraterone, but we don’t necessarily have prospective data.

Now in clinical practice, would I potentially sub-out abiraterone if somebody really was intolerant to it and they’re potentially high risk? I mean it’s having that shared conversation with the patient to discuss risk-benefit. But we don’t really have Level I evidence to say that, yes, this is the right thing to do.

DR LOVE: All right, Alicia, let’s take a look at some data.

Faculty presentation: Dr Morgans

DR MORGANS: Great. So we’re going to talk about the Current Management of Nonmetastatic Prostate Cancer. And as has already been said, I think one of the most important things to remember about this population in the hormone-sensitive or castration-resistant setting is that there is a heterogeneity of the population where we can really see that some patients will have very slow progression to metastatic disease or death from prostate cancer, but we’ll see that other patients certainly are at a very high risk for those complications.

And this is a chart that actually was alluded to earlier by Emmanuel from some Johns Hopkins analyses that looked at PSA doubling time and the association between this and the rate of prostate-specific survival. And we can see that in this hormone-sensitive, biochemical recurrent population, there’s a clear association with a shorter PSA doubling time clearly being associated with a greater risk of developing death from prostate cancer.

And in the castrate-resistant nonmetastatic setting, we see the same thing. And here we can see an inflection point somewhere between 7 and 9 months, suggesting that as our PSA doubling time hits that very short timeframe or low level, we can see such an increase in the risk of developing metastatic disease and death from prostate cancer.

As we think about choosing androgen deprivation therapy, one thing that we think about in the nonmetastatic setting is intermittent therapy, and the HERO trial demonstrated that relugolix may be another option for androgen deprivation therapy in this particular setting, or in any setting of course. But this was a randomization for patients who needed at least a year of treatment between relugolix and leuprolide, so a GnRH antagonist and a GnRH agonist. They looked to see if they really achieved similar levels of castration at a 48-week timepoint, and found that they were actually similarly able to achieve castration and that relugolix may even be slightly superior to leuprolide in that context.

What we can see on the right is that there was a faster increase in testosterone to normal levels in those patients who were treated with relugolix when compared to leuprolide at that timepoint after treatment. And so sometimes as we’re thinking about intermittent therapy and we want fast-on, in terms of lowering of testosterone, and fast-off in terms of resolution of treatment, this may be something that’s attractive to us.

Additionally, we have to recognize that relugolix may be associated with a lower rate of major adverse cardiovascular event as was also demonstrated in this study. As you can see on the left, a 54% lower risk of major adverse cardiovascular event associated with relugolix versus leuprolide, and that seemed to be most pronounced among patients who had a history of a previous MACE event, so a heart attack, a stroke in the past, perhaps making them the highest risk patients to be treated with androgen deprivation therapy.

Moving on, we have alluded to this as well, that those patients with nonmetastatic, but locally advanced prostate cancer also are patients that we want to intensify. And this was assessed in the STAMPEDE trial where patients, as you can see in that upper right green box, who had node-positive disease or at least 2 of each of the T3, T4, PSA greater than 40 or a Gleason greater than 8 criteria, could be enrolled in the STAMPEDE trial for nonmetastatic disease, in which patients who were being treated with radiation to the prostate with definitive intent were randomized to receive ADT and abiraterone with our without enzalutamide, or ADT alone.

What we can see is, those patients who had the intensified hormonal therapy had a better metastasis-free survival in this particular curve, as well as a better overall survival in this curve. And we can see that that hazard ratio suggests a 40% reduction in mortality with that intensified strategy in this nonmetastatic but high-risk patient population.

PRESTO was a more recently published study of patients with biochemical recurrence. This is a hormone-sensitive biochemical recurrence high-risk population, and a really interesting study that came out of the Alliance. And this patient population had a PSA doubling time of less than or equal to 9 months, so they had biochemical recurrence with a PSA of greater than .5. Patients were randomized 1:1:1 to receive treatment with an LHRH analog, or that plus apalutamide, or the ADT plus apalutamide plus abiraterone. And they were followed for PSA progression.

What we can see is that apalutamide plus ADT prolonged PSA progression-free survival in this population versus ADT alone. And that when we added abiraterone as well we continued to see this prolongation of that PSA progression-free survival. So this intensified strategy could prolong PSA progression-free survival and this was really assessed and confirmed in patients who had testosterone recovery, which is so important when we’re thinking about PSA progression. When testosterone recovers of course patients are more likely to have PSA progression if the disease persists.

We’ve been talking a lot about EMBARK tonight and we know that this is a patient population, again with high risk biochemical recurrence — this is a castrate-sensitive or hormone-sensitive biochemical recurrence — in patients with a PSA of 1 or greater if they are post-prostatectomy, or at least 2 nanograms above the nadir per those criteria in patients with treated with radiation. And they had to have that PSA doubling time of less than or equal to 9 months. Randomized here again to enzalutamide and leuprolide versus enzalutamide alone versus leuprolide alone, as we heard recently. And they were followed after — they were continued to be followed for about 37 weeks. And if they achieved a PSA of less than .2, they were able to do an intermittent approach to their systemic therapy, so they could stop systemic therapy. If they did not achieve that really low PSA level, then they did have to remain on their therapy.

They were then followed for a metastasis-free survival endpoint.

So here we can see the curves for MFS, and we see that enzalutamide plus ADT was associated with prolonged metastasis-free survival, as compared to ADT alone in this high-risk biochemical recurrent population. We can see that there was trend perhaps, towards overall survival being improved with the combination, but I would say here that this is very immature and a long way to go in this particular analysis.

And then what we can see on the next slide is that enzalutamide versus ADT was also studied, as we mentioned, and we also see a prolonged metastasis-free survival for enzalutamide alone versus that ADT alone. Importantly, again, this is an intermittent strategy for patients who achieve that low PSA.

These are the side effects, or some of the side effects that we have been talking about tonight, and they’re generally very similar between the arms. But we can see that hot flashes are lower in those patients receiving enzalutamide monotherapy. Whereas, if we look at the very bottom, gynecomastia and nipple pain actually higher in enzalutamide monotherapy. Fatigue, similar across the board.

So, what this is going to look like in our practices I think remains to be seen. We’ll have to figure this one out.

And then to close, nonmetastatic CRPC of course is something that we’ve been thinking about for several years. Three studies: SPARTAN, PROSPER and ARAMIS — assessed these populations and looked at ADT versus ADT plus apalutamide, darolutamide or enzalutamide, and all had a metastasis-free survival endpoint. The combination therapy prolonged metastasis-free survival in all of these studies demonstrating that ADT plus an AR signaling inhibitor was superior in all, and also superior in terms of prolonging overall survival across the trials.

And so, patient selection is really important in this nonmetastatic patient population. Abiraterone, when added to ADT in combination with radiation, prolonged survival in high risk, locally advanced prostate cancer as we saw with STAMPEDE.

Intensified treatment with ADT and apalutamide can prolong PFS in high risk biochemical recurrence. ADT and enzalutamide prolongs MFS in high risk BCR.

And intensified treatment with ADT and enzalutamide, apalutamide or darolutamide prolongs MFS and OS in nmCRPC.

Thank you.

DR LOVE: Kind of interesting to think about the fact we’ve been using ADT for a long, long time. And even enzalutamide monotherapy beat it. So, another question I was thinking about Karim is what do we know about apalutamide and darolutamide without ADT?

PROF FIZAZI: Without ADT? Actually, apalutamide was tested in a trial in Brazil. It actually showed very consistent data as what we just saw. It works. Whether it’s good enough and well tolerated enough to justify use, not sure at all.

For darolutamide, a randomized trial is ongoing in Europe. I don’t think the data have been reported. I won’t comment on that, but this is ongoing. Darolutamide, I mean appears to be quite well tolerated generally speaking. So the hope is really that the side effects we saw with enzalutamide or apalutamide as single agent will be lower with darolutamide, but this remains obviously, to be demonstrated as a single agent. We just don’t know.

DR LOVE: Just kind of curious, show of hands the people here in the audience, how many of you have actually used enzalutamide, darolutamide or apalutamide without ADT?

Okay. A consensus!

Case: A man in his mid 60s with localized prostate cancer and biochemical recurrence 5 years after neoadjuvant and adjuvant leuprolide and intensity-modulated radiation therapy to the whole pelvis — Neeraj Agarwal, MD, FASCO

DR LOVE: Here’s another issue that I wasn’t really thinking too much about, and actually this next case made me think a lot about, which is just the issue about intermittent therapy. And I guess somehow along the line I didn’t realize the importance of what the form of ADT was. There’s a big difference between using an antagonist, degarelix or relugolix, versus an agonist, LHRH, leuprolide or goserelin. And this was brought out by this case from Dr Agarwal, a patient who ended up getting relugolix intermittently. Here’s the case.

DR AGARWAL: This patient had detectable PSA of 0.1 ng/mL 2 years after radiation. Now 5 years after radiation in 2020, PSA is 10.2. Conventional scans are negative. And then finally, he’s decided to start intermittent ADT.

DR LOVE: So how is this man doing at this point?

DR AGARWAL: He is doing great. Happy with a real break — he is in his break period or off period. He started relugolix, the PSA goes down very quickly to less than 4 within 2 months. And then, he took a break. Break lasted for 5 months. And then once he restarted, again the PSA goes down.

We achieve the goal rapidly and then break period usually lasts for 4 to 5 months.

DR LOVE: So Oliver, any thoughts? When I first started hearing about the antagonists, I was focused on the cardiovascular issue. I wasn’t really thinking about how quickly you get recovery. Can you talk a little bit about how that plays out.

DR SARTOR: Sure. So if we go to the original agonist, that’d be a leuprolide type drugs, it turns out that you may give them for 6 months, but there’s a pretty persistent lowering of the testosterone that can go on for much longer.

I think one of the advantages of the antagonist, as opposed to the agonist like relugolix, give pretty rapid reversibility. So an intermittent approach you definitely have the advantage of being able to see on again/off again, on again/off again, with reversibility so the testosterone is a little more controllable. Using the agonist, the testosterone can take a long time to recover.

DR LOVE: Rana, any comments about relugolix? It’s an oral agent, which would seem to be an advantage, although, potentially may be more difficult to access. And what are your thoughts about the cardiovascular link? What type of cardiovascular profile will get you to want to use these drugs more?

DR MCKAY: Yeah, that’s a very good question. I like what Alicia said about the fast-on/fast-off approach with regard to relugolix, with an oral medication, especially those individuals that have a history of a prior cardiovascular event. I think those are the people that worry me the most that have cardiovascular risk factors or maybe I’m worried about tolerance. That’s the beauty about relugolix is it’s an oral pill. If you run into trouble with it you can easily stop it. And the time to testosterone recovery is a lot quicker when you discontinue therapy. And additionally, there is, even though the rates of cardiovascular events in the context of the HERO trial were low in general, there did seem to be a benefit with having an antagonist onboard as opposed to an agonist. Probably driven by the effect of FSH and more rapid lowering of FSH.

So I do think that there is beauty to having this oral fast-on/fast-off option.

DR LOVE: And for the general medical oncologists in the audience, which I think there are quite a few, you immediately will start seeing analogies to breast cancer. And on Monday night, we’re going to talk about the issue of tamoxifen alone compared to tamoxifen plus LHRH agonists. And clinically, although they’re different diseases, the oncologists will begin to see that maybe there’s a paradigm, that we’re going to talk about Monday night in breast. It’s well-fleshed out that may be starting to come into prostate cancer. We’ll see.

Case: A man in his early 80s who underwent radical prostatectomy 15 years ago and received radiation therapy and ADT for biochemical recurrences is now diagnosed with M0 castration-resistant prostate cancer with quickly rising PSA — Dr Morris

DR LOVE: Here's another very fascinating issue that I hadn’t really thought much about. This is an 82-year-old man, a patient of Dr Morris.

DR MORRIS: 82-year-old male, treated prostatectomy 15 years ago and then had radiotherapy for PSA recurrence. He started ADT for that PSA recurrence.

His PSA did drop but it only nadired to 3.0 which is kind of a concerning finding for any of us, and then started rising again, and now the PSA doubling time is 6 months. He had a CT and bone scan imaging for staging. This has been years ago so there was no PSMA PET or fluciclovine PET available. It was kind of confirmed as nonmetastatic CRPC with a quickly rising PSA. And so he started on apalutamide. He had a response with a PSA drop to undetectable. He eventually had to have a dose reduction due to fatigue. But he has been on apalutamide for 5 years now with a PSA drop to undetectable and on most recent imaging has a CT and bone scan with no metastatic disease noted.

So the question I think clinically coming from any of this is with the idea of EMBARK where you’re inducing and getting good responders is when is it appropriate to deescalate therapy? He’s tolerating the medication but it’s more of having to apply for grants, having to try to get the drug in his hands, and his out of pocket exposure. And he just would like to come off therapy if he could.

DR LOVE: So Karim, I’m curious. When I heard this case I’m like, does this really happen? So I’m curious, have you seen cases like this? Do you ever stop therapy? Any role — I mean any thoughts about how you might manage this? And also, why is this tumor, or this patient different than everybody else who doesn’t do as well? Any speculations biologically?

PROF FIZAZI: Wow, those are hard questions to answer, particularly the last one. I’ll start with the first one, which is, if I recall it well, did I see similar patients? And so is yes. I mean, as we’re using more and more the AR pathway inhibitor earlier in various settings of a disease, we do see very long-term survivors with complete response basically, including by PSA. And what Dr Morris is asking as a question is a key one. Honestly, I don’t have the answer. but it’s sort of tempting to go for de-escalation in some patients. I tend to do it, especially when the treatment is not well tolerated because actually I believe this is easier. And this is true also with ADT, to be honest. For example, in metastatic hormone-sensitive setting, I had some patients benefiting for 5 years, 10 years, 15 years, and sometimes honestly, I tend to stop. But we need guidance. We just don’t know what is good, what is bad. When should we stop and when we should not.

We are about to launch a Phase III trial for men who are good responders after ADT plus intensification for metastatic hormone-sensitive disease, not exactly the same setting as this gentleman, in Europe. And this is going to randomize for patients with detectable PSA at 6 months just carry on with the treatment classically, versus discontinuation, and restart in the case of the progression. And I think this will be a very important trial to conduct.

But I’m sorry, I really don’t have an answer to provide to Dr Morris. I would be tempted, especially in an 82-year gentleman, to make a pose, but this is one of the things we need to discuss openly with patients, sharing the lack of evidence, and the pros and cons.

DR LOVE: So if you remember all the questions, it’s like a cognitive test. You left out the one of biologically what’s going on.

PROF FIZAZI: So I tried my best to avoid it.

DR LOVE: Different androgen receptor?

PROF FIZAZI: Obviously, some prostate cancers are very, very, very driven by the androgen receptor machinery. This is an obvious thing. And actually, many men who die from prostate cancer do die with an active AR machinery ongoing, which means that we should keep targeting AR in many situations of advanced prostate cancer. But why? I mean, we do have some potential explanation biologically speaking, for example, SPOP predicts for hormone sensitivity. But I’m quite sure we don’t understand everything, to be honest. There are probably some other biomarkers that we need to identify.

DR LOVE: So Oliver, I’d like your thoughts. And also, I learn so much when I meet with the faculty. We sit down for about 45 minutes. We come in there, they’re like blasting me with all kinds of stuff. And one of the things you mentioned that you’ve got to tell them about, is this trial with the oligomets and the lutetium again. So, any thoughts about Karim’s comments, and then how about this trial?

DR SARTOR: Sure. So, one comment. There’s been a little bit of work that looks at the transcriptomics and you can kind of divided this into luminal and basal, and you can look at Luminal A and B, and it turns out that there’s differential sensitivity to hormonal therapy. And that these basal, sort of transcriptomic markers, are a little less ADT responsiveness, and maybe the Luminal-B a little more. So there is kind of a luminal/basal story that some people will play to.

One of the things that I think is important to discuss, and this gets to the second part of your question, is we’re using a lot more PSMA-PET under these circumstances. So, imagine you just stop the ADT in this type of patient and if his PSA does rise, then why don’t we go look for it and see if we can find it on the PSMA-PET. And some of the things that we can do might include what we call SBRT, stereotactic body radiotherapy, and when you see a little met and a little met there, then sometimes we can control it quite well with the SBRT.

So thinking ahead, just for a brief moment, because men don’t like to be castrated, and we talk about ADT and we talk about sort of systemic therapies, but what we’re really talking about castration, and men don’t like that. So an alternative could be, and now we’re going to move forward into that PSMA-detected oligometastatic situation, giving SBRT as a standard of therapy, but now, instead of the ADT, we’re going to be adding in the PSMA lutetium in a randomized way.

So this is a prospective, randomized Phase III trial, metastasis-free survival endpoint, just like in EMBARK, and looking at the question of whether or not PSMA lutetium might inhibit the development and prolong...

So, anyway, just another way of thinking about it. And that’s going to be coming down the pike, probably be opened up this fall.

DR LOVE: Totally amazing how often I talk to these people and I still hear things everyday I’ve never heard. And another thing I heard, and Rana, maybe you want to comment on this, I’ve heard about this scenario of the patient who, like in the past, and EMBARK would have been called M0, but they didn’t have PSMA. Now you do the PSMA and it’s positive. And I just assume all these people get treated like hormone-sensitive mets. I hear about the stories about oligomets and, of course, that makes a lot of sense, but I assumed that was unusual. And yet you all in the faculty room were telling me actually, that’s a very common thing. Like, what fraction of people in that situation actually fit into this oligomet scenario, Rana?

DR MCKAY: I think it’s actually ever increasing with the increased utilization of PSMA-PET imaging. I mean, every single weekly Tumor Board that we have, we have a case being presented of somebody with negative conventional imaging and they’ve got some areas of potential disease on their PSMA-PET and we’re sitting there and scratching our heads, like is this real? Is this unequivocal? Should we biopsy it? Should we SBRT it? Are we going to wed this patient to life-long hormonal therapy as if they were an mHSPC patient? Or are we going to give SBRT alone? Are we going to give SBRT with short-course ADT? I think we don’t have prospective data to guide what to do at the present time but there’s a series of clinical trials, the one that Oliver described, and others, that are actually looking at the strategy of SBRT, short-course ADT. These patients, I think, are a little bit different than patients that were overtly metastatic on conventional imaging.

DR LOVE: You can’t think of a better example of what’s happened in oncology in prostate cancer. It was not that long ago that when we did a program, what are we going to talk about? And now, tonight, in 2 hours, we’re just going to touch on a lot of stuff. And I’ll turn it over to Karim for some more data.

Faculty presentation: Prof Fizazi

PROF FIZAZI: Sure, happy to. Thank you Neil.

So I guess we all know for almost a decade now that we should intensify men with metastatic castration-sensitive disease. Really clear benefit of intensification. Multiple trials shown.

Docetaxel was the first drug to show this benefit. And when first shown in CHAARTED, approximately 40% reduction in the risk of death was originally reported. Unfortunately, when a longer follow-up was achieved, not only in CHAARTED, but also in STAMPEDE docetaxel, it appeared that the benefit of docetaxel alone was lower than initially announced, approximately 20% reduction in the risk of death. Not anymore 40%. Better than nothing, obviously, but still, patients die. And you see this banana kind of form, if you will, for the Kaplan-Meier curve. Maybe because we’re just giving docetaxel for 4 months, not for continuously. And after some time, patients progress.

Now on the other hand, 2 years after that, starting in 2017, we saw the eve of second-generation AR pathway inhibitors starting first with abiraterone in LATITUDE and STAMPEDE, and for longer-term follow-up analyses of these 2 trials appeared — I mean provided good news to us with a benefit quite sustained and approximately 45% reduction in the risk of death, which was great obviously.

This was confirmed with the other agents: enzalutamide and apalutamide. And the benefit appeared to be very similar to that of abiraterone.

Now a key question I guess to us, to medical oncologists, is really should the systemic treatment defer according to metastatic burden, but also to timing of metastasis? And timing would be relapse versus de novo metastatic disease.

And here I’d like to show you this picture and let’s say that those are you next 100 patients with metastatic castration-sensitive disease. And they kind of appear to be the same, if you will. And actually, for a long time, we’ve been treating these patients the same with ADT alone and we’re still missing a biomarker to help us for decision-making. But, still, if you’re using simple criteria, clinical criteria, you will separate different scenarios.

This gentleman here has de novo disease and just a few mets, low burden, low volume, low risk, whatever we call it. This other gentleman also has de novo disease — he was diagnosed today with his prostate cancer and the metastasis at the same time — but he has really disseminated disease, with multiple mets. And then you have the 2 other scenarios, a recurrence with low burden disease, which is quite frequent amongst the recurrences, and a rare situation of recurrence with high burden disease.

Why am I showing you these 4 things, these 4 scenarios? Just simply before — because the natural history is not the same, especially for patients with a recurrence and oligometastatic disease, they’re outcome is just much better — even before the eve of all treatment intensification, the likelihood for survival was approximately 8 years, as opposed to just say, 4 years for the 3 other scenarios.

So if you’re putting these patients with the other ones, just because of this you can have different results, not necessarily depending on treatment, but just because of the biology of the disease.

And also, and very importantly, we’ve been kind of fighting sometimes about whether docetaxel should be used or not in both low-volume and high-volume disease, but it actually appears to be confounded by this timing effect. And I’m saying that because an internal analysis of all off-label trials clearly established that patients who relapse, so metachronous patients, and low-volume, so oligometastatic disease, just don’t benefit from docetaxel chemotherapy. Thus, probably explaining why CHAARTED was negative for these patients. But the other 3 groups — so all the de novo, if you will, and the rare of situation of relapse and multiple mets, actually derive approximately the same benefit from docetaxel chemotherapy, approximately 10% reduction in the risk of death. Which means that in patients with de novo disease, eventual struggling as to whether you should use docetaxel, you actually can. And your patients, statistically speaking, may benefit. I’m not saying all patients, of course, should receive it.

Now with second-generation AR pathway inhibitor, we saw efficacy across the board, low volume/high volume, also mostly because these patients had de novo disease in the trials. Patients who relapsed were very rare in all trials I’ve been speaking about today.

The next question was obviously, should we even intensify further all the systemic treatment and use 3 drugs instead of 2? So this is why we did the PEACE-1 trial, which is asking 2 questions: one question is about systemic treatment, and the second question is about the radiation therapy directed to the primary. You’ll need to wait for tomorrow morning because this data will be first presented at the Congress of the overall session tomorrow. But regarding the systemic treatment, we do have the data and they’re positive. Clearly, if you’re using 3 drugs, ADT/docetaxel and abiraterone, your patients will do better in terms of radiographic progression-free survival, 2 years versus 4.5 years, so you’re providing basically 2.5 additional years of good life to your patients adding just 4 drugs. And they will benefit also by overall survival with a 25% reduction in the risk of death.

So if try to put this into perspective, and I chose here patients with the worse disease, de novo and high-volume for comparison purposes. A decade ago we were using ADT alone and these patients would live 3 years max as a median. Very consistent across the trials.

Docetaxel improved survival with approximately 43 months as a median, abiraterone 53, and now with the triplet treatment these patients live over 5 years as a median survival. so in just a decade we went away from less than 3 years to now more than 5 years, again full dose with the worse disease at presentation.

What is the price to pay for patients in terms of toxicity? Increase in liver mets — in liver transaminase increase, sorry, 6% versus 1%. So it happens. You need to monitor. Hypertension, 22% versus 14%, those are Grade 3 and 4. So again, please monitor your patients. Nothing crazy to do and nothing very difficult to do.

This is now confirmed with the second Phase III trial, ARASENS. Clean trial, testing ADT/docetaxel plus or minus darolutamide. And clean answer, where overall survival is significantly improved with 32% reduction in the risk of death favoring the triplet strategy.

This is very consistent across the board. We now have ENZAMET also, a subgroup of patients form ENZAMET. And you see it’s really the same Kaplan-Meier curves.

Again, in ARASENS, high-risk and low-risk patients were tested and they tend to benefit pretty much the same with a caveat of course, of subgroup analyses including sometimes small subgroups.

So I guess there are many good reasons now to choose a triplet strategy in fit men with de novo metastatic disease. First those agents don’t work the same in terms of mechanism of action. And we know that one drug can prevent resistance to the other one from COU 301/AFFIRM and CARD. It goes both ways.

We also know that this is a heterogeneous disease. Again, we don’t have a biomarker to help us to decide who should get X, who should get Y. so until we have that, we should probably better use poly-treatments.

And if ever you’re using just a doublet, well basically the next step with docetaxel, which doesn’t work fantastically well in CSPC. So why not using it earlier up-front for better efficacy and less toxicity in a younger man and fitter man?

And at the end of the day, really 6 cycles of docetaxel is just 4.5 months and mostly well tolerated with G-CSF support. And I recognize that there are exceptions. If your patients do not tolerate it, just stop.

So take-home messages. I think the current standard has evolved. We should use for de novo high-volume disease probably mostly a triplet. For those who are unfit, just a doublet without chemo. For low volume, more difficult to say. And please wait for tomorrow for maybe more data.

For patients relapsing, we need just to be extremely cautious. The Phase III trials actually did not include many men with relapses. So whatever we say, we need to be very cautious about this because it’s very easy to make mistakes.

We also have to take care of patients in the elderly. And sometimes we have to use ADT alone. I mean, when we have to we have to. And most importantly, we need new trials. And those will be my last 2 slides.

We have 4 big, Phase III trials currently ongoing at least. Actually, more than that. Those are examples. PSMAddition I think is a very important one. And Oliver is the Chair. This is testing PSMA lutetium. But there are also others. And for sake of time, I will not detail all of them.

We are also doing academic world, and PEACE-6 is a platform of Phase III trials. And we are focusing on different population of men: oligometastatic disease, radiation to the max. The vulnerable population, can we still intensify those patients with darolutamide? And then we spoke about it, we’re just about now to open 2 trials, 1 for good responders by PSA at 6 to 8 months. the other one for poor responders because we need to improve the outcomes of these patients.

Thank you so much.

Discussion

DR LOVE: So, maybe just sort of a second opinion. That was the name of this thing here. And I’m going to very humbly ask this question, and tomorrow night we’re going to be jumping all over the myeloma people who want to give quadruplet therapy, transplant when there’s no survival benefit. But, okay, you want to present that to the patients, it’s up to them. That’s fine. But just kind of let them know what the deal is. So Oliver, I’m thinking about a younger patient who could tolerate a triplet. Walks in — you’re going to see a case like that in a second from Sandy. All of a sudden is dealing with metastatic prostate cancer. A shocking thing. About to go on ADT and more. And then the question is on top of everything else, are you going to give that patient docetaxel? Based on what we just heard, the answer would be yes. But would you say to the patient, well, we really don’t have clear-cut evidence that by adding docetaxel it’ll be better than giving intensified endocrine therapy? And how do you discuss this with your patients?

DR SARTOR: So great question, Neil. And one of the things that I think is a little bit complicated here is the history in the CHAARTED trial and in the STAMPEDE trial was to add the ADT/docetaxel. And then the question was could you have greater effect by putting in abiraterone, enzalutamide, whatever? Darolutamide. It turns out that there’s another question in my mind and that is, what’s the value of docetaxel?

Now Karim makes really good points. It’s not a great therapy in the castrate-resistant setting, and maybe you get more effect when you give it up front. But I think if we’re strict about the way we look at the data, that we would say ADT and, say, abiraterone, could be a standard. And the question is, what does docetaxel add? Now that study has not been done. And so, if we are conservative and a little bit strict to the way we interpret the data, we can ask what’s the value of docetaxel? And I think the honest answer is we don’t really know.

Now the triplet is going to be better. If you’re going to be using ADT/docetaxel, I think adding in the darolutamide or abiraterone makes a lot of sense. I really do. But on the other hand, if you question the use of docetaxel and you’re going to be going with some ADT/abiraterone and keep enzalutamide, ADT, apalutamide, darolutamide, whichever — we don’t have actually have the data with darolutamide — but if we look at the intensification with the hormonal therapy, I think it’s legitimate to ask what does docetaxel add.

DR LOVE: Alicia?

DR SARTOR: I mean I want to look at the others because sometimes I get a little bit fixed in our mind, but I want to make sure about reality.

DR LOVE: That’s why we’re here. Alicia.

DR SARTOR: Reality check.

DR MORGANS: And that’s exactly why we’re here to have these conversations. The way that I think about docetaxel is that I’m going to use it now, or I’m going to use it later in a patient who’s going to be fit for docetaxel. From my perspective, I want to give it when I know that there’s clear evidence of that triplet activity, when the patient’s younger and healthier, probably than they’ll be in a few years. Certainly they’re younger than they’re going to be in a few years. And if they’re fit, and they have the social support and they understand the side effect profile, I would rather do 6 cycles now than 10 cycles later. And that’s just generally how I think about it. But I ask the same question. I think we all ask these questions, and it’s just a matter from my perspective, again, of when?

Case: A man in his mid 60s diagnosed with mHSPC and PSMA positivity in the pubic ramus, bilateral external iliac nodes and lungs — Dr Srinivas

DR LOVE: So let’s bring us to a real case. Rana, I want you to listen to this case and tell me how you would discuss the options with a patient. Here’s Sandy.

DR SRINIVAS: CEO of a startup company. Through the pandemic he had no health checkups. So he went in early part of this year to have a PSA done and was shocked that his PSA came back at 184. He literally told me the story how he walked out of that room totally devastated about what’s happened.

He them gets a biopsy that, no surprise, was a high Gleason score. He gets a PyL PSMA scan that shows disease in the prostate but has also got disease in his inferior pubic rami bilaterally, external nodes, and also has lesions in the lung.

He’s young, he is chemo fit, he has visceral disease, which is in the lung. So should he get a triplet? Should he get radiation to the prostate?

And I do have a question about visceral mets. Are they all the same?

DR LOVE: So, like, his lung and liver similar prognostic, et cetera? Rana?

DR MCKAY: Yeah. No, I think these situations can be quite challenging. And first I would ask, I know this patient was diagnosed by a PyL PSMA-PET, but I do want to see what their conventional imaging shows. I want to see where those mets actually observed on that corresponding CT scan. Did the patient have a bone scan that identified those lesions? Because I think our categories — categorization schema that Karim went through with us is based off of conventional imaging.

And so, you’d hate to put this patient in the category of high-volume disease when they could potentially benefit from potential radiation to their prostate or some sort of local therapy.

I think this is a patient that I would definitely discuss treatment intensification with potentially triple therapy. I do think that the dynamics of lung metastases can be quite different than the dynamics of liver metastases. I think we’ve seen that in clinical practice. And quite honestly, I think we’ve been talking about clinical parameters to think about clinical decision-making in the context of mHSPC, largely around timing and volume of metastases, but I think, in the era of next-generation sequencing, we’re actually learning more about these tumors. We’re learning more about the presence of tumor suppressor loss, SPOP alterations, other things like that that can potentially inform treatment decision-making. We don’t necessarily have prospective data, but I think just from the subset analyses from existing studies, I think that data can potentially be useful. But I think this is a potential individual who could benefit from treatment intensification.

And I think the big question to ask is, are you ever — we don’t know the answer to this — but are you able to make up the difference from an OS standpoint with sequential use of docetaxel than as opposed to giving it up-front. Like, if you give it up-front, that benefit that you get in the mHSPC setting, are you going to be able to overcome that in the mCRPC setting? So I think we don’t know the answer to that. But in all of the strategies where we intensify it up-front, you can’t make up the delta in the mCRPC setting, like the benefit is just so profound in the mHSPC setting.

DR LOVE: So Emmanuel, this seemed to be almost the child for the perfect situation almost, to consider a triplet. How would you discuss it with the patient? I mean, let’s assume the patient is educated — maybe the patient is a medical oncologist. How would you discuss it? And how would you discuss the issue of docetaxel now versus not?

DR ANTONARAKIS: Neil, many of these patients may not have a positive CT scan for the pulmonary mets, so —

DR LOVE: Let’s say it’s positive.

DR ANTONARAKIS: That’s a caveat. But if he’s truly positive, there’s no question — I don’t think anyone on this panel would disagree that liver mets are the bad prognosis. Visceral mets and lung mets, sometimes those patients can live forever. They’re very hormone-sensitive. There’s been publications on that. The molecular profiles are different. They’re more characterized by SPOP mutations, less p53, RB1 loss, et cetera. But yes, this technically counts as high-volume disease, according to the CHAARTED definition, and the patient is young. We assume he’s otherwise fit. And in the absence of preexisting neuropathy and provided that the patient is game for maximal therapy, I think the addition of docetaxel would be appropriate here. And that could be done with ADT plus darolutamide plus docetaxel or ADT plus abiraterone plus docetaxel.

DR LOVE: Karim, would you like to weigh in on this case? How strongly would you feel — putting aside whether a patient could go into a protocol – but if the patient said, wow, I’m going to be dealing with ADT. My whole life is changing. Can we hold off on the docetaxel? Would you be okay with that, or would you really feel this is not a good idea; he ought to get a triplet.

PROF FIZAZI: Oh, in such a situation I would clearly recommend the triplet. And typically, when patients are telling me where I don’t like the idea of receiving chemotherapy, either in this situation or in another one, I tend to negotiate with the patient and say give it a try. You will decide. Don’t worry. I’m not going to run after you and catch you and inject the chemo. Just get a first cycle and we’ll speak again for next time. If you don’t like, you don’t like it, and we stop. And most patients actually tolerate it okay and carry on until 4 or 5, 6 cycles.

So this is typically the conversation I would have with someone who is really hesitant.

DR LOVE: All right, Rana. Let’s talk about some data.

Faculty presentation: Dr McKay

DR MCKAY: Great. Wonderful. So we’re going to dive into Available and Emerging Strategies for mCRPC, kind of go through these objectives to talk about what’s the clinical decision-making that you all think about, the disease factors, the patient factors that you think about for deciding on any given therapy.

We’ll talk about older drugs and newer drugs that are emerging as well.

So this is sort of the landscape of advanced prostate cancer. We’ve been talking a lot about what’s been happening in the metastatic hormone-sensitive setting, but there’s, of course, a series of agents that are no utilized in the mHSP — or mCRPC setting from taxane chemotherapy, the AR pathway inhibitors, sipuleucel-T, cabazitaxel, radium, and more recently lutetium PSMA. And we’ve also got a biomarker-selected therapy with olaparib, rucaparib, and pembrolizumab as well.

I think that factors that impact my treatment decision-making in the mCRPC setting include disease factors — we’ve talked a lot about these. I think it’s ever more important what prior therapies have they received, particularly what have they received in the mHSPC setting? Are they coming into mCRPC being naïve to taxane, naïve to an ARSI? Or have they been exposed to one of the other or neither?

Burden of disease. I think disease kinetics also matter. Do they have just PSA progression and they’re coming into M1 CRPC based off a PSA progression alone? Or is based off of radiographic progression, sites of mets, Gleason score. Less relevant here, but genomic parameters.

I think clinical factors also matter. Is the patient symptomatic? What’s their Performance Status? What are their comorbidities? What concurrent medications are they on?

And then of course thinking about the drug factors, the mechanism of action of the agent that you’re potentially thinking about utilizing, mode of administration, and cost as well.

When people develop CRPC, there’s multiple different pathways of how patients come into metastatic CRPC. They can have continued AR-driven disease, and we’ve heard about that from Karim earlier today, whether it be alternate ligands that are activating the receptor, AR amplifications, AR mutations that disease continues to be AR-driven? Or is it ligand-independent with upregulation of alternate pathways?

And I really like sort of the breakdown of the NCCN Guidelines. I know this looks like a laundry list of agents, but I think we’re moving away from sort of this one-size fits all model and actually taking into account what that patient may have received in the metastatic hormone-sensitive setting to really help guide what to potentially do in the M1 CRPC setting, based off of whether they’ve received a prior taxane or a prior NHT. Whether they received one of those medications or both of those medications.

So just going through a little bit regarding the prior available therapies — we’ll talk about sipuleucel-T — this is an autologous dendritic cell vaccine. It’s been around for a long time, since 2010. It demonstrated superiority in a large Phase III trial. I think some of the — the question is, does it still have relevance in the modern era? It’s not associated with PSA responses. It’s not associated with objective responses. I think potentially where it has a role is people who are asymptomatic, low-volume disease, lack of visceral metastases, potentially developing M1 CRPC with PSA progression alone. And you’re kind of dragging your feet regarding the need to put them on any given therapy. I think that’s actually probably the sweet spot for utilization of this agent. But when we look at data about how it’s being used in the modern day, probably less than 10% of patients are ever seeing sipuleucel-T.

Here are various studies that have looked at sipuleucel-T. I think we need to take these studies for what they are, they’re small — the first 2 are prospective trials, but they’re not large, randomized trials. STRIDE looked at concurrent versus sequential, ARTA use. STRIDE looked at the use of enzalutamide, whether it be given sequentially or concurrently. STAMP looked at concurrent versus sequential abiraterone. And it seemed like the concurrent strategy was associated with improved outcomes when given with sipuleucel-T as opposed to the sequential strategy. Again, these are small numbers, small trials. Kind of thinking about how to potentially integrate use of an ARSI with sipuleucel-T.

With regard to combination therapy with Radium-223, I think this is data actually from the Johns Hopkins group that conducted a study looking at the combination of sipuleucel-T with or without the addition of Radium-223, demonstrating a signal when the 2 are used concurrently. There’s also some retrospective data about the concurrent sequential use of ARTA in the combination — in combination with sipuleucel-T.

I think people that receive sipuleucel-T, just from retrospective data, seem to do better even after correcting in multivariate analyses. I think we need to be careful about these kinds of data. There’s a lot of bias around who would actually receive sipuleucel-T. These patients tend to be asymptomatic. They tend to be associated with lower disease burden, lower rates of symptomatic disease. But I think we do have some evolving data about the modern day use of sipuleucel-T in the current era.

Here is a study that we actually conducted, a Phase II, multicenter study of enzalutamide in the castration-resistant setting. I know this snuck in here — looking at PSA responses based off of prior therapy with enzalutamide in the mCRPC setting. Really, this trial was designed about understanding the genomics around enzalutamide utilization in the mCRPC setting. We did paired biopsies in the context of this study. I think it kind of snuck into the slide deck — it was kind of in the appendix — but the biggest thing that we found was actually patients that had — this is a very messy slide here, but had TP53 alterations, that had tumor suppressor loss, that had Rb loss, seemed to actually do worse. People that actually had AR alterations seemed to actually, potentially, do worse. SPOP alterations did better with the utilization of enzalutamide. So I think we’re learning more about the utilization of these ARSIs in the context of mCRPC.

I think a lot of these patients now may have potentially already received an ARSI for metastatic castration-resistant disease.

A little bit about the cell cycle. I think we have to go back to biology here. So every cell, when it’s undergoing the state of cell division, it’s usually sitting in cell cycle arrest in G0, but when it actually kind of decide to proliferate and grow it enters into the cell cycle pathway. And you’ve got critical checkpoints, particularly between the transition from G1, which is the first growth phase when you’re getting into the S-phase, which is where you’re basically at that step where you’re about to synthesize the DNA. There’s very critical checkpoints that are at that level, including Cyclin-D, CDK4 and 6, that regulate that transition, going into S, finally G2, and actually cell proliferation. And there have been some drugs that have actually developed to intercede on the cell cycle pathway.

There’s a lot of cross-talk between the cell cycle pathway and the AR pathway. We know that androgen receptors like the estrogen receptors are key regulators of cell cycle and are really instrumental in transcriptions of genes that allow that transition from G1 to S. And preclinical studies have certainly demonstrated the inhibition with CDK4/6 actually triggers this G1 arrest in the cell cycle. And that there can actually be potential synergy in preclinical models with CDK4/6 inhibitors and AR signaling pathway inhibitors.

There are several CDK4/6 inhibitors that are being tested or have been tested in patients with advanced prostate cancer: abemaciclib, ribociclib, palbociclib. These agents are already FDA approved for the treatment of advanced breast cancer. Abemaciclib also has an indication in early breast cancer that’s HR-positive/HER2-negative.

There are differences with these agents regarding their activity at CDK4/6. Abemaciclib is the most potent, with a really IC50 at CDK4/6, and also does have some activity at CDK9. So it has a little bit of a distinct mechanism of action compared to ribo and palbociclib.

And then, as we think about the pharmacology of these agents, abemaciclib has a little bit shorter half-life. It’s given on a twice-daily basis. Does have CNS penetration. And you can see the side effect profiles there. There’s a little bit more GI toxicity that’s associated with abemaciclib. Less myelosuppression than is seen with ribociclib and palbociclib.

And so we’ll highlight some data from the CYCLONE 1 study. These were data that were presented at AACR by Dr Agarwal. This was a study that looked at abemaciclib given as a monotherapy in a heavily pretreated patient population. These are sort of the topline data from this trial. I think we need to keep mind again that this was a pretty refractory patient population, but looking at the objective response rate with 6.8%, not everybody was evaluable for response in the context of this advanced study. The stable disease rate was at 40.9%. Disease control rate, right around 50%. I think very underwhelming median radiographic progression-free survival of 2.7 months. But this is, again, small study, really being conducted in the refractory setting.

There are other studies that are looking at abemaciclib in this context. The CYCLONE 2 trial is looking at abemaciclib in combination with abiraterone in the front-line mCRPC setting. This was a large Phase II/III study with a go/no go signal after the Phase II to potentially proceed into the Phase III which it did. The trial is closed. And we’re awaiting the results of this trial.

And I think that is the key items to highlight.

So, let’s go back. So I think really the main strategy here is that there is a lot of new drugs that are being developed in the mCRPC setting, particularly the Cyclin/CDK4/6 pathway is being looked at pretty heavily in this context.

We’re learning more about the use of older drugs in the modern era and how to potentially integrate them in the mCRPC setting.

DR LOVE: So I can just hear the brains buzzing out there. The oncologists who — we’ve been talking a lot about CDK in breast cancer. Monday we’ll be talking about that. So just a little bit about this. So fascinating. And still ringing in my head is Karim’s earlier comment about the fact that the androgen receptor remains intact late on. So, really, just because abiraterone doesn’t work after enzalutamide, it doesn’t mean that something else would.

So Alicia, Dana-Farber really, to me, is the place I think about when I think about CDK inhibitors. Your colleagues in breast cancer — I’ve actually worked with Sara Tolaney, and on Monday night we’re showing some videos, and so Sara is on one of the videos. And one of the things I was asking her — you pointed out the differences in the 3 agents used in breast cancer, and incidentally, we all know that abema now has moved up into the adjuvant setting. FDA-approved. But at this meeting, ribo is being presented in the adjuvant setting. One big difference— I don’t know if you know — certainly oncologists know this, abema is given continuously; the other two are intermittently, whether that’s an advantage or not... But also, the tolerability. Of course, this is given with hormonal therapy. But diarrhea was something that came out with abema.

Sara and her group were one of the people who really first saw that. In the video, interestingly, that we’re going to show Monday, I asked Sara what’s the likelihood that you can get somebody through 2 years of abema? And she said in the trial 27% of people dropped out because of diarrhea. But nowadays they know what to do. They know how to dose reduce. They prep these patients and they rarely drop out. Sara Hurvitz from UCLA also was commenting on sort of the refinities of how they look at this. It’s not just the number of times per day that people have diarrhea, but whether or not it comes on unexpectedly during the Pilates class, et cetera.

Any thoughts about — I’m sure you’ve been seeing all this happening in breast cancer – how this might play out in prostate cancer, Alicia.

DR MORGANS: Yeah, absolutely. So I think we actually investigated palbociclib a number of years ago in hormone-sensitive prostate cancer. And I think Emmanuel, you may have been involved in that study. Maha Hussein was involved with that. And Karen Knudsen actually came up with a lot of the sort of background preliminary data there. And I put some patients on that trial as well. And it was actually well tolerated. There was a small amount of pneumonitis on that study, some neutropenia, but well tolerated. And it was so disappointing that it was negative, unfortunately. So disappointing. And that was again several years ago.

I think now I’m much more excited about the data I’m seeing with the CYCLONE program. And I know Rana has a study, I think in the HSPC population, where I think that the combination may be with these AR-targeted agents is going to give us a better opportunity to have some activity with this agent.

And the other thing I would say is that tolerability is always the name of the game when it comes to actually getting medications into patients. They don’t work when they sit on the shelves. And I think that our interest in supportive care in GU oncology is really so intense. And I’m certain we can get people through things. And I so appreciate, too, that our colleagues in breast cancer are working through some of these issues because we can take those learnings and anyone who’s a general oncologist already has those learnings and you can already apply them. And we as GU oncologists hopefully will be able to learn them, too, from our colleagues.

DR LOVE: Yeah. And we already know ribo and palbo, you see neutropenia, usually asymptomatic. So a different — whether that has to do with the schedule or not or the drugs themselves, but clearly different toxicities.

Any comments, Rana?

DR MCKAY: No. I think the biggest thing is being super proactive. And actually doing a lot of education with the patients around the diarrhea. I think that’s the biggest thing with the abemaciclib.

I think, in the context of metastatic hormone-sensitive disease, it’s even more critical to be proactive about it because patients can stay on therapy for a long time and be on therapy for years potentially. So I think prophylaxis is the name of the game, close monitoring, engagement with your nursing stuff and other staff is going to be really important.

I think there’s a lot of newer targeted therapies that are being looked at and evaluated in prostate cancer that are going to be really important. Capi in the mHSPC setting as well, I think is important.

DR LOVE: Right. I saw that on the slide. Capivasertib, and AKT inhibitor. Phase III trial, just presented at San Antonio. Positive. People are thinking it’s going to be proven. Another hormonal agent. They have these SERDs. We’ll talk about maybe — what they call it, Protac’s. and we’ll talk about that later. But it will be really interesting to see how this plays out.

Also interesting, they started out — I didn’t realize, looking at abema alone. Because actually, abema’s the only one that saw activity without endocrine therapy in breast cancer. Although, now, people don’t use that very much. But they did see activity. But really, it’s combined with hormonal therapy for sure.

Case: A man in his early 50s with mCRPC after enzalutamide receives olaparib; somatic BRCA2 mutation; TP53 mutation on liquid biopsy — Dr Agarwal

DR LOVE: Well, now we get to the really good stuff. Just kidding! But… here we go. PARP inhibitors. So another incredible advance that’s happened in prostate cancer. Of course, we all just saw the approval of the PROpel situation with olaparib. We’re going to get into that in a second because we have a patient like that. But I’ll ask Emmanuel what he thinks about this case from Neeraj.

DR AGARWAL: He continues to receive olaparib to date, almost 3 years now.

DR LOVE: Any tolerability issues?

DR AGARWAL: He did experience nausea and vomiting initially after use, starting olaparib, but without reducing the dose, we were able to manage those symptoms with antiemetic medications, mostly Compazine and occasional lorazepam on a prn basis. Both of the medications were very effective and allowed us to continue olaparib at the full dose. He did develop anemia, but his anemia has not become severe and he continues to tolerate olaparib with a hemoglobin level of approximately 12 g%.

DR AGARWAL: He continues to have stable disease on imaging and PSA continues to respond.

His PSA is actually quite low. It remains below 2 ng/mL even now.

DR LOVE: Any questions you'd like to hear them discuss?

DR AGARWAL: Fortunately, we had tissue available in-house and we were able to test the patient. It is not uncommon for local laboratories to discard the tissue after 10 years.

Do you favor obtaining comprehensive genomic profiling at the first diagnosis of metastatic or nonmetastatic castration-sensitive prostate cancer and not wait until the onset of metastatic CRPC?

DR LOVE: So a thought, I never even thought about that, Emmanuel. I should have mentioned, this patient had castrate-resistant disease and a somatic BRCA2 mutation. And as you can hear has been on olaparib for 3 years. Any thoughts? And also, maybe reflect a little bit on some of the tolerability issues he talked about.

DR ANTONARAKIS: So we know that BRCA2 is the most sensitive mutation to these agents. I also discussed this case with Neeraj.

DR LOVE: Oh, really!

DR ANTONARAKIS: He told me that the patient has a homozygous BRCA2 deletion. That means that he has complete genomic and protein loss of BRCA2. And these patients, anecdotally, have very long responses because they have no BRCA2 protein whatsoever. It’s not just mutated, it’s entirely gone. And these patients can have profound responses lasting 3 years like this case. So that’s just a little pearl.

DR LOVE: Do you see that on like the NGS or germline report?

DR ANTONARAKIS: You can. It’s not that common. It’s about 5% of the BRCA2 mutations.

DR LOVE: And what does it say?

DR ANTONARAKIS: It just says homozygous loss. Or it says homozygous deletion.

DR LOVE: All right.

DR ANTONARAKIS: In terms of the side effects, I think the nausea is the thing that we hear about the most from our patients. There’s a few tricks there. The antiemetic often does work, as he did here. Another trick is taking the medication with food. I found that if you take it with a snack or some food, the nausea is actually less severe. And of course, over time, the cytopenias can be a problem. So about a 15% Grade 3 anemia with this agent. And there’s patients that do require blood transfusions. It’s not common, but it happens.

And of course we shouldn’t forget that we can reduce the dose. So you can start with the 300 BID of the olaparib. You can go down to 250 BID or 200 BID.

Case: A man in his early 70s with high-grade localized prostate cancer treated with proton beam therapy and ADT for 2 years now has rising PSA and a CT scan positive for a retroperitoneal node; somatic BRCA2, TP53, FOXA1 and MEN1 mutations; microsatellite stable — Dr Morris

DR LOVE: So we’ll talk a little bit more about tolerability issues. But I want to bring in another case and see what Karim thinks about it. And as I said, we just saw the FDA approval of the sort of, I guess you could call it the PROpel strategy. There are a couple of other trials out there and we’ll see whether niraparib gets approved also, or talazoparib. But I’m curious, putting aside regulatory issues because I’m not exactly sure what the situation there is in EU, but I’m curious what you think about this case. Here’s Dr Morris.

DR MORRIS: 72-year-old man. He did have good nadir response on his ADT and radiation, down to 0.1, and then a year later, unfortunately was rising to 11 and his testosterone was still castrate. So he was still during that induction period. He just did not have a very long period of response to that 2 years of ADT induction.

He had somatic testing with a BRCA2 mutation. He had new imaging, the bone scan with no uptake, a CT with a retroperitoneal node. And so he has not been on any additional therapy at this stage, but has a BRCA2 mutation and is currently CRPC because his PSA’s rising while he’s on his initial 2 years of ADT.

So the patient had not gotten any AR intensification on the front end, so he certainly fits as a patient who would’ve been considered for many of the trials that’ve been presented on PARP inhibitor combinations.

For BRCA2, it looks very clearly positive that if you have this sort of patient, it’s an ideal person that they should start therapy with a PARP inhibitor combination if you’re planning on using an AR agent.

DR LOVE: So I’m just kind of getting warmed up for tomorrow morning with ovarian cancer. We’re going to get deep into all the different mutations, somatic versus germline. But Karim, any thoughts about this case? What would you like to be able to do? And if this patient didn’t have a BRCA2, they were BRCA-wild-type, would you, if you could, use olaparib?

PROF FIZAZI: So I’ll start with the case itself. Understanding he has a BRCA2 alteration, mutation, if I’m not wrong.

DR LOVE: Right.

PROF FIZAZI: So I think he would be a really good candidate for an early PARP inhibitor, early meaning right now, combined with an AR pathway inhibitor. He has obviously, castration-resistant disease right now. This was confirmed by the tumorist. We saw data from 3 randomized trials for this man in the last year or so: MAGNITUDE, PROpel and then TALAPRO-2, and for patients with BRCA characterizations, I think the data are crystal clear. The benefit is really enormous.

I have a presentation tomorrow with the data for TALAPRO-2 in this second cohort of men with DNA repair defects, including BRCA2, but I’m not going to comment too much about it tonight, But really, regarding what’s already in the public domain, those are really the men who benefit from a combination of a PARP inhibitor and an AR pathway inhibitor. So I think that that would be clearly my recommendation to this man.

Now for your other option with no BRCA2 alteration, much more difficult because obviously not a good cancer at all. He’s progressing quite rapidly from localized disease to CRPC, basically within 2, 3 years. So that’s not good at all. I would still give it a try probably to an AR pathway inhibitor, but also understanding that he may not have a very hormone-sensitive disease and that chemotherapy might need to be considered soon and/or a treatment such as a PSMA-targeting treatment. But that would be actually a much more difficult situation to be honest.

DR LOVE: So Alicia, when we talked to your colleagues Dr Matulonis and Lui, one of the most controversial things in ovarian cancer is the patient who is BRCA-wild-type, LOH-negative. They’re are data actually with niraparib interestingly enough, and it’s actually approved in that situation, not nearly as much benefit. A lot of controversy.

We actually did a satellite the day PROpel was presented and Fred Saad was on our panel. And he said, okay, we’re giving – I want to give to everybody, just like in the trial because we saw a benefit, but yet the FDA decided it was just going to be BRCA.

Any thoughts about what you’d like to do in a patient who’s wild type, Alicia?

DR MORGANS: Sure. I actually think that there may be for some patients either uncharacterized alterations that were in the wild-type group in these studies and perhaps had some responses, or there may be some synergistic activity. I do think that may be possible. The reason I think this is because of Study 8, PROpel and now TALAPRO-2, all having this sort of consistent message.

I do think that I’d love to see more — I’d like to see more data from TALAPRO-2. There was an uncharacterized population that still has not been characterized. And I want to understand if part of that population may have BRCA2 and may be driving some of the signal there. But I think from my perspective as a clinician, I would like to have the opportunity to have a shared decision with a patient so that they, if they are young, if they’re healthy, if they want to be more aggressive, may be able to make some of those decisions with me as the clinician, rather than having a restricted label. In Europe, the label is different, which is so interesting, and the reverse of what we often see where they actually have the opportunity. I’m not sure if in France, but in Europe in general, it seems like you may have the opportunity to use this in an unrestricted way, regardless of HRR, right, Karim?

PROF FIZAZI: That’s correct. Surprisingly, the EMA provided an approval for the all-comer population for PROpel, which is unusual, to be honest. Now in Europe, the approval doesn’t mean everything, because we have social medicine. So we need a reimbursement to be able to use it even treatment. And at the end of the day, this will be the reimbursement equation, which we all decide whether we will use that or not for patients in the all-comer situation.

But I kind of agree with you, general speaking, regarding — regardless of approval and reimbursement, I think for BRCA patients really the data are crystal clear. For other patients, I think we just need more data. In PROpel, overall survival was not improved. Quality of life was not improved, also. So it’s mostly an image which is getting better, rPFS is, at the end of the day, just an image. Are we truly providing good care or improvement to all the patients. I’m not sure. Because there is also toxicity from PARP inhibition combined with AR pathway inhibitors. Anemia is very often there, and it’s Grade 3 or 4 in, like, 30-, 40% of patients, which means transfusion for most of these patients on top of fatigue and everything.

So I think we need to be very cautious, at least with the available data. For patients without DNA repair alterations.

DR LOVE: In a strange way it kind of reminds of a discussion we had here yesterday about upper GI cancer, first-line metastatic disease, where the FDA approved, regardless of PD-1 level, and the investigators said, oh, we don’t treat less than 5 because when you split it out they don’t benefit. And yet, a lot of people in practice will use it because the FDA approved it. They’ll sit down with the patient and say, look, I’m not really sure. But the point is, they gave the patient and the doc the opportunity to make decisions. And actually Dr Morris said the same exact thing you did, Alicia, I wish we could have — I wish they would have allowed us to do it.

All right, Emmanuel, let’s take a — Emmanuel is the one who pointed out to me a long time ago that actually it shouldn’t have been called BRCA, it should have been called PRCA.

Faculty presentation: Dr Antonarakis

DR ANTONARAKIS: This is going to be like a speed dating…

All right, homologous recombination repair mutations. What are they? What are the genes? And who should we test?

So this is the Antonarakis list. This is not published. I would never dare to do that. So my first tier, the true homologous recombination genes, are those on the left: BRCA2/BRCA1, PALB2, and then 2 rare ones. And then on the right side, the third tier, ATM, CDK12. We used to think of these as HRR genes. They probably don’t function like that. So, don’t have very high hopes when you use a PARP inhibitor in those patients.

If you add them all up in metastatic castration-resistant biopsies, you’re going to have about a 25% chance of having 1 or more of those. If you look at the germline, the inherited DNA of those patients with metastatic disease, about 1 in 8 patients, or 12%, are going to have 1 of them and the most common, as you can see on the pie chart, is BRCA2.

So who should we test? The NCCN recommends germline testing and somatic testing separately. For germline testing, it’s anyone with localized high risk or very high-risk disease and anyone with metastatic disease. So that’s the easy one. And then for somatic testing, there’s really no clinical indication outside of the M1 metastatic disease, for somatic testing it’s only those patients that have metastatic disease, not the high-risk, localized yet.

Now let’s review some of the clinical data, first for the monotherapy and then for the combinations.

One slide about the rationale. The rationale is this term that we’re all familiar with now, we never knew what it meant in 2005 when it first came out, synthetic lethality. Sounds like a movie title, maybe Bruce Willis should be playing in that movie. But you need to wipe out both single-strand DNA repair and double-strand DNA repair to cause cell death. And these patients that have BRCA mutations, the double-strand repair is crippled, and now you’re also crippling single-strand repair by blocking PARP.

There are 4 PARP inhibitors that we have tested in prostate cancer and these are very similar to other cancer types. They have differences in terms of their enzymatic PARP1 inhibition, and then there’s this other component called PARP trapping. It turns out if you can PARP the trap enzyme on the DNA during the DNA replication phase, you can get what’s called a replication fork collapse where that cell is not able to replicate its DNA and therefore, can die. And the most potent PARP trapper, you can see with the 4 pluses there at the bottom, is talazoparib.

Now, this is going to be in slide set and I’m going to go through it, but the monotherapy studies have shown about a 30% to 40% response rate in the HRR patients, again mainly due to the BRCA2 patients.

I want to go through the 2 pivotal trials in a bit more detail. The PROfound trial was the randomized study of olaparib versus the alternative androgen receptor targeting therapy. This had a population of CRPC patients. They had to have received at least 1 AR-targeting therapy, and they could have received a taxane but the taxane was not mandatory. Then they were randomized into olaparib, 300 mg BID or the alternative AR-targeting agent. Cohort A was BRCA1/BRCA2 or ATM patients. Cohort B was 12 other genes. And the statistical design of this trial was an RPS whereby if the Cohort A was positive, the study had the statistical power and the permission to combine Cohort B plus Cohort A, then reanalyze PFS in that entire patient population.

And when they did that, because Cohort A was, in fact, positive for PFS, the sum of Cohort A plus B, encompassing 14 different genes, was positive for rPFS and also had a very strong trend for overall survival. And the FDA said, this is good enough for us to approve olaparib as a monotherapy after abi or enza for all 14 of those genes. However, if you look at the supplements of these papers, and this data was in the paper — it was just hidden away — you can see that it’s the BRCA2 patients that have the greatest difference between olaparib and control, whereas many of the other genes have relatively equivalent efficacy of the PARP inhibitor versus their control group.

And in May 2020, which is now 3 years ago, olaparib was approved with any of those 14 genes shown across the bottom, including BRCA1 and BRCA2 plus 12 others.

The TRITON 2 and 3 program, we’re focusing on an alternative PARP inhibitor, rucaparib. The TRITON 2 program was a single-arm, uncontrolled study, whereby about 100 patients with a BRCA1/BRCA2 and some other mutations, were given rucaparib as a monotherapy in the post-AR and post-taxane situations, so a third-line mCRPC setting. And this was the first time in the history of prostate cancer that the FDA granted an accelerated approval based on objective response rate in soft tissue disease in a nonrandomized, uncontrolled study.

And the approval was limited to BRCA1 and BRCA2, so that was a difference between olaparib and rucaparib. And the second difference was in these patients they also had to have failed not just an AR-targeting therapy, but also a taxane. So really a third-line population. And of course, they mandated the randomized Phase III study, which was done, and that was TRITON 3. And this was an interesting trial whereby this was mCRPC, prechemotherapy, and the control group here could include either abi or enza, or docetaxel. And that’s very important because this is the first time we have docetaxel in the control arm for a randomized Phase III study. And they snuck in ATM as a third mutation. So remember, the approval so far was for BRCA1/BRCA2. They added ATM.

And the overall rPFS was positive, showing that rucaparib improved radiographic progression-free survival relative to either abi, enza or docetaxel. But the most interesting thing about this trial was actually the subsets. And you can start on the right-hand side, ATM group, truly no difference whatsoever in the — in other words, rucaparib did not beat the control arm in that setting. But in the BRCA1 and BRCA2 subset, the difference was very, very clear.

Now this has not yet led to a full, or expanded approval of rucaparib as a monotherapy. It might. But the question that remains is, will the ATM be added to the label or will it remain as BRCA1 and 2? I have my suspicions. I think it will be BRCA1 and 2 alone.

And then this brings us to the 3 combination trials: PROpel, MAGNITUDE and TALAPRO-2. There was recently an editorial in the European Urology called PROpel, MAGNITUDE AND TALAPRO Blues because it’s’ getting so complicated, even for the experts. PROpel was an all-comers study, abiraterone, olaparib versus abiraterone. And then there was a post-hoc analysis of the biomarker subsets. So the primary endpoint here, as we’ve been discussing, was the overall population, rPFS and the rPFS was met with superiority of olaparib plus abiraterone over abiraterone.

If you look at the forest plot at the bottom, the HRR-positive group had an even greater improvement in rPFS, and the BRCA1/2 subset, which is not shown there, had an even more profound effect.

MAGNITUDE had 2 populations: HRR biomarker-positive and biomarker-negative. Unlike the previous study, the biomarker-negative group here was negative. So they had an interim analysis. It was stopped for futility. But in the biomarker-positive group, there was an improvement in rPFS both in the overall HRR population with niraparib, in this case, plus abiraterone versus abiraterone alone. And the difference was even more magnificent, no pun intended, in the BRCA1/2-mutated group.

And the tiebreaker so to speak, I will not be talking about the unpublished data that Karim will present tomorrow morning, so please go to his presentation to see it, but in the Cohort 1, which was the all-comers cohort, again similar to the PROpel study whereby patients were allowed to enroll in them, they were prospectively tested for the biomarker, but here we were reporting the biomarker-positive and -negative groups.

In the overall patient population, Kaplan-Meier curve on the left there was a statistically significant and clinically meaningful improvement with the addition of talazoparib to enzalutamide above enzalutamide alone. And when you look at the HRR-positive and -negative groups, the HRR-mutated group, which is also called deficient, is on the top, you can see that the Kaplan-Meier curves split to a greater degree. But even in the HRR-nonmutated or unknown group, that difference — you can see on the bottom right — was also statistically significant.

Now, on April 28^th, the Oncology Advisory Committee, ODAC, was convened by the FDA, and maybe a surprise to some of us, or at least me, there was an 11 to 1 vote against the approval this for the unselected population, that is olaparib/abiraterone. And in the history of the FDA, whenever they’ve convened an ODAC, I think with only 1 exception, they have listened to the ODACs advice. And when I was getting on the airplane to come to Chicago this press release came, and as we may all know by now, or perhaps you haven’t see it yet, the PROpel study, so abiraterone plus olaparib in first-line mCRPC, the label will be restricted to BRCA1 and BRCA2, germline or somatic, but just those 2 genes.

So in conclusion, germline and somatic alterations are common, more common in mCRPC than in localized disease.

In terms of the monotherapy, we do have an FDA approval already for olaparib for HRR-mutated patients, 14 genes, as long as the patient has failed 1 AR-targeting therapy. Rucaparib also has a monotherapy approval. Right now at the moment, it’s for BRCA1 and BRCA2 alone and it’s a third-line mCRPC post-taxane.

We’ve talked about PROpel, MAGNITUDE and TALAPRO. And I have to add that fifth bullet point on the airplane, we do now have an FDA approval for abi and olaparib, but only for BRCA1, BRCA2. And we’ll see if that becomes a precedent for the other study, including TALAPRO.

DR LOVE: So to be continued. Again, we could spend a couple of hours just talking about PARP inhibitors. But just 1 more question back to you Emmanuel, if you think about a patient, let’s say who has a BRCA2 germline mutation, and imagine that you’re looking at a patient who’s going to die of prostate cancer. When do you think ideally, based on what we know right now, is kind of “right” optimal time to integrate a PARP inhibitor? Because to me, it seems like it would at least be hormone-sensitive metastatic. But you tell me.

DR ANTONARAKIS: I have a suspicion that at the first sight of hormone-sensitive metastatic prostate cancer, if you know you have a germline or somatic BRCA2, I suspect, although we don’t have data yet, that that will be the place to use it. At the moment, we have to restrict that use to the first-line mCRPC. But there are 2 Phase III studies ongoing to answer that.

DR LOVE: Do you think, and I know at one time you were doing sort of a pilot study in M0 disease without hormone therapy. Any thoughts about bringing it down even earlier?

DR ANTONARAKIS: We did a 50-patient study with biochemical recurrence, rising PSA alone, with olaparib in the absence of ADT. And we had 11 BRCA2 patients in that trial — every single one responded — so 100% response rate. And to date, with about 3 years of median follow-up, we’ve only had about 2 of the 11 that have recurred.

DR LOVE: Fascinating. Was that published?

DR ANTONARAKIS: It was presented at this meeting this morning.

DR LOVE: Really? Awesome!

Case: A man in his late 70s with multiregimen-refractory mCRPC and a germline BRCA2 mutation receives olaparib with a sustained response for several years — Dr Srinivas

DR LOVE: Okay, final topic, we’re going to get into radioligands. And Rana, I’d like you to listen to this case and give me your thoughts. This is a patient of Dr Agarwal.

DR AGARWAL: Patient shows PSMA expression in the tumors. The patient asks for lutetium therapy and we don't have lutetium available. So what are the options, alternative options? How do you think of cabazitaxel in this setting based on the data from TheraP trial and the VISION trial combined together?

What is the role of cabazitaxel in this setting when patient has received 8 cycles of docetaxel chemotherapy, there is a high level of PSMA expression on the gallium PSMA scan.

DR LOVE: Is this bone-only disease?

DR AGARWAL: This is bone-only disease. That's a good point, yes.

How do you sequence lutetium after radium or radium after lutetium?

DR LOVE: So we’ve talked a lot this week already, and we’re going to be talking a lot more in the next couple of days about chemotherapy shortage, Rana. What’s the current situation in terms of lutetium? And what are you doing in situations when you can’t access it in a situation like this? Here you do have the alternative of radium, because this patient has bone-only mets. But what’s going on right now? Are you able to get lutetium right now?

DR MCKAY: I think actually we finally potentially overcome the manufacturing issues. I think a new plant has been established and I think it’s becoming more readily available for utilization in the clinic. So I think hopefully we’re beginning to see those supply issues not really become a huge factor. When looking at the TheraP trial, the TheraP trial was a very specific study that looked at both the dual selection factor of having PSMA-positive disease and lack of discordant disease with FDG-PET imaging. Patients were randomized to receive cabazitaxel versus receiving lutetium. And the study’s primary endpoint was looking at PSA response and demonstrated a significant PSA response with a PSMA targeted therapy, as you would expect. There was no difference with regard to overall survival, though, really the study was a small study, it wasn’t really powered to look at overall survival. So I think we have to interpret that data with caution.

I think at the present time we don’t necessarily have data to say that you should use cabazitaxel over lutetium in this context. I think both could potentially be utilized.

I think the struggles with Radium-223 are that there’s really no activity outside of the bone. There’s no PSA response. There’s no objective response. There’s no actual way to tell that that therapy is working for that given patient, with the caveat that it does seem to improve symptomatic bony disease, and actually improve pain and improve the risk of skeletal-related events. So we don’t necessarily know what’s the right sequencing strategy. I think this gentleman could be an excellent candidate for cabazitaxel. Could also be a good candidate for lutetium-223. I think what we’re — lutetium-617.

I think what we’re going to run into is issues with myelotoxicity and myelosuppression when we start using sequential chemotherapy, sequential radioligand therapy in this context.

DR LOVE: So, just to clarify then, and of course I’m going to ask Oliver also, the issue of patients who do have bone-only mets. It sounds you’re maybe favoring lutetium. But do you take into consideration the degree of PSMA expression?

DR MCKAY: Absolutely. I mean we even saw earlier today that that does seem to be potentially a biomarker regarding response to lutetium.

So at the present time we don’t necessarily have the right threshold. We don’t know what we can’t — Oliver can probably speak to this more, we’re not getting SUV means, SUV maxes don’t really seem to be as predictive of response. But I think what does matter is making sure that patients don’t have like, say, discordant disease, that lack of PSMA-positive lesions, like liver metastases and so forth.

DR LOVE: So I’ve always admired Oliver’s passion for radiopharmaceuticals. Now you’re the Director of Radiopharmaceutical Clinical Trials. I’m not sure how many other people have that kind of a title, but I think it tells you how important this is to you. Let’s talk about some of the data. Also, maybe before you even begin, can you answer this question of what comes first, radium or lutetium?

DR SARTOR: I think the lutetium has kind of taken over right now. The PSMA-PET positive biomarker, that’s really important. I think you have a lot so show that lutetium is working. Ou have objective responses. You have PSMA declines. You have rPFS. You have OS. So you’ve got a totality of evidence I think with the PSMA lutetium now that is a little bit different than the radium where you did have the survival. But I’m going to mention this Neil, the radium was older context. It was not in the abi/enza era. There was a lot of differences between the patients that were treated in that 2013 trial and the current trials where we have so much more treatments available as opposed to then.

DR LOVE: Would you use radium after lutetium?

DR SARTOR: I actually have not. So I don’t know if others have. But we’ve used radium before lutetium. And we actually have a study called the “RALU” study that we’ve published that on that. But on the other hand, I don’t have much experience on — I have no experience of radium after lutetium.

DR LOVE: All right, let’s take a look at some data.

Faculty presentation: Dr Sartor

DR SARTOR: So thanks Neil for the opportunity to be here. And I was asked to kind of cover some of the radium, cabazitaxel and PSMA lutetium. And I think it’s a little bit of an interesting era that we’re in now because we’ve had thematically tonight, the story about the hormones coming earlier and earlier. And there’s really no doubt in my mind that the early use of hormones makes a tremendous difference. And when you have study after study after study to show that’s the case. But the implications are that the castrate-resistant disease that we see today is very different than what we saw yesterday. And furthermore, we have the triplet therapees that are changing it yet again.

So, so much is different about CRPC today than what we used to call CRPC. And yes, I can go through all the different algorithms and talk about pre- and post-docetaxel. I think these are well-known, so I don’t need to cover it a lot.

I’m going to be covering 3 agents here. I’m going to talk about radium, cabazitaxel and the PSMA lutetium.

The radium is an alpha-emitter. The first alpha emitter in medicine, which I think is important. We’re going to hear a lot more about alpha emitters. It’s just going to be targeted alpha therapy that’s coming down the pike.

The alpha-remitter radium will bind to bone stroma, actually binds to hydroxyapatite. Does not actually target the tumor itself, but it targets the areas of active bone turnover — the blastic lesions, if you will.

Cabazitaxel is a taxane, binds to tubulin and inhibitors microtubular function. And the PSMA lutetium will bind to PSMA expressed on the cell surface of the tumor cell. And that’s important because we now have tumor-targeted therapy. And, of course, it makes a difference.

Now, if we go back to what we’re going to call the ASYMPCA trial, that was the original Phase III with radium, and again, I think a very important trial because it showed that the radiopharmaceuticals could prolong survival. A bone-targeted therapy could prolong survival in selected patients. But I think we have to look at it again in the context and kind of the lens that we use today.

So that trial was performed in patients who had failed ADT monotherapy or ADT/docetaxel. There was no utilization of apalutamides, enzalutamides, abiraterones that we commonly use today. The population, the biomarker if you will, was bone scan positivity and symptomatic and excluded the visceral met. You certainly don’t want to be treating a patient with radium if they’ve got liver mets or big, bulky lymph nodes. That’s probably not the right patient for radium.

The control arm was standard of care and excluded the chemotherapy, but standard of care then was more about dexamethasone/bicalutamide than it was abiraterone/enzalutamide type things.

The overall survival was unequivocally positive, which was why it was FDA-approved, why it was it a New England Journal article. But I think that we have to look at the limitations – radium only goes to bone stroma. It’s not going to be going elsewhere.

It unequivocally moved the field forward, but now we have a very different landscape. And so, when I look back at that 2013 study, what I’m going to say is I’d really like some new trials that are going to demonstrate the efficacy and this sort of modern era.

Now there is a trial called the PEACE-3 trial, and Silke Gillessen and others have presented parts of that in a preliminary way. We don’t actually have the results. And I’ll simply say that I look forward to PEACE-3, and that will be a combination of enzalutamide plus or minus radium. I think that’s an important trial.

Now, cabazitaxel. I did not present here the original TROPIC trial published in 2010. But the important thing about cabazitaxel is, it does work. And we have multiple trials that have shown to be positive. This is the CARD trial — thank you, Karim, for helping educate me a little bit earlier today. We have French trials…is more Dutch. But it turns out this important European trial, looking at cabazitaxel versus abi/enza in patients who’d already received docetaxel and abiraterone/enzalutamide. And this patient population was kind of all-comers, if you will. There are a few exclusions I’m not going to get into because I don’t think they’re that important. But the bottom line is, the primary endpoint, which is rPFS, was unequivocally positive. The overall survival was unequivocally positive. And this is sort of a modern era, if you will, of the abiraterone/enzalutamide pretreated patients with an abi/enza control, cabazitaxel showing positivity. That’s important.

Now there are a couple of other trials. One I’ll point out on the top, there’s one called the CABASTY trial. And this one utilizes a q2wk docetaxel — not docetaxel — cabazitaxel, and compares it to the q3wk. And it turns out you pretty much have the same efficacy but less in the way of neutropenic...I think for elderly patients it might be an option.

The OSTRICh trial, I don’t think it’s that relevant. The CARD trial is better.

If we look sort of a summary statement of cabazitaxel, I think it’s an important step forward. And we’ve known this since 2010 when in the post-docetaxel space we had the TROPIC trial show prolongation. Got the FDA approval.

I think the limitation is, in the US, only about 50% of patients with mCRPC are actually treated with chemotherapy. And that’s true, by the way, when we go to Europe as well. A lot of patients never ever receive any chemotherapy. And cabazitaxel is a second-line chemotherapy. So we did another trial that was called FIRSTANA, to look at the comparability of cabazitaxel/docetaxel. It turns out cabazitaxel looked pretty much the same, a little different spectrum of toxicity, but it’s not FDA-approved in that setting.

One of the things that I think has been a game-changer is the PSMA lutetium. This is also a New England Journal paper. And this is in the modern era, if you will. We had ADT. We had abiraterone/enzalutamide pretreatments. We had docetaxel pretreatments. Cabazitaxel pretreatment in 41% of the cases. This was a really, really heavily pretreated patient population.

The biomarker, if you will, was PSMA-PET selectivity. So everybody got a PSMA-PET, and you had to have metastatic disease with a PSMA-PET uptake greater than the liver in order to get on the trial. Now interestingly, that was 87% of the patients. A little bit higher than what I was thinking.

The control arm was the standard of care, standard of care plus or minus the lutetium, excluding chemotherapy because we didn’t have any safety data with the chemotherapy. But, remember, all the patients had prior docetaxel and 40% of the patients had both the cabazitaxel and docetaxel. Very, very heavily pretreated.

There’s an overall survival benefit. Hazard ratio was 0.62 on the OS. rPFS was 0. 40. Unequivocally positive, FDA approved, and that’s really important.

One of the things that’s interesting is the PSA declines at about 12 weeks, were actually associated strongly with survival. if you look at this particular slide you can see that those patients who had a good PSA decline actually went on living a long time, where those patients who had a less good PSA decline or PSA rise-only, not so good. So PSA remains a pretty viable biomarker, even in this far advanced setting. And it’s a little bit of a surprise to me. I didn’t think it would turn out that good.

One of the things that was mentioned earlier, and I think this is very important, there was an Australian trial called TheraP, and in this case, there was a comparison of the PSMA lutetium versus cabazitaxel. Now, it was a randomized Phase II. It was not done as a noninferiority; it’s not done as really — it was done as a superiority with PSA as an endpoint. But this was reported by Michael Hofman and colleagues, the hazard ratio for overall survival in this PSMA-PET selected patients, was previously exactly the same, hazard ratio 0.97 in OS. Now the quality of life was better with the PSMA lutetium. But, nevertheless, I think the survival was surprising to the Australians about how good it was with cabazitaxel.

We have some important new trials, one called the PSMAfore. It’s a prechemotherapy mCRPC trial. So, patients who would have not had received docetaxel would have received abi or enza. And this trial is positive. It was announced positive December 5^th.

The SPLASH trial is another one using a different PSMA binding ligand called PSMA I&T instead of PSMA-617. It’s completed accrual. So we’re going to get some interesting data coming up over the next year in these 2 steps.

Now, the PSMA lutetium was a really important step forward. The supply chain was incredibly problematic. It’s now easing. It’s now better — much better today than it was even 4 weeks ago. So, the supply chains are being worked on and they’re being solved. And I think that this is an important new therapy. I think the VISION trial established the importance of PSMA-617. I think the PSMAfore trial is going to move it earlier. And we’re going to look at the SPLASH trial as well. So it’s a lot of interesting data we’re going to have accessible.

One thing that has struck me, and I threw this kind of as a last slide, if you will. I think we continue to miss the important elements to the biology of mCRPC. We had these adenocarcinomas, AR-driven, and they’re really important. I think they’re about half the patients. We get through abi/enza, but nevertheless, you have more to the story.

Now neuroendocrine we’ve talked about for a long time. But it turns out neuroendocrine is only a minority. There are other things out there. This particular paper wanted to call a stem cell-driven component and also another component being driven by the Wnt pathway. So, I don’t think we’re targeting all the heterogeneous disease that we need to target. And I’m just going to say, I’m going to be working on trying to solve some of these other populations of cells that we’re not hitting very well right now.

Andy by the way, I really enjoy the PSMA lutetium. It’s not perfect. We can do better. So let’s keep working.

DR LOVE: So I don’t know if you ever heard of ERS1 in breast cancer. We’re going to be talking about that Monday night. There’s mutations in the estrogen receptor. Do you see that in androgen receptors?

DR SARTOR: Oh, absolutely. Actually, I had a poster this morning where we looked at the androgen receptor mutations. There are some that are pretty common. One called the 875, 878 mutations are pretty common. And they’re potentially targetable with things like ER degraders. And there’s also some data, and Karim’s been very influential here, looking at a molecular, one of the ODM series, I forget what number it is. But, nevertheless, Karim and colleagues have shown that the engine receptor mutations, ligand binding receptor mutations, can be sensitive to a variety of new ways to approach that disease.

DR LOVE: I like the name of the SPLASH trial. That has a little bit of zip to it, a little bit.

Anyhow, thank you so much. Thanks to the 3 docs who presented cases. Thank you for attending. Come on back tomorrow morning, we’re going to talk about ovarian cancer.

Have a great night.