Introduction

DR SMITH: Good evening. Welcome to this Research To Practice program, Beyond the Guidelines: Urologic Oncology Investigators Provide Perspectives on the Optimal Management of Prostate Cancer. I’m Dr Matthew Smith from Massachusetts General Hospital Cancer Center in Boston. I’m pleased to be joined by an outstanding faculty, including Himisha Beltran from Dana-Farber Cancer Institute, Stephen Freedland from Cedar-Sinai, Fred Saad from the University of Montreal, Neal Shore from Carolina Urologic Research Center. This promises to be a lively and entertaining program, and we’re pleased to have your active participation for those of you here in-person as well as the many folks joining us online.

We thank our commercial supporters for this program. We also thank Research To Practice CME Planning Committee members, staff and reviewers.

This is our agenda. Module 1 — Management Approaches to Nonmetastatic Prostate Cancer. The second module will focus on metastatic hormone-sensitive disease. Third module will be therapeutic considerations for patients with newly diagnosed prostate cancer. The fourth module will be contemporary management in mCRPC in patients with HER2-positive gene mutations. Then we’ll close with current and emerging strategies in the treatment of recurrent mCRPC.

This slide summarizes the prostate cancer survey respondents. You’ll see cases presented and the responses from these panelists.

Management Approaches for Nonmetastatic Prostate Cancer — Dr Freedland

DR SMITH: Our first module is Management Approaches for Nonmetastatic Prostate Cancer. And we’re going to begin each module with a discussion question. So the question we have for today is what is your take on the EMBARK study, particularly the enzalutamide-alone arm? Dr Shore, would you like to take that question? And congratulations on your presentation at this meeting.

DR SHORE: Thank you very much. For the enzalutamide monotherapy arm alone, in comparison to traditional leuprolide acetate monotherapy, hazard ratio .63, which met the statistically significance and the primary endpoint of metastasis-free survival, so a successful comparison in this 3-arm trial.

I think that we saw some differences in tolerability, unopposed AR blockade without T-suppression. You saw some more gynecomastia, which you saw in your trial that you did, Matthew, a few years ago with unopposed enzalutamide oral monotherapy. And we saw that in ENACT.

We have some PROs that we’ll be presenting, Steve Freedland and I, but overall a successful trial for that particular arm.

DR SMITH: So EMBARK was a study of patients with nonmetastatic hormone-sensitive disease, nonmetastatic being defined by conventional imaging. So Dr Beltran, how do we put the results of this study in the context of what we already know from mHSPC by conventional imaging?

DR BELTRAN: I mean, it was really nice to see this practice-changing study presented and it really kind of confirms what we know about metastatic hormone-sensitive, that adding a potent AR pathway inhibitor to the backbone of ADT is better than monotherapy and many of these patients now at higher risk for developing metastatic disease may already have micrometastatic disease on PSMA PET scan. And so, essentially, EMBARK is just saying that we should be treating earlier with potent AR drugs, as they improve outcomes.

I’d love to commend the other investigators. I think that the difference here also is that this was an intermittent approach, which is our standard of care for biochemical-recurrent disease. And so, this, I think, has an advantage of coming in early and the opportunity to come off of therapy for some individuals. I think the question of the doublet versus the enzalutamide-alone is really, I think, going to come down to quality of life, and who are those patients that are really going to benefit from monotherapy that we haven’t seen before.

DR SMITH: Dr Saad, are there any caveats from this study? Are there concerns about the study design? Anything else we should consider in how we might apply this evidence to clinical practice?

DR SAAD: Honestly, I think the trial was designed very pragmatically. I think it addresses an important question. I think the thing that we have to keep in mind is that these were really high-risk patients. So I wouldn’t say that this is applicable to every patient with biochemical recurrence, and it’s our responsibility not to over-treat patients that are unlikely to suffer. But I think the take-home message is this adds to the evidence that if somebody truly needs ADT we need to do better than ADT alone. And we’re seeing this consistently 1 trial after an another that confirms that if patients are going to suffer, develop metastases and eventually possibly die from the disease, you have to do the very best you can up front.

DR SMITH: Dr Freedland, your thoughts?

DR FREEDLAND: I agree. I keep saying I want to live in a world where ADT is ADT plus an AR-targeted therapy. And we know that in mCRPC, in mCSPC, nonmetastatic CRPC, we now know it for high-risk PCR. The one other place where we use ADT with good evidence is in radiation patients. Those trials are ongoing. But I think if those studies are positive, and I have every reason to believe they are, this is just the way we should do ADT. And to Fred’s point, not everyone needs ADT, but if you do, do it right.

DR SMITH: Yeah, I think that’s really a great point. And we do await the results of these trials of patients being treated with curative intent. But we do have some evidence already from STAMPEDE, right, the addition of abiraterone in patients who have very high-risk and regional risk-prostate cancer receiving ADT and radiation, particularly of NCCN Guidelines. And I think you’re right, we really need to change the terminology, right. So future — current ADT is more than a GNRH agonist or antagonist; it really needs to be combination therapy. So I think really important take-away message.

It's also remarkable I think how there are sort of convergence of the field. So this terminology metastatic/nonmetastatic altered ways of defining these disease states by conventional and PSMA PET scan, in many ways lead down to the same path because we have separate evidence about the importance of treating the primary tumor, for example in patients with low-volume de novo metastatic disease.

So we’re going to move on to cases — this will be a part of each of the sections, and we’d like to thank Drs Hafron and Morris for contributing these cases from their practice. These are derivatives or real cases, and we appreciate that. So I think you’ll find them to be very practical in the way we’re thinking about managing prostate cancer.

So the first case is a 66-year-old man who presents with Gleason 4+4 disease. PSA is 12.7. Bone scan is negative. CT imaging reveals uptake in pelvic nodes. And the question is what approach to primary therapy would you most likely recommend for this patient?

So NCCN regional-risk prostate cancer, Gleason 8, PSA 12, node-positive by conventional imaging, choices were external beam radiation therapy as primary treatment or radical prostatectomy. You see most respondents voted for radiation but not all.

Dr Saad, is there a role for prostatectomy in patients who are clinically node-positive?

DR SAAD: So there is always a role with a shared decision, but most of my patients would get radiation therapy rather than radical prostatectomy. But we have done this kind of approach knowing the surgery would not cure the patient alone. In patients in their 40s, very aggressive approach, in a Tumor Board setting. But for the average patient, I would agree that external beam radiation plus hormone therapy intensified, probably, would be my first choice.

DR SMITH: Dr Freedland, would you offer surgery to a patient similar to described in this case here?

DR FREEDLAND: Absolutely. To Fred’s point, a shared decision-making for sure, and it’s always tough of what you’d recommend because we try to be a little more agnostic and present the data. Have I operated on patients like this? Yes. And I do think there’s a role for surgery.

Fred, you say surgery isn’t curative. I would argue radiation’s not going to be curative if we have nodal disease. So, we have a randomized trial data, not in this patient population, but in others, surgery and radiation are equivalent. I would imagine they’re equivalent in this. Probably going to need some sort of systemic therapy at some point, which should be intensified we now know. But I would definitely offer this as part of shared decision-making.

DR SMITH: Dr Beltran, does the evidence from STAMPEDE, for example, that intensification in a patient like this, improve survival? Does that alter the equation in terms of whether the patient should be offered surgery or radiation therapy? I know that that was not the question of the trial, but we’re often confronted with comparing across different clinical trials.

DR BELTRAN: Well, this would have been a patient that would have met eligibility for STAMPEDE, M0, and where intensifying with ADT plus tiers abiraterone with the radiotherapy, similar to the prior discussions earlier, and we don’t yet have the data for a post-radical prostatectomy, salvage setting. Likely that patient would have needed additional therapy, as mentioned, with pathologic node-positive disease, likely salvage or adjuvant radiotherapy plus 2 years of ADT, based on radicals Hg, and we still don’t have the data for abiraterone. And this is a patient where I think is really at high risk that I would like to bring in a potent AR therapy even earlier.

DR SMITH: I certainly share the views of my fellow panelists. We would advise a patient like this no single therapy will be curative and they’re going to need multidisciplinary care. And many patients like this, we would offer surgery to, but with the full understanding that they will require subsequent treatment.

Our next case is a 61-year-old man who presents with Gleason 4+4 disease. He undergoes robotic prostatectomy. Final pathology reveals T3bN1 disease with 2 of 10 positive lymph nodes. Regulatory and reimbursement issues aside, would you recommend hormonal therapy at this point? Although not specified in the — well, I’ll let you in your answers comment on the role of post-operative PSA result informing this decision. But Dr Shore, what would you advise such a patient?

DR SHORE: So I would probably — I think I would go with ADT and abiraterone, given these low-volume disease. And I think that both LATITUDE and STAMPEDE arm would support that. I would offer that. I don’t think I would just do monotherapy ADT.

DR SMITH: Dr Beltran?

DR BELTRAN: I would do that in combination with radiotherapy for a patient with — or at least consider it or discuss that with the patient with 2 of 10 lymph nodes, and some sort of a salvage situation.

DR SMITH: Dr Freedland.

DR FREEDLAND: Yeah, I was going to add to what Himisha said. I think it’s important to consider the radiation, whether it’s salvage or adjuvant — we can debate semantics. There is some retrospective data that in node-positive patients post-prostatectomy, that radiation can improve outcome. So I would do it with aggressive ADT, as we’re learning now, but don’t forget the salvage radiation.

DR SMITH: Yeah, I think it’s a good point. This kind of brings to the issue of the convergence of our systemic and local therapies, right. So, patients need really good local control. And there is a clear and consistent evidence for improved outcomes by intensified systemic treatment by the addition of an AR pathway inhibitor.

Dr Saad, what are your thoughts here?

DR SAAD: Yeah, I agree. Clearly, I would avoid trying to keep this patient on systemic therapy for the rest of life. So that’s why we would give radiation. We’ve had several of these patients who’ve done very well with radiation, more likely in the adjuvant setting I think you wouldn’t have a PSA of undetectable. But even if he does, this is the kind of patient we would adjuvant, even considering radicals. And we would try to give short-term intensive ADT and abiraterone in the range of about a year and then see what happens. This is relatively low-volume N1 disease.

DR SMITH: And you can see each of the respondents provided their thoughts about optimal duration of hormonal therapy. There is a range there, but most of them converged around 24 months.

Our next case is a 64-year-old man who underwent prostatectomy about 5 years ago for Gleason 4+5 disease. Pathology reported T3N0 with negative margins. His post-surgical PSA was initially undetectable, but then rose to 0.2. He undergoes salvage radiation therapy to the pelvic — to the prostate fossa and pelvic nodes and receives concurrent androgen deprivation therapy. Despite that salvage therapy, his PSA promptly rises to 0.23 ng/mL. Conventional imaging is negative. And then he has a PSMA PET scan that reveals a lesion in the right anterior first rib. We’ll specify that that was a compelling finding. And then, in addition to radiation therapy to that site, what would be your most likely treatment recommendation?

Dr Beltran?

DR BELTRAN: So I think this is kind of a challenging case, in that it’s oligometastatic disease, low PSA, detected by PSMA PET scan. Not clear if it was seen on conventional imaging. Also an area where sometimes we see false positives, also. But assuming that this is a real lesion and doing radiation therapy — and we know that for low-volume metastatic disease, and high-volume, that intensifying is important, as we’ve discussed, but there is data to think about doing metastases-directed therapy to delay the need for ADT. And so, I think I would discuss options with the patient and weigh the side effects and the duration of therapy. And everything with this, I think there are certain situations where — in most situations I like to intensify therapy, but there are certain situations where I’m delaying ADT may be really clinically meaningful to that patient.

DR SMITH: Yeah, I agree.

Dr Shore, what are your thoughts here?

DR SHORE: Yeah, I’m glad I guess by you saying that the PSMA PET in the rib was compelling, positive rib lesions on PSMA PET have a high false-positive. Ribs are obviously difficult to biopsy. We’ve had some success if they’re pretty large rib lesions and that makes them particularly compelling.

I would agree with Misha, in that I would look for some form of combined therapy.

DR SMITH: That’s a great point to conclude our first series of cases. We’ll now move on to management approaches for nonmetastatic prostate cancer. Dr Freedland.

DR FREEDLAND: Thank you very much. We’ve got a lot of studies here to come through, so we’re going to go through these quickly here. We’re going to talk about ADT, when and how to do it. We’re going to review the role for novel hormonal therapies, both nmCPSC and the nmCRPC.

So when and how do we do it? So we still don’t know when to start ADT, even if the patient is clearly going to need it. And we still don’t know how to do it, whether to do intermittent or continuous? There are randomized trials showing no difference. They were not stratified by doubling time and variables that we now know are important. Whether you do combined or ADT? Whether agonist or antagonist? And I do think EMBARK answers some of these but certainly not all of these questions.

So pros and cons to agonists versus antagonists. I’m not going to go through the details in-depth, but I think with the antagonist, you get a rapid T suppression and a return. Perhaps reduced cardiovascular risk. So I think in sense, makes some sense. These are new medicines. They’re oral. That could be both good and bad, but they tend to be more expensive. And urologists, we have Lupron sitting on our shelves and can easily give it to patients. Lasts for 3 months. So again, pros and cons.

So this was actually tested in a study led by Neal up here, the Phase III HERO study. And these are basically men needing ADT, randomized to relugolix versus leuprolide. And the primary outcome was at 48 weeks in terms of testosterone sustained castration during that time point.

And what we see here is a percentage of the patients that get to and have sustained castration, was actually better with the relugolix. We tend to think of leuprolide. For many of us, we give a shot. Of course it works. We don’t necessarily check testosterone or think about it. And this was a little bit eye-opening for me, the fact that we’re not even hitting 90% sustained castration levels. So again, superiority for the relugolix arm.

And the curves are kind of what you’d expect, with the leuprolide testosterone levels actually go up, and then come down. If we look at 5 weeks, so we’re past a month, we’re still not necessarily getting to that castration in all patients. And eventually we get there but it can take quite a while. Whereas with the relugolix, we get there very, very quickly. And then, once they stop treatment, the leuprolide keeps on working, as opposed to the relugolix, where you start to see testosterone is already starting to recover within a few weeks.

And very, very intriguing secondary outcome. But what they saw was, when they looked at major adverse cardiovascular events, actually saw lower rate with relugolix, relative to leuprolide. This has been seen with other studies, with degarelix always as a secondary outcome. The 1 sole trial that actually looked at this as a primary outcome ultimately closed early and was a negative study. But there’s a lot of thoughts that patients were aggressively managed and that in itself reduced the risks. So I think it’s still an unanswered question but very intriguing.

So, as we move into the novel hormonal therapies in the nonmetastatic space, STAMPEDE has already been mentioned. Basically, it’s predominantly radiation patients. And a comparison of standard of care, which was ADT with 3 years, versus ADT — standard of care with ADT for 3 years but also adding either abiraterone for 2 or abiraterone plus enzalutamide. And abi plus enzalutamide was really not better than abi alone. And so, they were able to combine the groups, primarily radiation patients.

So, about 90% of those were getting primary radiation. If you look at metastasis-free survival, very impressive hazard ratio of 0.53, really important clinically. Significant improvement. They actually looked at overall survival, hazard ratio of 0.6. So really, I think for that really high-risk patient undergoing primary radiation, I do think this is the standard of care now. The question is, what if you’re just regular high risk? What if you’re unfavorable intermediate? Where do we draw that line? Unknown at this point?

So PRESTO was a study in the biochemical recurrence setting, looking at apalutamide. So these were men who had a PSA recurrence after surgery or radiation, doubling time less than 9 months. This was only surgical patients. And basically they randomized to ADT, ADT plus apalutamide, ADT plus apalutamide and abi. And again, you’ll see in a minute, the doublet — 2 novel hormonal therapies, really no better than 1. And then the therapy was stopped at 52 weeks and they were followed for PSA-progression, but it’s really a castrate-sensitive progression. And what you see here, the hazard ratios are essentially identical, whether it was apalutamide or apalutamide plus abi. But statistically significant improvement in PSA progression, which, again, clinically I’m not sure exactly how to interpret this.

This was formerly tested in the EMBARK study, which was presented by Neal so eloquently yesterday. Biochemical recurrence patients, doubling time less than 9 months. 75% of the patients had had surgery; 25% had failed radiation. Again, needing ADT. Randomized to enzalutamide plus leuprolide, leuprolide alone, or enzalutamide monotherapy. Very intriguing. We don’t have time to necessarily get into here on the slides, but PSA was measured at 36 weeks. If it was less than 0.2 they came off therapy. And then ultimately was restarted when they reached certain PSA thresholds. Primary outcome was metastases-free survival.

And what you can see here is a very, very impressive improvement in the metastases-free survival, which is metastases or death, with the enza plus ADT versus ADT alone. Hazard ratio of 0.42. Extremely impressive, clinically important.

If we look at overall survival, it’s interim, but clearly trending in the right direction. Hazard ratio of 0.59. It’s certainly tempting to look at that p-value of 0.01 and claim it’s statistically significant. It is not. The prespecified efficacy boundary of p less than 0.0001. That’s the threshold we needed to call that significant. But clearly trending and moving in the right direction.

If we look at the time to PSA progression, this was, for me, the slide that was most wow! If you look at it, the enzalutamide combination therapy, time to PSA progression, is almost a flat line. Extremely impressive compared to a slow decline in the control arm, with a hazard ratio of 0.07.

If we look at the monotherapy arm, what you see is statistically and clinically significant improvement in metastases-free survival. So enzalutamide with or without ADT was better than ADT. Hazard ratio here of 0.63.

If we look at OS, quite immature in the data, but also trending in the right direction. Hazard ratio of 0.77. Nominal p-value of 0.2.

And then the most common treatment-related adverse events: hot flashes, fatigue, and I’m sure we may get into some of the questions, enzalutamide monotherapy had fatigue rates that were similar actually to the combination and the leuprolide-alone arm.

In terms of the nmCRPC, basically all the trials were very similar in that there were patients with CT bone scan-negative, rising PSA, nmCRPC, doubling time less than 10 months, randomized to some sort of drug — we’re going to go through all 3 really quickly — versus placebo with a metastases-free survival endpoint. This is the enzalutamide PROSPER study. Updated data. And this is the OS endpoint, so secondary endpoint, but statistically significant, hazard ratio of 0.73.

If we look at the SPARTAN study with apalutamide, what you see is a hazard ratio of 0.78, again very similar.

And if we look at the ARAMIS, which is darolutamide, you see a hazard ratio of .69. Again, all 3 quite similar with the most recent updated data.

So in summary, again for certainly ADT, relugolix is a new standard of care option. And for patients with high-risk biochemical recurrence, I think EMBARK does establish a new standard of care of ADT plus enzalutamide. And we know that novel hormonal therapies certainly benefit MFS and OS in nmCRPC. And again, my hope is we can live in a world where ADT means ADT plus an AR-targeted agent.

DR SMITH: Thank you, Dr Freedland.

We’ve got a really interesting question from the audience as it relates to EMBARK, and that is there were 3 arms in EMBARK, 1 of which was enza monotherapy. Does that present a realistic option, Dr Shore, for a patient who would like to avoid ADT? And would there be an expectation of better quality of life with enza monotherapy compared to say ADT alone or ADT plus enza?

DR SHORE: Yeah, a very important question. We obtained numerous validated questionnaires and patient-reported outcomes, the PROs. We’re reviewing those now. We will have those presented later this year. And I think that’s particularly the arm that will be quite fascinating to your colleagues, avoiding T suppression, just doing powerful AR blockade with an obvious novel hormonal agent such as enzalutamide. And particularly for patients where sexual function may be a high priority, I think this will be a very intriguing option.

DR SMITH: Yes, I think it will be really important to see the Phase III data. There’s a modest sized Phase II experience comparing to ADT alone, and at least in that setting enza monotherapy has most of the physiologic negative side effects of ADT. And at least with that smaller study, had substantia impact on sexual function and other quality-of-life domains. So the Phase III study will certainly help define that in a more compelling way.

Optimizing the Care of Patients with Metastatic Hormone-Sensitive Prostate Cancer — Dr Saad

DR SMITH: The second module is Optimizing the Care of Patients with Metastatic Hormone-Sensitive Prostate Cancer (mHSPC).

Dr Beltran, in this disease state, when do you use docetaxel? Who are the appropriate patients to receive docetaxel as part of their systemic therapy?

DR BELTRAN: So metastatic hormone-sensitive prostate cancer is a heterogeneous disease. And we know, even within that, there are people that have worse prognosis, those with de novo disease, high-volume disease, compared to those with metachronous or low-volume disease. And there’s a wealth of data now, multiple trials, that have shown that ADT plus an AR pathway inhibitor is standard of care for all patients, regardless of risk. Who you intensify with docetaxel kind of really depends on where in that spectrum that patient is. And data from the ADT/docetaxel versus ADT suggested that patients with high-volume disease and de novo high-volume disease in particular, benefit the most from chemotherapy.

And so, the trials that looked at triplet therapy had — the standard arm was ADT plus docetaxel compared to ADT plus docetaxel plus darolutamide or abiraterone. And so, I would only really consider triplet therapy in patients I would have been giving docetaxel/ADT to, which would have been those high-volume/high-risk patients. And these trials do look — seem, at this point, that there is more of a benefit for those patients. And so, really those high-volume patients defined by the CHAARTED criteria, young patients, visceral mets, these types of patients where you know that you need to more than ADT AR pathway inhibitor alone.

DR SMITH: So, just a quick follow-up question. Are there patient characteristics who maybe — not disease characteristics — patient characteristics that would lead you to recommend docetaxel to a patient, say, who don’t meet either high volume or high risk criteria?

DR BELTRAN: Yeah. I think that it’s a conversation. There is data to suggest that perhaps more than just the high-volume patients might benefit. I think that I particularly don’t like patients that have very low PSAs and unusual sites of mets although they would meet high-volume criteria if they have visceral mets in that situation anyway. Younger patients that want to be aggressive, it’s something I would talk to them about.

DR SMITH: Very good. Dr Saad, do you have a preference among the AR pathway inhibitors in this disease state, intensification for mHSPC?

DR SAAD: I would say, based on what I’ve seen in nmCRPC, and what we’ve accumulated over the time, I think there are 32 very effective AR pathway inhibitors. So there are obviously, some patients where we would shy away from enzalutamide or apalutamide, if there are issues in terms of cognitive concerns, patients with history of seizures. But, overall, I think there are 3 extremely effective agents that have performed very, very well. So it would be hard say. We personally use a lot of apalutamide. The darolutamide for now in Canada is reserved only when we’re going to give the triplet therapy. So this is an issue and I think might be attractive if we can show that monotherapy works. And the enzalutamide has a long history and we’ve have very good successes.

So, it’s also a decision. Patients are, interestingly, interested in the different ones and sometimes do their own research and come in and say, I’d like to get this one for X reasons. To say that I’ve got one that that I think is clearly superior would be hard for me to say.

DR SMITH: Dr Shore, how do you think about this problem in your practice?

DR SHORE: Well, we have the luxury of having access to doublet with abi or enza or apa, and arguably triplet with daro. We will see doublet trials with daro come forward and read out in early 2024, the ARASEC and ARANOTE trials.

I think this goes back to both the reviewing the specific interesting adverse events of interest, of course, the practicality of what’s accessible. But all the trials, whether it was TITAN or ARCHES, LATITUDE, ARESENS, PEACE-1, are very effective. I’m a big proponent of triplet therapy in chemo-eligible patients who are high volume, absolutely. And for low volume, that’s a shared decision-making conversation for I really want patients to have that opportunity to at least think about it.

DR SMITH: Very good. So, let’s move on to the cases for this section. And again, I’d like to thank David Morris from Urology Associates of Nashville and Dr Jason Hafron from Michigan Institute of Urology for providing these really great cases. I think they’re going to bring out a number of interesting points. And we appreciate their collaboration in developing these cases.

In general, which systemic therapy would you recommend for a 65-year-old patient presenting with de novo, Gleason 8 prostate cancer and 3 asymptomatic bone metastases. You see the distribution of votes there. There’s a great enthusiasm for intensification with only 1 outlying voter for ADT alone. Everyone else intensified by either addition of 1 of the 4 AR pathway inhibitors, or a triple therapeutic docetaxel and darolutamide.

Dr Freedland, what would be your typical approach to a patient like this?

DR FREEDLAND: So I think we first need to keep in mind that the STAMPEDE data for patients with de novo oligometastatic disease actually showed a survival benefit for radiation to the prostate. So to your point earlier, Matthew, about local plus systemic, this is someone I would treat the prostate. As surgeons, we like to think if radiation works, surgery will work equally as well, though that’s not formally been tested. So I’d certainly counsel them on local therapy of his choice, and then for the metastatic disease, he has metastatic disease, the data would certainly support intensification. And I think you get into the same issues of which drug do you prefer? And I think you could make an argument multiple ways. I tend to use enzalutamide, but I think you could make an argument for multiple of them.

DR SMITH: Dr Saad, in the same patient who then goes on to have a PSMA PET-CT scan that shows, say a dozen or so sites of metastatic disease to bone, does that information change your management? How do you incorporate that additional results of PET imaging in the management of patients in this disease state?

DR SAAD: You said me, yeah?

DR SMITH: Yeah, please.

DR SAAD: I’m still basing the data and my way of treating on conventional imaging, based that the trials were based on conventional. And I think we need to work out what that translates to in PSMA. So I wouldn’t shortchange that patient and say, no longer will I treat the prostate because PSMA up-staged him. And I would continue to insist on doing the maximum I can in terms of systemic therapy. I personally don’t use abiraterone anymore because of the issues of metabolic issues that need to be followed, even though they’re hormone-sensitive and doing very well.

DR SMITH: Very good. Let’s go on to the next case. In general, which systemic therapy would you recommend for a 65-year-old patient with de novo, Gleason 8 prostate cancer with multiple bone and liver metastases? And here, yo see the voting is a little bit different. There’s a lot more interest in adding docetaxel, with the majority looking at ADT/docetaxel and a secondary hormone therapy — I hope that means darolutamide or abiraterone where we have evidence from PEACE-1 and ARASENS. There were also a few votes for ADT and docetaxel with no AR pathway inhibitor.

Dr Beltran, could you support that preference for systemic therapy? And then, if not, are there other patients in whom you would forgo treatment with an AR pathway inhibitor?

DR BELTRAN: No, I would – as long as an AR pathway inhibitor is available, I would add an AR pathway inhibitor in all situations of metastatic disease. And I would intensify a triplet therapy in this patient if the patient was chemo-eligible. I think in certain parts of the world where potent AR therapy is not available, I think ADT/docetaxel could be reasonable for some patients with metastatic disease.

DR SMITH: Dr Shore?

DR SHORE: Yeah, I agree. I think for this patient, let’s assume he’s an ECOG 0, your first shot tends to be your best shot. Hit the disease hard. I really like the idea that you’re having 3 distinct novel mechanism of action, the ADT, the docetaxel and the darolutamide or the AR pathway inhibitor.

And just as a side note on that last case, whoever picked the monotherapy ADT for mHSPC, it’s just no longer a standard of care. But having said that, we still see in the United States where almost 50% of the patients with mHSPC in 2023 are still getting monotherapy ADT. So there’s an educational disconnect and we really have to overcome that.

DR SMITH: Yeah, I think you’re absolutely right. And perhaps the most important take-away from this module is really the intensification is the standard of care, and intensification needs addition of an AR pathway inhibitor. While a patient like this with liver metastases, there’s concerns that he may be less responsive to AR inhibition. There is an established role for adding an AR pathway inhibitor. So while that may prioritize the addition of chemotherapy, that should not be at the cost of including an AR pathway inhibitor as part of the intensification.

The next case, for a patient with metastatic castration-sensitive prostate cancer for whom you’ve elected to use a novel antiandrogen therapy without docetaxel, do you have a preferred agent? It’s kind of similar to an earlier question we raised. So Dr Beltran, how do you — do you have a preferred agent? And if not, how do you think about this in your practice?

DR BELTRAN: I think any of the approved agents are reasonable in this situation. And I agree with my colleagues, it all depends on access and drug costs and side effects and monitoring. And I think any of these are reasonable. And I’ve used any of these in that situation.

DR SMITH: Very good. This is our next case, a 79-year-old patient with high-volume metastatic CSPS. His pretreatment PSA is 173. CT and bone scan show widespread bone metastases involving skull, thoracic spine, proximal humerus, ribs, sternum and lumbar spine. Regulatory and reimbursement issues aside, what would be your most likely treatment recommendation? And you see the most common response was triplet therapy with ADT/darolutamide and docetaxel.

Dr Saad, how do you think about triplet therapy in a 79-year-old man with high-volume, de novo, metastatic prostate cancer?

DR SAAD: You might think I’m crazy because I’m a urologist doing chemotherapy, but I’ve treated patients that are above 85 on a regular basis. So I don’t have an issue in patients who need chemotherapy to give it as long as they’re well and accept that there are going to be issues. So I would have this discussion with this 79-year-old man who has clearly aggressive disease. And I wouldn’t dissuade him from getting docetaxel. I would actually encourage him, but the shared decision that there might be issues. And docetaxel is not — there’s not a signed contract. You can give the first cycle, the second, third, and pull back if the patient is running into issues. So this is not a contract that it’s 0 or 6. And we see them every 3 weeks with each dose. So definitely it would be an option for this patient.

DR SMITH: Certainly, not an uncommon scenario, right. Prostate cancer is the steepest age-related incidence of any malignancy, though these are often elderly patients. And in addition to the point you raise, which is you can always have the option of discontinuing treatment, we would very comfortably dose reduce the patient at least for the first cycle in this age group or older as a strategy to improve the tolerability of that regimen.

DR SAAD: And he’s in his best shape now. After failing NHT, the response rate is so much lower and he’s going to be that much older and maybe unlikely to be able to get something that might actually make a difference.

DR SMITH: Okay, last case I think in this section. This is now an 84-year-old man who has recurrent metastatic prostate cancer some years after a prostatectomy. Imaging shows bone metastases described as extensive. Regulatory and reimbursement issues aside, what would be your most likely treatment recommendation? You see a distribution of choices here. You still have that 1 long holdout with ADT alone. I’ll refer to Dr Shore’s earlier comments about that choice. But otherwise, consensus about intensification but of different forms.

Dr Freedland, can you just quickly comment on your thoughts here. How would you approach this patient?

DR FREEDLAND: I think it’s chemo in the right selected patients can, as we just talked about, being gingerly given to older patients, so you have to assess his overall fitness, frailty. A lot of different assessments. Assuming he’s chemo-fit, that has been shown to have the best survival benefit, so I would favor the triplet. I think you could also make an argument; he took 11 years to develop metastatic disease, which is perhaps a little bit slower case, and that he might do very well with a doublet, especially at 84.

DR SMITH: Yeah, I agree. I think the fact that he has recurrent metastatic disease many years after his prostatectomy and some of the volume of disease reflects his lost to follow-up. I would consider chemotherapy in older individuals but not in this setting. I wouldn’t agree to treat this patient with chemotherapy. Certainly, I would specify not on a virtual visit. And I think as one of the things we saw during the pandemic, some less than optimal care of decisions being made without actually the seeing the patient in-person. And I’m sure all the clinicians in the audience are familiar with how different a patient can look on a well-staged Zoom call and how they look in person at times.

So our next presentation is by Dr Saad. Fred, take it away.

DR SAAD: Thanks, Matthew.

So I was tasked in 8 minutes to summarize a pretty vast topic. But really, just to set the stage, these patients that are metastatic hormone-sensitive will progress to mCRPC, which is the lethal state of prostate cancer and eventually the highest likelihood of actually dying of prostate cancer rather than with prostate cancer. And when we do ADT alone, and this is probably the main take-home message that we’ve been repeating, if you do ADT alone in an all-comer population of metastatic hormone-sensitive, you can expect them — and this has been shown repeatedly — to become castration-resistant within a year. So they don’t fail in 2 or 3 years. The median is less than year in almost every trial, and they will only live about 3.5 years if you start with ADT, even though you effective therapies in mCRPC. So we can do better.

And this was talked about, that local control does make a difference in some patients. And there are trials that have shown with the STAMPEDE, that if you had less than 4 bone metastases, you significantly improved failure-free survival. So what does that mean? It means you delay castration-resistance by treating the prostate. In itself, that’s amazing. Treating the prostate delays castration-resistance and turns out to significantly improve overall survival in the range of our systemic therapies. So to exclude local therapy in a patient that has low-volume disease on conventional imaging. I still don’t know how many mets on PSMA I would exclude a patient.

The role of systemic therapy, clearly there’s an established role. Chemotherapy alone with ADT significantly improves survival in patients with high-volume disease. Really didn’t look like it was helping patients with low-volume, not to say that it doesn’t help, but you’ve got a lot of opportunity to catch up with subsequent therapies.

In LATITUDE, abiraterone in high-risk patients significantly improves overall survival. But again, I highlight, these high-risk patients will become castration-resistant in 7.5 months. so there is no reason to start ADT alone. And why I said recently that I didn’t appreciate abiraterone compared to the other 3 AR-specific inhibitors is that you still need to follow these patients. It’s not because they do well and are going to live longer that you can ignore the fact that they’re on abiraterone. There is hepatic toxicity. But more important, hypokalemia, hypertension, that almost quadruples when you lower from 10 milligrams to 5 milligrams. To say that you don’t follow these patients might lead you to have significant issues. And so for a lot of reasons, I have excluded now, unless there’s a contraindication to the 3 others, of using abiraterone in hormone-sensitive disease.

ENZAMET showed significant improvements in progression-free survival and overall survival in an all-comer population. And when you look below, you see that the hazard ratio’s actually in the low-volume setting is actually even more beneficial, trending in the EMBARK and all the other studies that are showing the earlier you start, the bigger bang that you get for your investment.

ARCHES confirmed again that enzalutamide delays progression-free survival and improves overall survival significantly. And again, the low-volume disease has at least as much benefit if not more than the high-volume.

Apalutamide continued to confirm that an all-comer population will benefit. And again, whether you’re high or low volume, and these patients, even though they were allowed to cross over, had significant improvements in overall survival.

And then for us as urologists and for patients, PSA response is extremely important. And you see that the PSA responses are consistently better when you add an AR pathway inhibitor to ADT alone. And what’s most important and is becoming more and more our main objective as an early signal that we’re doing the right thing, is getting to below .2. And there, you almost triple the likelihood of getting to undetectable PSA by adding the AR pathway inhibitor. And this leads to significantly better outcomes whether it’s in time to mCRPC, time to radiographic progression. And there’s an 83% reduction in the risk of death in patients that reach that 0.2 compared to patients that don’t. and so, really this is what you need to be looking at in the early start of these therapies.

Then the question is, as was mentioned, we have AR pathway; we have chemotherapy. We’ve always had to choose 1 or the other. And so combining the 2 together to have the best biological attack to the cancer makes biological sense. And we have trials now that have shown in PEACE-1, that adding abiraterone to docetaxel significantly improves the outcome of patients compared to ADT and docetaxel alone. And this was most pronounced in the high-volume patients. The low-volume haven’t reached the median survivals yet, so it’s still a little early to say it doesn’t help at all. But clearly, the high-volume patients.

ARASENS was the first study to prospectively evaluate the triplet regimen compared to the doublet regimen. Anda gain, the doublet regime here is docetaxel plus ADT, since that was the standard of care when the study was designed. CHAARTED had come out, LATITUDE. The ARPI studies hadn’t already reported. And so the very best standard of care was the control arm. And as you notice, the only endpoint that really counted was overall survival. There was not an rPFS endpoint to insist on keeping patients on trial when they’re starting to progress. Investigators were allowed to give very early subsequent therapy if patients progressed. And this is important because some studies insisted until rPFS and didn’t allow you to get other subsequent therapies. So overall survival with the triplet up-front compared to the doublet of ADT and docetaxel showed a 32% reduction in risk of death.

And recently at ASGO GU it was reported and published that whether you were high risk or low risk, you seem to be getting a benefit. And the low-risk patient, with the addition of AR PI, is probably the reason they’re getting so much benefit with the addition — over docetaxel.

You see the time to CRPC, again confirming that these patients progress very quickly to CRPC and to first subsequent therapy, but even though they got very early subsequent therapy, that overall survival was reached very significantly.

And again, that Holy Grail of getting to undetectable PSA was achieved much more effectively with the triple therapy by adding darolutamide to docetaxel. And you see the docetaxel and ADT alone didn’t reach much more than about a 25% of patients reaching that goal. And why is that important? Getting to the under .2 led to a significant overall survival benefit whether you’d looked at 6 months or at 9 months, the time to that PSA undectable level.

So clearly the patients who don’t get to .2 is our next challenge. What do we do in the patients that don’t get to .2? Is there a strategy of more intensification? And what do we do to the patients who stay under .2 for a long amount of time?

So the future and more questions, since research is continuing, is that patients with mCSPC are very high risk of rapid progression and early death. Treatment beyond ADT is recommended in all patients. You have to justify why you wouldn’t do it. Adding in an HT must be considered in patients who received ADT and docetaxel. That is the Level I evidence from ARASENS.

Further intensification in some trials are ongoing. The role of PARP, radioligand, immunotherapy, but deintensification needs to be studied to try to pull back in some patients that have extraordinarily good results.

And just to encourage the multi D approach. Unfortunately, it’s no longer an era where urologists can do everything, all alone, in their own little setting.

Thank you.

DR SMITH: Thank you, Dr Saad.

So this week, the Oncology Drug Advisory Committee of the FDA recommended by a vote of 11 to 1, the approval of olaparib plus abiraterone and prednisone as first-line treatment for patients with mCRPC and a BRCA mutation. Further, they specifically recommended the FDA restrict use of that combination outside of that specific molecular setting.

So what do you think of that decision, Dr Beltran? Do you agree with that recommendation, and why?

DR BELTRAN: Well, I do think that BRCA mutated tumors are the patients that respond the best to PARP inhibitors and they are the people that respond to combination therapy. And, are there patients that don’t have BRCA mutations that might respond, or who were unevaluable on the trial, I do think that. But I think it’s our job to figure out who those patients are because there are toxicities with combination therapy.

So I think that the story is not over, and that this is the first step is to get the approval for the patients we know that are going to benefit the most. And now it’s really our job to figure out who are those other patients and what’s the best way to test. And do better to find those patients that might benefit from the combo.

So, yeah, I mean I do think that the biology of BRCA is there’s other variants within that same, HRD, and there’s other biology with the cross-talk that we need to figure out better.

DR SMITH: Yeah, I appreciate that perspective. And to your point is that we’re not depriving patients who have other mutations, DNA mutations, the opportunity to be treated with olaparib, it’s just this combination as part of first-line treatment. So I guess the message in there is the results from early approvals stand and so patients could receive olaparib monotherapy who have other alterations.

Another point I think we should — we sincerely hope that the population actually studied in this trial will decline over time because really all of these patients — most or all of these patients should be receiving an AR pathway inhibitor as part of initial systemic treatment for metastatic disease. So this idea that they’ll be patients receiving abiraterone or another AR pathway inhibitor for the first time when they have mCRPC should be declining as we move forward.

Therapeutic Considerations for Patients with Newly Diagnosed Metastatic CRPC (mCRPC) — Dr Shore

DR SMITH: Let’s go on to a few cases. This is a 65-year-old man receiving ADT for M0 disease after radical prostatectomy, found to have asymptomatic bone metastases. Genetic testing is negative for homologous recombination repair mutations. Regulatory and reimbursement issues aside, which systemic treatment would you most likely recommend? So, mHSPC, biomarker-negative testing for DNA repair mutations. Here there is some additional choices provided, including sipuleucel-T.

Dr Freedland, is there still a place for sip-T in managing patients with metastatic prostate cancer? And if so, is this the right setting?

DR FREEDLAND: Yeah. No, I think there is a role cand I think this is the right patient. He was on ADT and developed metastases while on ADT. So he’s mCRPC. No homologous recombination repair mutations, so you wouldn’t necessarily think about certainly PARP monotherapy. So standard would be abi or enza typically, but sipuleucel-T, he’s asymptomatic, 65 is increasingly young in our patient population and we have randomized trial data showing overall survival benefit. So I think it’s a great treatment. We know it doesn’t delay progression-free survival, so it’s not going to buy us tons of time. But gives him some time to contemplate and understand he has metastatic disease and then a few months later, you start abi or enza. For me, it would be more enza because I’m with Fred, I’m concerned about the metabolic issues with abi. But I think it’s a great first-line mCRPC for asymptomatic patients.

DR SMITH: I guess a quick follow-up question, how would you sequence AR pathway inhibition in a patient like this who has not received the prior AR pathway inhibitor, if you chose to use sip-T? Concurrently? Sequentially?

DR FREEDLAND: I would probably wait. I mean there’s not data for concurrent. Certainly, if you’re thinking abi with prednisone being immunosuppressive, there’s data that doesn’t really suppress the immune response to sip-T, but ultimately we don’t know. It’s based on biological markers. So I would give the sip-T first. You wait a few months, and then start AR-targeted. Again, in my practice it would be enza.

DR SMITH: Certainly is a common theme in managing our patients. We have remarkably limited information about optimal sequencing. So we have many available tools in our toolbox, we often don’t know the optimal sequence in which to use them. So we should celebrate when we do know the differences and make the best of those opportunities.

So this is our next case, 65-year-old man receiving ADT for M0 disease. A little bit different here, he has widespread, moderately symptomatic metastases. Genetic testing again is negative. Regulatory and reimbursement issues aside, which systemic treatment would you likely recommend? Docetaxel and secondary hormonal therapy? By that I’ll take that to mean an AR pathway inhibitor. Radium-223 plus an AR pathway inhibitor? Abi or enza? Or abi and olaparib?

Dr Saad, so this is mCRPC, widespread bone metastases. Moderately symptomatic. In someone who had not received a prior AR pathway inhibitor/chemotherapy, what would you recommend?

DR SAAD: Yeah, I’m not sure if people understood the question because docetaxel — this triplet regimen is for mHSPC. We have not really studied it in mCRPC. So I think there might have been a confusion in understanding. So I think the choices are docetaxel or an AR pathway inhibitor. And I think the worldwide consensus in first-line mCRPC, unless they’re severely symptomatic, viscerally metastatic, I think the majority would go with an AR pathway inhibitor and look very closely at how they’re responding. And I think this is reasonable.

This is the kind of the patient, 65-year-old patient that I would have considered abiraterone/olaparib if I had access to it. Because these patients, in the study, 65-year-old, had a 50% reduction in the risk of radiographic progression. And actually about a 35% reduction in the risk of death in those under 65, and they weren’t all mutated. So there’s something going on in these young, aggressive patients.

DR SMITH: Yeah, I think you raise a good general point there as well. There are times when we can generalize across different disease states — this is not one of them. And there may have been some misunderstanding by the respondents. But this is mCRPC, so I certainly wouldn’t be applying PEACE-1 or ARASENS data to first-line mCRPC. We just don’t have that evidence. And if you’re going to use those agents, they would be sequentially, not in combination.

I’d also further add that we have good evidence that, say, adding Radium-223 to abiraterone results in net harm in this setting and should not be done. And if you’re going to use radium-223 in an approved manner, you should also be doing so in combination with a bone-protective agent to spare patients the unintended toxicity of fractures.

So, our next discussant is Dr Shore. He’s going to take on the topic of Therapeutic Considerations for Patients with Newly Diagnosed Metastatic CRPC. This is a challenging topic because of the complexity added by management of mHSPC. So take it away, Neal.

DR SHORE: Thank you very much. So, the overview is, say, you can’t boil the ocean on this one, so I’m just going to focus on the overview here. We’ll talk about sipuleucel-T. we’ll talk about some of the biologic basis for PARP inhibitors with combinations with either abiraterone or enzalutamide.

We’ll talk about the combination trials that have read out now, these key Phase III trials: PROpel, MAGNITUDE and TALAPRO-2. I’ll try to restrict my commentary to those that these patients that did not have an HRR mutation. And I think in Matthew’s presentation he’ll be focusing on the HRR- positive patients for mutation.

And then we’ll touch base briefly on CDK4/6 inhibitors and some trials that are ongoing, known as CYCLONE 1 and CYCLONE 2.

So this is the schema of the IMPACT trial back in 2010. And so, what’s interesting here is sipuleucel-T approved only in the United States for asymptomatic mCRPC patients, both with either bone, nodal or visceral metastases, as long as they’re not symptomatic, on opioids. This is an all-comers population. So we have pembrolizumab, which is approved in tumor-agnostic, but only if you’re MSI-high; this is in all-comers. This was a successful trial. And ultimately it had Level I evidence to put into the guidelines in the United States.

And here’s the KM. What’s really intriguing, you look at the Schellhammer data, as it’s oftentimes called, is when you did this retrospective analysis, looking at it by cortile data, the patients who had PSAs under 22 as opposed to over 130, albeit they all have beneficial effect, it’s really rather marked if you start this therapy early. The quality aspect of starting sipuleucel-T, it’s over in 4 to 6 weeks. It’s 3 infusions.

The safety profile — remember, when this first came out people were like, oh, immunotherapy. This is new to us. This we don’t really get it. It’s sort of, not a gray box, but a black box. And what we realize now looking here, this is an exceptionally well-tolerated therapy.

Additional trial was done, the PROCEED, to confirm any lack of CV events, which was very nicely established, and that was an initial concern by the FDA.

And here again, looking at the PROCEED, this is almost 2,000 patients prospectively, receiving sipuleucel-T. Look at the SAEs, the Grade 3, 4 and 5s. They’re all remarkably low and almost all less than 1%.

And so the overall survival, again sort of recapitulating the Schellhammer data, looking at the lowest PSA levels, one sees if you’re going to use this, you want to use it early in the course of the disease. In this, we have had Phase II trials — Phase II, combining sipuleucel-T with enzalutamide as well as with abiraterone, probably mechanistically makes a little more sense to combine it with a non-steroid-containing agent, but that’s never really been shown that the 5 mg BID has a negative impact on the immunotherapeutic benefit.

Rana McKay did a very nice retrospective analysis, looking at this consort diagram may be hard for you to see, but the bottom line here from her study in this Medicare population, the top-line results, a 13.9-month survival, OS difference with sipuleucel-T versus starting out at as first-line versus starting of the androgen receptor pathway inhibitor. And you can see the additional complementary survival benefit starting it early on when sipuleucel-T is used.

What’s very interesting, is mostly used within the urologic community and some selected medical oncology practices. But there’s an enormous amount of data that’s been put out there in the last 13 years that it’s been available in the US.

So the Phase III trials of combining a PARP inhibitor and an androgen receptor signaling inhibitor in the first-line setting, of course we’re always trying to combine novel mechanisms of action to get some additional synergy. And this really is the basis.

The point of concept — or proof of concept, was known as STUDY 8. I don’t have time to show that, but very nicely presented at a podium presentation by Noel Clarke. And I believe Fred was also a co-leader of that trial which gave the concept that in an unselected population, a combination of olaparib and abiraterone bested abiraterone by itself with a comparator.

So now we have now published these 3 discreet trials that have clearly demonstrated a benefit of the combination, but MAGNITUDE has only demonstrated the benefit of the combination in HRR-unmutated patients, not the wild-type. But PROpel and TALAPRO 2 have. CASPAR still has not read out.

And here’s the PROpel trial led by Fred and Noel Clarke. What’s the rationale? I mentioned STUDY 8, but the concept here, and you can read through this, is essentially amplifying DNA damage repair by augmenting AR androgen receptor selectivity to DNA damage and also increasing activity of novel hormonal agents as well.

So there’s a synergy — arguably, this is very well demonstrated in preclinical models. And so we use this strategy now in PROpel and TALAPRO-2, and arguably in MAGNITUDE, which was a little bit of a different trial design. But here’s the PROpel trial design. It’s a 1:1 randomization. You can see the stratification factors that are listed there.

This was the approved of olaparib as well as abiraterone, the approved agency dose. The primary endpoint, rPFS. Secondary key endpoints you see listed here.

The Kaplan-Meier demonstrates here that this was a clearly successful trial, meeting its primary endpoint with a hazard ratio of .66 and a p-value less than .0001, in an all-comers population. And so, the curves separate and stay separated. The survival benefit is still forthcoming. And with each successive analysis, the curves are separating further but has not yet reached statistical significance.

Now the other key aspect here is the rPFS in the BICR versus the investigator assessment. Here you see a difference of about 11 months; in the investigator it’s about 6 months.

So the conclusions of PROpel are listed here. Unfortunately, and frankly for me, very disappointingly, as Matthew alluded, the ODAC was voted against the all-comers population for the benefit, but voted for insisting upon tissue testing, which is actually contradictory to what the EMA voted. And now, PROpel, within the EMA, is now approved. It’s also approved, the PROpel data — based upon these findings — it’s approved in several other countries, notably Brazil.

So the MAGNITUDE was also a very important study. It’s a little bit of a different trial design. In the biomarker-negative for homologous recombinant pathway, there was a futility analysis. So what continued to go forward is only in the biomarker-positive. So essentially the DNA — the DDR, DNA repair pathway, you see the panel listed here, fairly comparable to the panel but there are some notable differences as it relates to PROpel as well as TALAPRO-2. But this ultimately an unsuccessful trial in the biomarker-negative.

Some have argued that that’s because of the — there was a dose reduction in the use of niraparib because of toxicity concerns. And there were some differences in the inclusion criteria, mainly in prior exposure to abiraterone, about 4 months prior to baseline as opposed to TALAPRO-2, or TP2 as its oftentimes called, and PROpel, which was a 12-month avoidance prior to baseline.

So here’s the TALAPRO-2. It was just recently presented at ASCO GU 2023 by Neeraj Agarwal. Very similar design. There are some differences in the stratification factors. The HRR gene alteration status deficient, biomarker-positive, versus non-deficient or unknown, was prospectively acquired as opposed to in PROpel where it was retrospectively acquired. But nonetheless, as I’m going to show you, even with that caveat, the results are almost absolutely comparable in terms of the rPFS, in an all-comers population.

And the key thing in both PROpel and TALAPRO-2, it was an active comparator. Here the active comparator was enzalutamide and placebo, and in PROpel it was abiraterone and placebo. It’s very important to recognize. And yet there was an 8-month benefit at the median for the all-comers population.

Again, another way of thinking about reading the rationale for combining a PARP inhibitor with an AR pathway inhibitor, essentially it’s the co-inhibition may be efficacious. There’s very good preclinical data. And this was the basis for, as well as Study 8, and thus the basis for moving forward with this combination.

What’s remarkable is there’s just indisputable evidence: if you’re BRCA-positive, the results are just breathtakingly significant. The challenge for some, even though they make up a small percentage, about 10% of the total population of the trial that was reviewed, roughly speaking, for both TALAPRO-2 and for PROpel, the aggregate population, there was still an rPFS benefit in both TALAPRO-2 and PROpel in the HRR mutation-negative population.

And here’s the rPFS for the blinded independent central review in TALAPRO-2, also statistically significant, with a hazard ratio of .63. Comparable to the 0.66 that we saw in PROpel.

And again, this is another way of thinking about it and reviewing tissue testing.

Just a quick word on tissue testing. Tissue testing for somatic aberrations as well as ctDNA, the liquid biopsy, as well as germline testing, whether it was prospective or retrospective was rigorously performed in these 2 trials. What’s notable is that in the real-world, testing — there’s a paucity of testing — less than 50% of academic centers we published don’t do routine testing for this patient population, and way under 30% within the community. And yet, there was subset analysis, subgroup of a subgroup, by the FDA which they looked at, which I think was very unfortunate. And thus, I feel strongly that their decision was very disappointing.

The CYCLONE 1, shifting over right now to my request, was to look CDK4/6. CDK4/6 is approved breast cancer patients, I don’t treat breast cancer patients, but now it’s being looked at. And here’s some of the data looking at abemaciclib, or abema, in monotherapy and one can see response rates. Why the rationale? Kind of similar in the notion of combining 2 different mechanisms of action that we saw in PROpel, TALAPRO-2 and MAGNITUDE, now we’re thinking of how can you combine a targeted different therapy with abiraterone?

It's described here. The hypothesis at the end of the day is that the dual inhibition of the AR access in cell cycle — this really works on the mitotic spindle, the area what’s known as the CDK4/6 cyclin-D1 access. It’s very unique, interesting, targeted mechanism of action.

And here is an ongoing trial. I believe Matthew you are leading this trial. And so I think this is really interesting and could potentially add another proverbial tool to our toolbox. And we await the read-out of this very important trial.

Thank you.

DR SMITH: Thank you, Dr Shore.

You raised a really interesting point and that is the ODAC decision about PROpel and the difference with that in the European decision based on the same evidence. So, Dr Saad, you were principal investigator of PROpel. What are your thoughts about the ODAC decision? And how do envision…?

DR SAAD: I’m obviously very disappointed because the reality that Neal mentioned is, that a lot of patients are walking around and we don’t know their status. And as much as we’d like to know it, sometimes we just can’t. So I was very happy with the European decision, to allow the physician to make the decision. And from my understanding, it’s not because they allow it, that everybody is getting it. And it’s a little bit like the triplet therapy, you’re not restricted to saying you have to have liver metastases to be able to get triplet therapy. You’re looking at your patients as a whole and deciding that this patient might not do as well with the standard of care NHT. And with the 7.4-month improvement in overall survival in the ITT, I think it was very compelling. And it’s unfortunate that they’re limiting it to the patients that are going to get most of the benefit, but don’t allow us to consider it in patients that we either don’t know or might be negative but with other very high-risk features.

DR SMITH: I appreciate that perspective. Dr Beltran, what’s the optimal timing of PARP inhibition in a patient with a germline BRCA mutation, BRCA2, I’ll specify, mutation?

DR BELTRAN: I don’t think we know the optimal timing. I mean, it’s approved for mCRPC post-AR — now potentially in combination with an AR pathway inhibitor. Whether or not it’s going to happen in earlier stages, I think we’ll see the trials in the hormone-sensitive stage. In breast cancer, with BRCA germline mutations, it’s approved in the adjuvant setting. It’d be great to do those types of trials in prostate cancer. Germline mutation carriers are a minority and we see somatic much more frequently, but it does represent a very special population with poor prognosis. And so, it’s likely we’ll see an evolution of the optimal timing of this in the future as well.

DR SMITH: Thanks. We’ve got a number of really interesting questions from the audience. I’ll try to take on 1 or 2 of these as time permits. But we talked about the role of treating the primary tumor in patients with low-volume, de novo metastatic disease. But where you start and stop with radiating the metastases? Dr Freeland, how do you think about that issue?

DR FREEDLAND: Yeah, it’s a great question because I think we all want to do it for oligometastatic disease but we can’t necessarily, I’ll agree, on the definition of oligometastatic disease. I think it’s obviously very crucial in terms of multi D discussions. I mean the metastases-directed therapy is given by the radiation oncologist, so certainly bringing them into the loop in the discussion-making.

I think 1, 2, 3 metastases, absolutely. As you get to 4, I think we get a little bit more nervous; 5 and 6, a little bit harder to justify in that sense. And I think one of the questions that we’re facing now is, and to Fred’s point, conventional versus PSMA, if someone has a sole spot on conventional imaging you’d say, great, metastases-directed therapy. We’ll treat the prostate, et cetera. We know how to — we think we know what to do. And also he gets a PSMA, and it’s everywhere. Are you going to treat it like low volume? That’s what STAMPEDE said, take out the prostate or radiate the prostate. Are we going to do that in this case? Does he need chemotherapy? So, all of a sudden high volume, I would argue no, but I’ve certainly heard in our Tumor Boards of people arguing yes. So I think we need to reevaluate in the PSMA era. But I think certainly for 1, 2, 3 mets, yes to MTD.

DR SMITH: Yeah, the other point to be made I think is that there is a no going back from PSMA PET-CT, right. It’s widely used. And we talk about these issues almost in isolation, like conventional imaging and PSMA PET imaging. But going forward, we’re not typically doing sequential imaging in patients. And there is an interesting observation that the radiologists get a lot better at finding metastases on conventional imaging — CT part of a scan after they see the nuclear medicine part of the test.

So we’re just going to lose some of the prior definitions by conventional imaging as a consequence of introduction of that really disruptive technology.

One more question from the audience before we move on to some great cases and that is, what is the role of carboplatin in either mHSPC or — mHSPC? Dr Beltran, are there patients you would use carboplatin in mHSPC?

DR BELTRAN: I use carboplatin in situations where I see small cell neuroendocrine differentiation in combination with ADT/AR pathway inhibitor and even potentially I think about docetaxel/carbo situations. I think the AR pathway — it’s complicated I think in that situation. But there may be some situations where you might consider that. Otherwise, in later stages of prostate cancer thinking about cabazitaxel/carboplatin regimen for patients that have very aggressive features or small cell neuroendocrine features.

DR SMITH: Yeah. And I think I’d add, in the interest of time we won’t go into that, because it is complex. There’s a whole variety of issues that you would look at and you certainly know very well the issues of how to think about neuroendocrine differentiation, and it includes not just pathology but other …

DR BELTRAN: And I also I guess in the DNA repair aberration situation, too.

DR SMITH: And that’s a story we need a lot more evidence on as well.

Contemporary Management of mCRPC in Patients Harboring a Homologous Recombination Repair Gene Alteration — Dr Smith

DR SMITH: So we’ll go on to some cases. In general, what is the optimal approach to mutation testing for possible use of PARP inhibitor in mCRPC? Dr Shore, you commented on the range of testing that’s available and you see the choices here, the most common answer was really comprehensive germline and somatic testing. Is that the approach you recommend?

DR SHORE: Yeah, I completely agree with that. Yeah, if a patient hasn’t received any testing, you could certainly go this route. One could argue that, well, maybe you don’t need to do a germline if indeed their somatic is positive. But you’d certainly want to know the germline to inform their family. So oftentimes called cascade family testing and inform them about their risk for malignancy.

So I think this is really important. But I think as Fred said earlier, germline is easy. It’s a blood test or a buckle swab saliva and it’s fairly inexpensive by US standards. Oftentimes patients, if they’ve had a previous prostatectomy, you can’t get the specimen or it hasn’t been properly preserved, and if a patient is largely mCRPC with lots of bone lesions, they’re not always easily biopsied by your interventional radiology team so then you have to go with liquid-based testing. And then ctDNA testing can be faulty if you don’t have adequate tumor cell shedding.

So in my experience, and what I do for my metastatic patients is I get the somatic testing when they come in metastatic. I germline test all patients. NCCN says everybody except Grade Group 1 and 2, if they don’t have a family history, half the patients you talk to don’t know their family history. So I believe that germline testing should be universalized and democratized for anybody with prostate cancer.

DR SMITH: I appreciate that. So regulatory and reimbursement issues aside, for patients with mCRPC and germline BRCA2 mutation, if you’re planning to administer a PARP inhibitor, do you have a preference for which one? Dr Freedland.

DR FREEDLAND: Yeah, up until recently the data were certainly much stronger in terms of olaparib. We had Phase III trial data. Rucaparib was approved based upon objective response rates. We recently saw at GU ASCO overall survival benefit relative to chemotherapy. I thought it was relatively impressive data. I think there’s currently some issues in terms of company and supply and whatnot. I think there’s a familiarity with olaparib that would probably drive preference to that. But as rucaparib and niraparib is moving forward, not yet in this space, but talazoparib. I think in the future we will probably have a lot of choices, particularly earlier. But I think in this space, at this point, I think the data are strongest and most robust with olaparib.

DR SMITH: Yeah. Dr Saad, do we need more than 1 PARP inhibitor in prostate cancer?

DR SAAD: Do we need more than 1? I think we have to have as many choices as possible. I think their limiting choices is going to be issue. And there are patients that are going to possibly tolerate. We have never done head-to-head studies, at least not in prostate, and so, I think until we have head-to-head studies, it’s like saying should we limit it to 1 pathway inhibitor. I would be very disappointed if we were stuck to just 1.

DR SMITH: Yeah, I think it’s a valuable perspective, kind of analogous to the issue we confront with 4 AR pathway inhibitors, right. You could maybe do with fewer, but we’re glad to have them all and there are specific patients who we’re going to have a strong preference for 1 over the other, based on safety and in some cases strength of evidence.

In general, when administering a PARP inhibitor to a patient with metastatic prostate cancer, do you use prophylactic antiemetic or GI medications? What are your thoughts, Dr Beltran?

DR BELTRAN: I don’t usually use it prophylactically, but it does become an issue. So, in those situations, I do add it. I follow them really closely in the beginning.

DR SMITH: And Dr Shore, recognizing these are important issues for some patients on these medications, do you use prophylactic treatment to address potential GI —

DR SHORE: No, I don’t. I don’t. If you’re going to see the GI toxicities, which they tend to be mild to moderate, they’re not overwhelming. It’s early on. I think I’m more aware of querying patients. Sometimes patients won’t even bring them up. Maybe they’re having some change in just baseline mild nausea. But I do not prophylactically treat. I have not had the need to do that whether it’s with olaparib or rucaparib.

DR SMITH: Very good. So now we have a case, 67-year-old man presents with Gleason 5+4 prostate cancer. PSA is 12. CT and bone scan show spine and pelvic lesions and small positive lymph nodes in the pelvis. Germline testing is negative, but somatic testing from a biopsy reveals a BRCA1 mutation. Of interest, his family history includes a mother with breast cancer. Regulatory and reimbursement issues aside, what would be your most likely treatment recommendation for this patient? So this is mHSPC, BRCA1-positive.

Dr Freedland?

DR FREEDLAND: I mean I would say it’s certainly quite tempting to think about putting a PARP inhibitor into the mix, just he has BRCA1. We tend to think more BRCA2. But it’s likely at some point in his journey he’s going to get a PARP inhibitor, and everything we’re learning is if you’re going to get a drug using it earlier is better. That being said, there’s no data to support its current use in mCSPC. So I think we go where the data are, and we can debate whether he’s high volume or low volume, number of mets. He’s Gleason 9. Probably more on the high volume, so probably leaning towards a triplet. But it’s tempting to want to put that PARP — I want that data; we just don’t have that data yet.

DR SMITH: Yeah, agree. Dr Beltran, would you treat this patient with a PARP inhibitor in this setting?

DR BELTRAN: No. and I agree with the comments, we have data for the triplet, in this situation we’d probably consider triplet. They do have poorer prognosis, patients with germline BRCA mutations. But there’s no evidence to say that they won’t benefit from our standard of care drugs. So we should treat them with standard of care. And I think this patient would likely respond very well next line to a PARP inhibitor.

DR SMITH: Yeah. And Dr Shore, would the observation that he has somatic BRCA mutation impact your thinking about the role of docetaxel if you’re choosing between doublet and triplet therapy in mHSPC?

DR SHORE: If I’m hearing you correctly, if the patient has a positive somatic mutation, does that influence my decision to do doublet?

DR SMITH: So how would you treat this patient? And is the presence of the BRCA mutation increase your enthusiasm for adding docetaxel?

DR SHORE: Yeah. I would treat this patient with triplet therapy. And I would share with the patient that it’s clearly very important that he’s BRCA and that the moment he converted biologically to resistant disease that that would be my most like next therapy.

DR SMITH: Yeah, I agree. I would take the same approach. I think we have 1 more case. A 72-year-old man presented with Gleason 4+4 disease 2 years ago. CT and bone scan were negative. He had proton beam radiation therapy with 2 years of ADT. His PSA nadir was 0.1 and then rose shortly thereafter to 11. Subsequent imaging shows uptake in a lung nodule, retroperitoneal node and sclerosis in bones, although the bone scan is negative. He has a BRCA2 germline mutation. Family history is negative for other cancers. Regulatory and reimbursement issues aside, which systemic treatment would you most likely recommend? Dr Saad?

DR SAAD: I hear the question — the answer — This is first-line mCRPC with a BRCA mutation, BRCA2? This should be a no-brainer. This patient needs a PARP inhibitor in combination with an AR pathway inhibitor, and in the case of PROpel would be abiraterone and olaparib. Because this patient is going to progress extremely rapidly. The time to progression in these patients of PSA progression was less than 6 months; 8 months for rPFS. And when we introduced this therapy, the survival is tremendously better. We had a hazard ratio of .29 for survival compared to abiraterone alone.

DR SMITH: In the BRCA…

DR SAAD: In the BRCA-mutated patients. So this is absolutely necessary. And this goes back to even the PROfound data, that the earlier you introduce it the more chance you have of avoiding further resistant mechanism of coming up.

DR SMITH: Yeah, I agree with your perspective. And this really provides kind of an outstanding example of a good setting for which to use that now and soon to be approved setting to use that. These are patients who should receive a PARP inhibitor at some point in their care. And so the threshold to include it, in combination with abiraterone, I think should be quite low given the survival benefit that was observed in PROpel and you nicely commented on here this evening.

We’ll go on to my presentation. I have the task of discussing Management of mCRPC in Patients with HRR Gene Alterations. Some of this has been very nicely covered by Dr Shore and so I’ll just briefly comment on the sections of overlap as a method of reinforcement.

We talked a little bit about the importance of testing. And it’s notable that these are common findings. These are not rare events in prostate cancer. The frequency of DNA repair gene alterations increases in patients with metastatic disease versus localized disease. And about 20- to 25% of patients with metastatic castration-resistant prostate cancer have identifiable pathogenic mutations in a DNA repair gene. That’s a high enough rate that we routinely should be doing testing. And those mutations, as we’ve heard, are quite actionable. About half of the mutations that are found are germline mutations — that’s this beautiful data on the right from Pritchard that really was — it’s a landmark study showing an unexpectedly high rate of DNA repair mutations in patients with metastatic prostate cancer. This was the family history; prostate cancer did not seem to be predictive. And as Dr Shore pointed out, we often don’t have a detailed family history of our patients. So, really the need the importance of doing testing. The most commonly altered germline genes are BRCA2, BRCA1, CHK2 and ATM.

These are the NCCN Guidelines for testing. A lot of words there, but I’ll try to make it very simple. Germline testing is recommended for patients with a personal history of prostate cancer who have metastatic disease, regional-risk disease, very high-risk disease or high-risk or localized disease. Also, patients with any personal history of both prostate cancer and breast cancer, or personal history of prostate cancer with a strong family history of cancers associated with DNA repair. And that’s that long list on the left side.

And then there should be consideration of germline genetic testing for patients with intermediate-risk disease who also have intraductal or cribriform histologies as those are associated with a higher proportion of inherited DNA repair deficiency.

Somatic testing also has an important role, recognizing if you only do germline testing you’d only find about half of the mutations. It’s recommended for patients with metastatic prostate cancer as well as selected patients with regional node-positive disease.

NCCN also notes that in doing that testing, you should include testing for mismatch repair deficiency to find the 1- to 3% of patients who may be candidates for treatment with pembrolizumab.

PARP plays an important role in single-strand break repair. And PARP inhibitors induce synthetic lethality for patients with homologous recombination repair deficiency. There’s 4 commercially available PARP inhibitors: olaparib, talazoparib, niraparib and rucaparib. Differences and similarities between them are shown here. They have some differences in their potency of inhibiting PARP1 and PARP2, and differences in trapping, although the latter — the clinical significance of the latter finding is not yet fully established.

This is a summary of the PARP inhibitor monotherapy trials in mCRPC that really have established the importance of PARP inhibitors in metastatic castration-resistant prostate cancer. These studies look at patients with mCRPC and disease progression despite a prior AR pathway inhibitor and at least 1 taxane-based regimen.

TOPARP was the first study that looked at more or less all-comers and observed that presence of a DNA repair mutation was a strong predictor of activity. All of the subsequent Phase II studies listed here looked at molecularly selected patients. Although it’s worth noting they use somewhat different definitions or different methods of identifying eligible subjects. Consistent, very substantial rates of response across the different studies, varying from about 30-, some more than 50% objective response rates with PARP inhibition in this very treatment-refractory patient population.

And the results of these trials have led to pivotal studies of PARP monotherapy in mCRPC. This is the design of the very important and landmark PROfound study. PROfound enrolled patients into 2 different cohorts: Cohort A, BRCA1, 2 and ATM mutations. And then Cohort B, patients with other DNA repair mutations. Patients in both cohorts were randomized to olaparib or physician’s choice. And all of you are very likely familiar, this was a very positive study showing marked improvement in rPFS in the overall population of Cohorts A and B as well as an improvement in overall survival.

There are differences across different genes. This is a gene by gene analysis of PROfound looking at rPFS on the left and OS on the right. Among the more commonly altered genes, BRCA2 is a big driver of response, as measured by both rPFS and OS.

And the results of this study led to the FDA full approval of olaparib for treatment of patients with deleterious or suspected germline or somatic HRR gene mutations who have progressed following prior treatment with enzalutamide or abiraterone.

This is a summary of the rucaparib drug development plan, includes 2 trials TRITON2 and TRITON3. TRITON2 was in patients who were highly treatment-refractory, single-arm study. And then TRITON3 was a randomized controlled trial looking at patients who had progressed on a prior AR pathway inhibitor.

These are the results of TRITON2, showing a high objective response rate in the enrolled patients. Overall response rate, CR plus PR was about 45% in these patients. And the results of that study led to the FDA approval of rucaparib in 2020.

TRITON3 is a randomized controlled trial that went to patients who had failed an AR pathway inhibitor, mCRPC, rucaparib versus physician’s choice. This study stands out in that it included really an active comparator, so physician’s choice here wasn’t just the AR pathway inhibitor switch, but also docetaxel, and about half of the patients in this study received docetaxel as physician’s choice.

Rucaparib was associated with a significant improvement in rPFS, as well as in — and that was notable in that the improvement was seen versus both docetaxel and an AR pathway inhibitor. So this study is important and it gives us information about sequencing and argues that patients with BRCA mutations should receive a PARP inhibitor prior to docetaxel, based on the improvement in clinical outcomes.

Dr Shore has nicely summarized the results of the PARP-based combination therapies, so I’ll just be very brief here in going over this again. PROpel looked at abiraterone plus/minus olaparib in all-comers population. Showed an improvement in radiographic progression-free survival and consistency of outcome across subgroups. The greatest treatment effect was seen in patients who were so-called biomarker-positive and the largest effect was seen in patients with BRCA mutations, explaining the FDA decision, although we’ve discussed the controversies about that.

MAGNITUDE had a somewhat different study design; it enrolled into different cohorts. It’s almost like 2 parallel Phase III studies, biomarker-positive and biomarker-negative. Biomarker-negative patient population was discontinued early due to futility. And then the biomarker-positive study went on to complete accrual and analysis.

In MAGNITUDE, the addition of niraparib to abiraterone acetate improved our PFS in the biomarker-positive cohort, but the majority of the benefit seen in the BRCA1/2-muated group.

We’ve heard about TALAPRO-2 as well, another very important study, in this case looking at a different partner, this is talazoparib plus enzalutamide. And I think going forward, that will be a consideration depending on the individual patient, whether your preference for background AR pathway inhibitors, abiraterone or enzalutamide. As you’ve already heard there’s an improvement in rPFS in the overall study population, with the largest benefit seen in the HRR-mutated subjects in the trial.

IN summary, germline and somatic DNA repair mutations are common in metastatic prostate cancer, and we should routinely be doing both germline and somatic testing in appropriate patients. Olaparib is approved in HRR-mutated mCRPC. Rucaparib is approved in BRCA1/2-mutated mCRPC. PROpel has shown improved overall survival — excuse me — has improved radiographic progression-free survival in all-comers. And as we discussed, the recent ODAC recommendation for approval in BRCA1/2-mutated patients.

The benefit of niraparib was seen only in HRR-mutant patients, particularly in BRCA1/2. And talazoparib has shown benefit, similar to that seen in PROpel, in this case in combination with enzalutamide.

There is active, ongoing investigation looking at PARP inhibitor combinations in mHSPC.

Current and Emerging Strategies in the Treatment of Recurrent mCRPC — Dr Beltran

DR SMITH: So now we’ll go on to the last section of tonight’s presentation, and we’ll begin with a few questions and the last couple of cases. So what should be used first for patients with bone-only metastasis in PSMA-positive disease? So mCRPC. You’re making a choice between radiopharmaceuticals. Should it be Radium-223 or should it be lutetium PSMA? Dr Shore, you’ve a lot of experience with both of these agents, what are your thoughts?

DR SHORE: So this would be in first-line?

DR SAAD: So, mCRPC — we’ll specify for discussion that they’ve already received an AR pathway inhibitor and docetaxel.

DR SHORE: And docetaxel. Okay. So then, yeah. There’s FDA-approval based on the VISION trial for lutetium PSMA-RLT. And there’s also — based upon the VISION trial. And ALYSMPCA, you can give Radium-223 prior or after docetaxel.

I think that for the data that is — right now, if I had to pick one, if that’s the question —

DR SMITH: Which one first, yeah.

DR SHORE: I would probably go with lutetium first. But right now there’s a challenge because there’s a shortage, there’s been supply issues. If for some reason I couldn’t get access to it, then I’d be very comfortable in going with radium.

DR SMITH: Dr Saad — thank you. Dr Saad— or Dr Freedland, you nicely raised your hand. Supply issues aside, which would you prefer? Lutetium PSMA or Radium-223 in a patient like that described?

DR FREEDLAND: I just want to make a quick comment that we have randomized from the TheraP trial, and I know it’s not exactly your question, but they were selected to be PSMA-enriched. And we have randomized trial data of lutetium versus cabazitaxel, which would be second-line chemotherapy, showing no difference in overall survival. So, we certainly saw an rPFS benefit for lutetium there, so I think we just need to keep that in mind as another option. But I would refer to someone like Misha or Fred for actual management. I just wanted —

DR SMITH: Thank you for that. Maybe it’s important that those aren’t the only 2 choices. There are other choices.

DR FREEDLAND: Right.

DR SMITH: And it is one of the challenges that I alluded to earlier, we often don’t have information about optimal sequencing, candidly because usually these pivotal studies choose the weakest comparator that they can design the trials with. And so we often don’t know what the comparison against an active drug would be, and therapy is important in that regard.

So, Dr Saad, what do you think?

DR SAAD: You clearly specified that this is bone-only disease. There’s no visceral metastatic disease which would like change. But in most patients right now, if we have access to lutetium, we would go with lutetium. The PSA response is a nice feedback that we’re going in the right direction and I think patients appreciate the fact that we can continue to use PSA as a biomarker of response. But this is something we would discuss the patients. And radium is not excluded. I mean if we do things properly, I think we can sequence going 1 from the other — 1 after the other, and we have used radium post-lutetium and we’ve used radium pre-lutetium. The issue is when you wait too long you miss windows of opportunity.

Dr Freedland referred to TheraP study, very important trial, at least there was suggestive data from that trial that the intensity of PSMA PET expression was associated with relative benefit of lutetium PSMA.

Dr Beltran, do you use that information in making choices about the timing of use of PSMA lutetium?

DR BELTRAN: Yeah, and I think the data from both TheraP and VISION suggestion suggest that the SUV mean is maybe a predictor. But this is something that’s routinely being calculated. And so it may be in the future that that might help in decision-making. But I think for now it’s an active drug. I would want to give this drug — I would like to maximize the number of life-prolonging drugs our patients get. And I think the safety data of knowing that we can sequence radionuclides is important, and also trying to figure out that window where you can give the radium. But I don’t think at this moment I would use the PSMA PET, the SUVs, to make a decision just based on the fact that we have Phase III data to say that it’s effective.

For a patient who is chemo-eligible, who would you be prioritizing to use cabazitaxel before a radionuclide?

DR BELTRAN: I think that definitely I wouldn’t use radium also in a patient that had non-bone mets. And in the patient that has PSMA-positive disease based on VISION criteria but has significant PSMA-negative lesions that were smaller, that would have potentially been included in the trial or maybe liver metastasis, sort of these poor-prognostic patients who you don’t think are going to necessarily do that well with lutetium, I might think about doing chemotherapy. But you can still give lutetium after chemo. So oftentimes just even because of the drug supply issue, I’m bridging people with chemo anyway.

DR SMITH: Exactly. It is a hypothetical question at the present time. And we do look to, hopefully, having better information in the future about optimal sequencing and selection of patients.

We have a couple of cases to discuss before our final presentation. So this is a 71-year-old man with PSMA-positive bone-only mCRPC who experienced disease progression on multiple lines of prior systemic therapy, including ADT, enzalutamide, sip-T, and I’ll specific docetaxel. Which of the following therapies would you generally recommend first? Kind of a repeat of the general question I raised earlier, but now with a very specific case.

Dr Saad?

DR SAAD: I think it’s going in the direction of where we’re going. I would be comfortable with both. But with the PSA response as a biomarker that we’re going in the right direction, lutetium is becoming our first.

DR SMITH: Yeah, the way I view this, it’s really strength of evidence, right. I mean, the VISION trial has the benefit of being a more contemporary study, included patients exactly like this. We just have less information from ALYSMPCA. It was done at a somewhat earlier time. It is harder to evaluate response and resistance in patients treated with Radium-223. PSA declines are not an expected outcome from the treatment, although they can be occasionally observed. And so I think, based on strength of evidence, my preferred first-line treatment, including in patients with bone-only or bone-dominant disease, would be lutetium rather than radium-223.

And I think the point that’s already been made is you can sequence those therapies.

Dr Shore.

DR SHORE: Yeah, but in this particular hypothetical case, the patient hasn’t received docetaxel.

DR SAAD: He said he did.

DR SMITH: I added that.

DR SHORE: Oh, you added that.

DR SMITH: A fair comparison.

DR SHORE: Yeah, I get it. Okay, but based upon that. It’s actually incorrect the way the folks have answered the way the question is positive without your caveat.

And then there is upcoming data, the RALU study, radium and then lutetium, a lot of folks are concerned that there may be not adequate tolerability and excessive myelosuppression, and that’s showing not to be the case in most patients. So worth knowing.

DR SMITH: They will be very important considerations. I mean, part of the challenge of having the current approval of lutetium-PSMA so late, these are patients who often have very limited bone marrow reserve. And some of the cytotoxicities that we observe can be related to disease progression as much as the therapy that they’re receiving.

The next question, to what extent do you believe that dry mouth associated with lutetium-PSMA is problematic for your patients?

Dr Freedland?

DR FREEDLAND: I have been given the limitations of getting it. I don’t think we had enough patients treated for me to answer that.

DR SMITH: That’s fair.

Dr Shore, you were involved in the trial. So what’s your experience?

DR SHORE: Yeah, so we were a VISION trial site, in fact we were the highest enrolling urology site, a full-on homogenous urology site with no medical oncologists or rad oncs, except for the rad oncs who gave the therapy and got the radioactive material licensed for using this particular beta particle. And I’ve given it now post-approval. It’s really not very problematic. The dry mouth has not been particularly problematic.

I think that there is probably more data coming forward that numbers of infusions could potentially correlate with it become more of a significance. I think the interesting thing to me, Matthew, is if somebody’s responding after 2 or 3 cycles, and it’s been indicated for 6 cycles, do you stop to try to avoid that additional toxicity?

DR SMITH: Yeah, that is a fair — how do you think about the prechemotherapy, ongoing prechemotherapy, lutetium-PSMA study, the Topline results have been at least reported in a press release. We obviously look forward to the full details of that. So how do you think about that, Dr Shore?

DR SHORE: Oh, I think it’s really exciting. We participated in the PSMA4. We’ve participated in the SPLASH trials, which are both prechemotherapy mCRPC. I think it’s great. It’s like it really follows the traditional pathway of all of our approved drugs in advance prostate cancer: we start at the most advanced and we move it up proximally.

I think you’ll probably find that the tolerability is the same if not better. And adding to that patient/physician shared decision-making discussion, will be important.

DR SMITH: Yeah, I mean right or wrong, most, a substantial proportion, probably about at least half of patients in the United States never received docetaxel, including those fatal mCRPC. Some of that may be because they’re not suitable candidates or they just prefer not to receive treatment. So I think the ability to give an alternative treatment in that either chemotherapy-ineligible or patients prefer to avoid chemotherapy will be very important.

DR SHORE: So I love your comment because at the ODAC it was pointed out to the FDA that in a recent contemporaneous study of 2,500 North American patients, Canada and the US, over 2,500, 78% got 1 first-line mCRPC treatment, 38% got a second; 16% got a third. That’s inclusive of all the approved therapies today, so to your point. And less than 50% of patients ever receive a taxane.

DR SMITH: Yeah. And I think this also highlights how important it is to optimally manage mCRPC — mHSPC, excuse me, because we’re moving those drugs earlier; they should just be routine part of care. Not only keep patients alive longer, but ultimately give them access to appropriate subsequent therapies.

Dr Beltran, your thoughts on this topic. How do we think about sequencing — optimal sequencing in prostate cancer? And how do we improve basically clinical practice in the community to see that our patients are receiving the right treatments?

DR BELTRAN: I mean, I really think that the numbers of patients getting docetaxel is really shocking to me. Because it’s been around for a long time, it’s well tolerated. There’s clear activity in later stages and earlier stages. Hopefully, drugs like Plutivco — lutetium-PSMA moving earlier will increase the number of patients getting these life-prolonging therapies. But I think it is a serious problem and figuring out how to solve it is a longer discussion.

DR SMITH: Thank you for those comments and we’ll move on to your session, looking at the emerging therapies in this setting.

DR BELTRAN: Thank you. So we’ll now continue our discussion of mCRPC moving a little bit to later stages of the cancer. This is just an overall timeline just to highlight many of the drugs we talked about today. Really impressive drug approvals over the last decade, with the latest being lutetium-PSMA-617, as we just discussed.

So lutetium-PMSA-617 targets PSMA prostate-specific membrane antigen. That’s a cell surface receptor. It does have a function and it’s involved in folate uptake and some cell tumor — tumor profiling, but I think its function in prostate cancer is not well established, other than the fact that it’s a really great biomarker and targeted expressed in nearly all prostate cancers at diagnosis. The majority of HSPCs and about 80% of mCRPCs. So, expression can be dynamic.

It's not only expressed in prostate cancer, but also normal prostate, proximal renal tubules, small intestine and salivary glands.

Lutetium-PSMA-617 is a beta-emitting radioligand conjugated to a small peptide that binds PSMA. And also, as we discussed, it was approved post-AR therapy, post-taxane, based on the VISION trial in patients — was requiring patient selection using Gallium-PSMA PET scans.

The TheraP trial — Lutetium-PSMA has been used for quite some time around the world, but the TheraP trial was the first prospective study to look at this compared to cabazitaxel. And we, as we heard earlier, that there was a higher response rate and improved PFS, though no OS benefit. But this encouraging activity in this late-stage population was really the rationale for the VISION trial that enrolled patients post-AR — at least 1 AR pathway inhibitor, post- at least one taxane. Patients were randomized to receive lutetium-PSMA-617 plus standard of care versus standard of care. Just to not that in the standard of care arm, this excluded chemotherapy, immunotherapy, radium or other investigational drugs.

PSMA-positivity was defined by ate least 1 PSMA-positive lesion and no PSMA-negative soft tissue or visceral lesions greater than or equal to 1 cm, or lymph nodes greater than or equal to 2.5 cm. So a little bit of a looser criteria than the TheraP trial.

The trial met its coprimary endpoints of rPFS and OS. Many of you have seen this curve shown here on the right. So, this is now, of course, approved for our patients, but just to note on the left that all patients had to have an AR pathway inhibitor, and about almost half of patients had more than 1, and 40% of patients had 2 taxanes. And so, this is a later-stage population, many patients had cabazitaxel as well.

Most common AEs: fatigue, dry mouth, nausea, anemia, with Grade 3 and 4 being cytopenias and fatigue.

The TheraP trial used not just PSMA, but also FDG-PET to screen patients, with about 70% of screened patients being eligible. And in a more recent study, looking at the combination of PSMA and FDG, it’s tempting to optimize our imaging parameters to develop better predictive and prognostic biomarkers.

And as recently published, the odds of the PSA response to lutetium-PSMA versus cabazitaxel is significantly higher for men that had SUV means of greater than 10 compared to those that were less. So the bottom right graph are the patients that had the SUV greater than 10, who received the lutetium, versus less than 10 on the top panel. And this also has been seen in the VISION trial, reported at last years’ ASCO.

This is not something, as mentioned, is routinely available on our current PET scans but something that I think could be used in the future. And what they also found is that FDG volume, so patients that were PSMA-positive and FDG-positive tended to do inferiorly, suggesting that this may be a prognostic biomarker in the setting of lutetium-PSMA.

12.6% of patients in VISION had PSMA-negative disease and 20% in TheraP. And some of these may be due to neuroendocrine differentiation or other mechanisms. And the patients that screen-failed for therapy had a median survival of 2.5 months. And so, we do we need think about therapies for this type of population as well.

There’s preclinical data to suggest that the FOLH1 gene, which is PSMA, is indirectly regulated by the androgen receptor. When tumors lose the androgen receptor, they lose PSMA. And so I think this is also important thinking about new drugs that target the androgen receptor and thinking about how well they will work in the PSMA-low or -negative situation.

So response to PSMA-directed therapy is not universal, although it is quite impressive. And in our mCRPC population and understanding not only the expression of the target but also mechanisms of response and resistance will also help us thinking about other drugs that target PSMA that are now being developed in the post-lutetium-PSMA setting. Also, in the pre-setting for certain populations, including Actinium-PSMA-617, other radionuclide therapies by specific T-cell engagers, CAR-T, ADCs and others. And so understanding cross-resistance will help as well as thinking about combination therapies.

And there’s also opportunities of course to bring this earlier, and the PSMA4 trial, which we haven’t seen the full data, has been reported as a positive for its primary endpoint of PFS. I look forward to seeing this data and hopefully approval in this situation, as it does make sense to bring this drug to the earlier mCRPC situation where I think might be sweet spot for PSMA expression and response to therapy.

PSMA lutetium is not the first radiopharmaceutical that we’ve been using and radium-223, so as also discussed, is a very important drug that is an alpha-emitting isotope that’s bone-targeted. In the ALSYMPCA trial, it involved patients with symptomatic mCRPC and bone mets and demonstrated an OS benefit. And it is approved. And just to note again, as we also discussed, about a third of patients in the VISION trial had prior radium-223 — they had to have had it at least 6 months prior. And then the retrospective RALU study also looked at radium-223 before/after — before lutetium-PSMA, mainly to note that the safety seemed to be tolerable and was not higher incidence of cytopenias and efficacy of lutetium post-radium-223. So this seems to be a safe thing to sequence, which is, of course, is important as we get new drugs and new data — new drugs into our clinic.

Cabazitaxel is another option for patients post-AR therapy and post-docetaxel, the CARD trial. Took patients that had progressed within 12 months on abi or enza and had previously had docetaxel and randomized them to either cabazitaxel or the other AR pathway inhibitor. And there was an improvement in PFS and OS. So the cabazitaxel was also an active drug. And I think what this also established was that there’s limited activity in sequencing AR pathway inhibitors because the patients that were on the control arm did quite poorly.

We heard about genomic testing and the context of DNA repair aberrations. Lots of considerations in which tumors — which tissues to test. But beyond BRCA and that classic genes. Pembrolizumab is approved in a pan-cancer indication for patients with MSI-high, mismatch repair deficiency or high TMB greater than 10. And although prostate was under-represented in those pan-cancer approvals, patients can have significant response. Its present in about 2- to 5%. And I think important to really look for.

This is a patient of mine who had ctDNA test that showed at TMB of 23. No MSI. And his PSA went from 100 to 5 in a really short period of time receiving pembrolizumab.

So finding these patients, you may actually find exceptional responders. So, just important to consider.

Immunotherapy has not been really effective in an unselected population, but there have been a number of combination immunotherapy therapies that have been investigated, including cabozantinib plus atezo, which, in the COSMIC 021 study, showed — an early-stage trial in the prostate cohort, showed responses, impressive, I think, activity in the heavily pretreated population including visceral mets with a disease control rate of 80%. And this combination is now in a Phase III trial.

And then finally new and emerging therapies for mCRPC. The androgen receptor is still a key driver mCRPC, even post-all of our AR pathway inhibitors. And there are a number of drugs being geared towards targeting the androgen receptor.

As mentioned, there are a number of PSMA-directed therapies, as PSMA can still be expressed in patients post-lutetium-PSMA.

PSMA has also paved the way for other cell surface targets: TROP2, B7-H3, DLL3 and others that have opportunities for similar types of approaches — ADCs or even molecular imaging.

Targeting non-AR-drive disease is important such as the neuroendocrine phenotype. Targeting other genomic alterations such as biomarker-driven studies looking at PTEN loss.

And then rationale combination strategies. AS we know, this is a heterogeneous disease but there’s been a lot of progress. And hopefully, we’ll see more data from these early targets in the future.

DR SMITH: Thank you, Dr Beltran, and thank you to the rest of the faculty for their outstanding presentations and active engagement in the questions and the cases.

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