Introduction

DR ANTONARAKIS: Good morning, everyone. We’ll get started. Thank you for coming so early on a Friday morning. My name is Emmanuel Antonarakis. I’m a Professor of Medicine at the University of Minnesota, and it’s my pleasure to be joined today by 3 esteemed faculty and good friends, Raoul Concepcion, the Chief Science Officer at US Urology in Nashville, Tennessee; Matthew Smith, Professor of Medicine at Mass General Hospital; and Dr Fred Saad at University of Montreal, Professor and Chief of Urology. So thank you for joining me today.

A few housekeeping issues here. So half of the audience is here live, and a good portion is also doing this online. So you have the slides in front of you. There should be opportunities to ask questions that you can send via the internet, and then at the end please complete your evaluation. And for those who are attending by Zoom, similar guidelines. The program slides should be available, and please answer your survey to get your CME credits.

This is an enduring program, which means that there’s a live component here, but you can also watch the audio recording later at the Research To Practice website.

Now tonight there will be a second similar presentation of cases for the urothelial bladder cancer session moderated by Dr Monty Pal. And this is our session here. And this is a unique forum because we’ll be discussing real cases from urologists and oncologists in the community, and then we will be using our 10-minute lectures to reinforce some of the points and then have discussion amongst the 4 of us.

So here’s the slide about the commercial support, and this is a CME activity.

I’m just going to quickly pass through the disclosures, so please look at these.

And so this will be split into roughly 4 modules of 3 minutes each. We will have 2 or 3 cases from the community that have been prerecorded on video, and then we’ll be discussing some of the issues that come up with each case followed by a 10-minute presentation by each of the 4 discussants. If we have time in the 30 minutes we will take your questions, depending on how punctual the speakers are and how punctual I am at keeping everybody on time.

These are the 5 urologists or medical oncologists who have submitted cases, and you’ll be watching the videos from each of these. And they were interviewed by Neil Love prior to this symposium.

Management Approaches for Nonmetastatic Prostate Cancer — Raoul S Concepcion, MD

DR ANTONARAKIS: So first we will begin with Module 1, and this the management of nonmetastatic prostate cancer, M0 prostate cancer. And every section will start with a pretest questions, polling question. So if you are able, please submit your answer to this. The question is “For your patients with high-risk biochemical recurrence following primary radiotherapy, in general, if you could access a PSMA PET scan would you?” Please select yes or no.

So the majority of participants, 89%, said they would try to obtain a PSMA PET scan for a biochemical recurrent patient.

Okay, now Dr Laura Bukavina will present her first case. Let’s see how this works.

DR LOVE: Good morning, everyone. I’m Neil Love from Research To Practice, and welcome to our real-world case library that came to life during the pandemic, and for the second consecutive year for this AUA Meeting we met with urologists and medical oncologists prior to the conference to hear cases from their practices and hear questions for the faculty.

The first case is presented by Dr Laura Bukavina, whose 70-year-old patient had an M0 recurrence after primary radiation therapy, and the Axumin scan showed nonspecific activity in the pelvis.

DR BUKAVINA: A 70-year-old with prostate cancer, underwent IMRT in 2013. He had salvage cryo for biochemical recurrence in 2017, and then in March of ’21 he had another biochemical recurrence.

He underwent an Axumin scan. It’s difficult when you’re looking at things like urine within bladder or kidneys because it does light up on the scan. He had a PSMA PET, which showed increased activity along the urethra worrisome for tumor.

If you had a patient who has biochemical recurrence would you order a PSMA scan? Or if their PSA is above 1 would you order an Axumin scan? And what are the benefits of 1 versus the other?

With the recent approval there’s still a lot of difficulties in getting our patients to get PSMA scan. Axumin, on the other hand, because it’s been around for a lot longer, it’s much easier to get.

The patient already had cryo. The patient already had radiation. Would you consider doing ADT in this patient despite all the quality-of-life issues that are associated with it?

DR ANTONARAKIS: Great. So just to summarize the case, and Raoul, I’m going to ask you first, but — so this is a person with primary radiotherapy to the prostate gland, recurrence, had in-prostate cryotherapy, salvage cryo, had a further biochemical recurrence, Axumin — fluciclovine we should say, let’s not use brand names, was negative, and then a PSMA scan shows 1 avid lesion maybe in the urethra but in the prostatic bed area. How would you think about this patient?

DR CONCEPCION: Yeah. I mean I think it’s interesting. First of all, thank you to everyone for having me. I think it’s interesting that the patient actually did get both scans. Obviously, as we said, access is a critical issue. Access is 1 issue, and not everybody has access. Number 2, I think both scans — and hopefully the audience recognizes they’re fundamentally different mechanistically. And to me I think actually both perform pretty well, although the data might suggest that PSMA might be a little bit more sensitive at lower PSMAs, but I think it really comes down to the experience of the reader. Because if you do a lot of fluciclovine scans you get very — you’re very used to reading those, and the same way with PSMA.

I think the thing on this patient, critically, is what is his current PSA, what is his doubling time, what’s his ECOG status. I think all of those have to be taken into play here.

DR ANTONARAKIS: Fred, is PSMA PET scan available in Canada for biochemical recurrence?

DR SAAD: The answer is yes, but there has to be a good reason to do it. Is it going to change how we’re going to manage this patient? And I agree with Raoul. I mean the most important for us would be his PSA doubling time to decide early versus delayed intervention, and you’ve done a lot of work in this. And that is really our driving factor irregardless of what we would see. I think the jury’s still out as to running after oligometastatic metachronous disease and starting to irradiate. I think the standard of care, even though there are adverse events, is ADT in the high-risk patient to avoid the long-term consequences.

DR ANTONARAKIS: And then Matthew, we had a question about ADT in a patient who has a single recurrence detected only on PSMA PET and not on conventional imaging, with the PSA, I think it was in the single digits, and a low doubling time, would you start ADT, or would you wait?

DR SMITH: Hard no. I would not start ADT for an asymptomatic what appears to be isolated local recurrence, low PSA. We didn’t get the years, but it sounds like this developed over the course of years. So he’s at low risk for symptomatic progression. The goal of treatment — I can’t find a good goal for treatment by starting ADT now.

And I think the question that wasn’t asked that should be considered is whether there’s a role for salvage local therapy. He’s potentially curable by salvage surgery, although we understand that that comes along with typically a lot of morbidity.

DR ANTONARAKIS: Raoul, would you consider a salvage prostatectomy in this patient?

DR CONCEPCION: Again, I think, as everybody as said, it depends upon symptomatically. You’ve got to believe if this guy had bone scan, CT, traditional imaging, it’s probably going to be negative. And so, again, I think it would depend upon clinical symptoms, PSA doubling time. But as we know, salvage prostatectomy, either open or in the robotic era, is fraught with increased complications, including rectal injury and probably near 100% incontinence.

DR ANTONARAKIS: And then final question. We have a minute left. Let’s suppose this was a solitary pelvic lymph node outside the radiation field. Fred, is there a role for a surgical lymphadenectomy?

DR SAAD: Short answer, no. I think that is — the jury’s clearly out on the value of that. Now depending on where the site is, maybe radiation therapy, but in combination with at least short-germ hormonal therapy is what we would do in our center. And this is a tumor board question. This is not — there is no Level 1 evidence for what we should do with that.

DR ANTONARAKIS: Thanks very much. Okay, great. We are still on time, and let’s proceed with the second video.

And before we do that, here is our second polling question. “What form of ADT would you most likely recommend for a 53-year-old man with high-risk node-positive prostate cancer found at radical prostatectomy?” Number 1, relugolix. Number 1, leuprolide. Number 3, goserelin. Number 4, other. In my opinion, “other” should also include no hormone therapy, but that’s just me. You guys are fast.

So now we will hear a case from David Morris; Nashville, Tennessee. A 53-year-old man with I think the scenario that I just described.

DR LOVE: The next case is presented by Dr David Morris, a 53-year-old man who presented in 2017 with Gleason 3 + 3 disease.

DR MORRIS: It’s a relatively young man with low-grade disease at presentation. The biggest question for me was active surveillance appropriateness and surveillance programs up front. He wanted to avoid definitive treatment because of some health concerns with obesity and also side effect concerns. So if the faculty could talk about best active surveillance programs. Unfortunately, he had progression during active surveillance, actually from 3 + 3 to 4 + 3, progressed to a prostatectomy and actually had 1 of 6 nodes that were positive.

DR LOVE: So you managed him from the beginning?

DR MORRIS: Managed from the beginning.

DR LOVE: How did you feel after the surgery and you saw what was going on there?

DR MORRIS: I’ll be honest, not great.

DR LOVE: Yeah, I imagine so.

DR MORRIS: Everything fit as an active surveillance candidate. He certainly was not a great surgical candidate.

DR LOVE: If and when you were to get to that position where you would use hormone therapy what kind would you use?

DR MORRIS: So probably if — I’m just doing ADT monotherapy, unless he wanted to be super aggressive and add in abiraterone. I think most of these patients we would be looking at the new oral therapy with relugolix both for the ease of use onset and also the fast offset if we’re trying to get recovery of his T therapy after dosing.

DR ANTONARAKIS: Great. So for my benefit I’m just going to recap the case. 3 + 3 = 6 Gleason score, undergoing active surveillance, very appropriate, and then exited from the surveillance program because of an upgrade to, surprisingly, 4 + 3, and then even further was found to have N1 disease at the time of radical prostatectomy.

So first a question for Fred. In a patient who’s on active surveillance how often do you see a 3 + 3 going to a 4 + 3 with N1 disease?

DR SAAD: Not so frequent, and I think there are signs that would tell us something’s going on. If the patient was on a 5-alpha reductase inhibitor I think we have to be very careful of minimal changes in PSA. We do routine MRIs in these patients. We’re being a little less aggressive, but we get at least 1 biopsy a year after diagnosis in a patient on active surveillance.

So this is probably a case where the 4 + 3 was missed on the first series of biopsies. It’s hard for me to believe that a 3 + 3 progressed that quickly to a 4 + 3 and became metastatic. I think we probably missed something. And this is where MRI comes to help up sometimes, to make sure we’re not underestimating a patient that we think is a good active surveillance candidate.

DR ANTONARAKIS: Yeah. The only time I’ve ever come across that is in a patient with a BRCA2 mutation, where the cancer advanced very quickly, within 6 or 12 months, and then they had 2-score upgrade on the Gleason grade.

Now Raoul, this is problem that we’ve been facing for a long time, the N1 at radical prostatectomy patient. What we didn’t hear was what is his postop PSA, if one has been done. But in your hands, if you just completed a radical on a 4 + 3 = 7 patient with 1 out of 6 positive nodes, what would be your next step? And would you be thinking about immediate ADT or doing some other things up front?

DR CONCEPCION: I think your point is well taken, Emmanuel, as I think all of us in the room who have operated on these high-risk patients, what was their PSA postoperatively, what is the location of the node. More than likely this is locoregional disease in the obturator chain. And the other thing, which goes back to the Messing data back in the ’80’s and ’90s, is this a grossly-positive node or is this discovered on histopathology at the time of frozen section or routine processing, because there is some data to suggest that grossly-positive is much different that micrometastasis.

So for this particular patient, depending upon if it’s micrometastatic disease, I don’t necessarily believe that I would institute ADT at this point immediately. I would probably check his PSAs, monitor that every 3 months. But I would not necessarily start this patient immediately on ADT, and I’m assuming he had a staging scan that showed no evidence of disease outside his pelvis.

DR ANTONARAKIS: Yup. Fred, you wanted to make a comment.

DR SAAD: I think there’s still an opportunity for actually curing this patient. I think we overestimate the negative aspect of 1 single positive node. Even without any treatment there are a certain percentage of patients that will never recur. But this is a kind of patient we would again discuss short-term hormones, radiation, he’s a T3 patient, and trying to aim for a cure in a very low locoregional high-risk patient. I think we should not exclude.

DR ANTONARAKIS: And then the other question that Dr Morris posed is would you use the STAMPEDE M0 paradigm and treat this person now with ADT plus abiraterone, Matt?

DR SMITH: I’d certainly consider that, but I agree with the comments of my panelists, that you’d want to see the postop PSA. If it was elevated, I would begin with a PSMA PET/CT because you want to know where the disease is. This is the perfect setting to do that.

If the PSA was elevated, and there were detectable multisite metastatic disease in nodes or otherwise, I would aim for ADT plus an AR pathway inhibitor, abi or another drug, based on the STAMPEDE data. And that would be for a finite period of treatment as well.

DR ANTONARAKIS: Yeah. I would agree with that. I think in the absence of a PSA recurrence I also would not offer systemic therapy here.

Okay. We will move on now. And Raoul, it’s your turn to give us the first presentation. Please try to stick to 10 minutes if you can. Thank you.

DR CONCEPCION: Great. Thank you, Emmanuel. Good morning, everyone. Yeah, again, appreciate you all coming out. I think this is a great panel discussion.

So I’ve been tasked to really discuss the management approaches for nonmetastatic prostate cancer. And we’re going to — I’m going to approach this in a little bit of a different fashion. So I think for most urologists the clinical challenges that face us now in 2022, to me, come down to the following. So now, especially with this previous case, we’re very concerned. We’re trying to determine what — who has clinically significant disease. We know that not all prostate cancer necessarily needs to be treated immediately, so we’re trying to also minimize the number of biopsies, which is obviously associated with certain degrees of complication.

So detection of clinically significant disease for the patients that come in really is a challenge for this. One of the topics that we’re going to discuss is really the management of high-grade, high-risk disease, nonmetastatic. The other thing that we’re referring to now, which is front and center — which for the next few years is going to be how will molecular imaging change the current landscape.

As all of you know, the current staging is bone scan/CT, but now with the most recent approvals for PSMA and the indications, which is really the suspicion of metastatic disease, which is a little bit different from fluciclovine. What we’re going probably start seeing, especially if you have access availability, PSMA molecular imaging up front for staging. And so I think this is going to uncover a whole different group of patients that are going to probably be oligometastatic.

And then obviously the last thing, especially as we move into looking at new therapeutics in the earlier stage, is optimizing therapeutic choices and side effect profiles in the patients with nonmetastatic castration-resistant prostate cancer or even castration sensitive.

I really want to encourage everybody to really stick with somatics because, again, back in the ‘80s when I trained we just thought about it as prostate cancer. And now, as the field has changed rapidly not only for local disease, for advanced disease, I think as we discuss cases with our colleagues and in formats like this, we really need to be — delineate who we’re talking about.

For — again, for localized prostate cancer we really need to adopt, on a routine basis, the NCCN risk stratification, which is very low risk, low risk, favorable-intermediate, high risk, and very high risk. And the reason for that is because, again, the treatment recommendations are different for each one of these. And again, Dr Morris alluded to a case earlier about when it is appropriate for active surveillance.

In the advanced prostate cancer world, especially in those of you who are in practices that are wanting to manage these patients, which has really come about over the past 10 years, what is defined as advanced prostate cancer? And again, not necessarily all of your partners, or everyone in this room, has really stayed up and really wants to manage these “advanced” prostate cancer patients.

So to me, I think it really comes down to do they have metastatic disease, yes or no, and do they — are they on continuous hormonal status, yes or no. I think if you can answer those questions and pigeonhole them you can probably then move them into certain buckets. And again, the reason why that’s important is because of the treatment paradigms.

So I’m trying to really encourage people to utilize the terminology castration-resistant prostate cancer, which we adopted 10 years ago, but now we’re moving into the castration-naïve prostate cancer, which is what the NCCN has utilized, or castration-sensitive prostate cancer. Those are both analogous terms.

So when you look at this slide, so these are, again, these are the risk stratifications for the NCCN: very low risk, low risk, favorable-intermediate, unfavorable. And this is the 2021 guideline, when you look at how high-risk patients really, depending upon their estimated survival. So back in 2021, if you were a patient that was relatively asymptomatic, or we thought — because this has been the standard. If a patient can live more than 10 years we should probably offer them definitive therapy.

And so for these high-risk or very high-risk patients it’s generally been external beam radiation therapy plus usually 24 months of ADT plus docetaxel for very high risk only, external beam plus brachy plus ADT. Or, for those of us that are fairly aggressive, RPs, usually robotic — robotically assisted, and again, then depending upon the nodal status. But again, over the past — over the past couple years we have had a number of studies now where we are adding therapies, usually hormonal therapy, this concept of novel hormonal therapy, to managing the primary.

Back when I trained, essentially we left the primary in place. And Fred and I are old enough to know that we regretted that. And now, as I think we have more active drug, what we’re seeing is the addition of agents, either neoadjuvantly or adjuvantly, as we manage these primary tumors. And again, as I alluded to, what’s going — this is going to be even more challenging as more and more of us adopt PSMA scanning and molecular imaging.

So these are a number of trials that are incorporating neoadjuvant or adjuvant hormonal therapy, usually with these novel hormonal agents, in combination with either surgery or radiation. And again, many of you also remember — this trial also is looking at the same thing. This is the EMBARK trial.

As we all know — so again, a recent trial that was read out — or it’s ongoing, is really the use of abiraterone acetate and prednisolone with or without enzalutamide, again, for high-risk nonmetastatic prostate cancer. And this is part of that European big study of the STAMPEDE trial.

And again, this is how — this is how STAMPEDE has been played out. So in this particular case patients were randomized to get either standard of care ADT or ADT plus abiraterone. And then another subset, they actually got standard of care plus abiraterone plus enzalutamide. So it’s this whole concept of androgen receptor annihilation.

And as most of you have seen this data, relative to these high-risk patients, the combination of ADT plus abiraterone acetate and prednisolone, with or without the enzalutamide, actually had a survival benefit — 6-year survival improvement, from 77% to 86%. But what was interesting is that when you look at the side effect toxicity, is that it definitely increased with the addition of enzalutamide to the abiraterone, with really not much difference in terms of survival.

So again, it becomes important as we start layering therapies, doing couplet therapy, triplets, that we have to take into account the side effect profile of agents.

So again, now as we look back — so now in 2022, because of a lot of this data, when you look at, again, this high risk or very high risk, again looking at this same category — so if you have high-risk patients, now the recommendation is ADT plus docetaxel for 6 cycles or for very high risk it’s ADT plus abiraterone.

So again, I think it’s important to understand even for localized prostate cancer what we’re seeing now is the addition of agents. And we’ve been looking at this for decades. Early on we used to give ADT neoadjuvantly. That really didn’t pan out as well. We’ve tried looking at docetaxel. But now because of this STAMPEDE data this becomes — this becomes very critical.

The other thing I think that we need to be cognizant about is ADT. And again, as urologists we are the ones, for the most part, are initiating therapy. And again, we all recognize that the standard pretty much has been LHRH agonists, but there has been a lot of data. And this is the Pinthus data, that really looks at cardiovascular morbidity, comparing patients that got started on LHRH agonists versus antagonists. And without belaboring this, what we’re starting to recognize is that in patients with significant cardiovascular history, events and risks, that the number of significant cardiovascular events really is heightened by — in patients who are started on an agonist versus an antagonist.

And as you know, prior to a few years ago the only LHRH antagonist available was degarelix. Now in June of 2020 this data — this paper was released. Dr Saad is one of the authors. And so this is for the oral LHRH antagonist of relugolix.

And so when you look at the HERO study, which is what this paper was appropriately named, so in terms of sustained castration rates by subgroups, whether it was relapsed, metastatic, overall population relugolix actually — again, the goal of LHRH therapy is medical castration. So sustained castration levels is equivalent relative to the comparator group, which was leuprolide. And then when you look at the cumulative incidence of cardiovascular events, of MACE, there was a significant — there was a decreased incidence of cardiovascular events relative to patients on relugolix.

So I think the key to this, and I think the key for us urologists moving forward, we need to do a better job in terms of identifying patients who may be at risk for major adverse cardiovascular events. So I’m a believer that moving forward that if you’re thinking about initiating LHRH therapy part of this should be making sure that we identify cardiovascular events, and appropriately those patients could probably be put on an LHRH antagonist.

And the last piece here is really just as we start to utilize all of these drugs the side effect profiles because we’re starting to — all these drugs are now going to be available early on in this space, whether it’s darolutamide, apalutamide, or enzalutamide. And these are the trials for the nonmetastatic CRPC space. This is kind of a comparative slide here. And then when you look at treatment-emergent adverse events they’re pretty much across the board, although we’re not supposed to do trial comparison.

All of them are associated with significant cardiovascular events. And I think what we have to do is if we’re going to use these drugs we need to be — really be cognizant of what the side effect profile is. So hypertension, rash we all know about with apalutamide, but the one thing that really I think stands out in this is with darolutamide we seem to see a little bit less of neurovascular and fatigue versus the other drugs.

So with that in mind I think we’ll move onto the second module with Dr Antonarakis.

DR ANTONARAKIS: Thanks very much. Well, we do have some time for questions, and we’ll start with some that we got from the audience in the chat. So I may begin with asking Matthew. “If you have a patient who’s already on an LHRH agonist, and you discovered he’s got serious cardiac disease, would you ever then drop the agonist and switch to relugolix?

DR SMITH: I have not adopted that approach. We really don’t have evidence that the switch would actually reduce risk. I do believe the observations from the HERO trial, as well as prior exploratory analyses from degarelix, it’s at least plausible that GnRH antagonists reduce the risk of cardiovascular events. Although I think it is yet to be definitively established there are ongoing trials to look at that in a more comprehensive way. So someone who I’m initiating treatment I think that’s a good approach. I have not adopted the approach of making the switch.

DR ANTONARAKIS: Thank you. And Fred, a question for you, which is “Who is the perfect patient for relugolix?” And the corollary to that is who would you not use relugolix in?

DR SAAD: The perfect patient is hard to say. Clearly it’s a form — it’s a form of ADT, and I think it’s appropriate for every patient where you want to give ADT.

Where I think it probably has the biggest role is, I think what was mentioned, in patients with high-risk for cardiovascular events. Even though I think there are studies that have shown that probably the most important thing is to manage the cardiovascular risk with the help of a cardio-oncologist to really minimize the risk. Because whatever we do we’re exposing these patients to castration, which in itself is not a good thing.

Who I would think is a good patient is somebody who’s got really bad symptoms, where you want to avoid the flare going onto radiation therapy. There’s really a very — a big advantage of very early, immediate castration, within 3 days we saw the castration. And the flip side is who I would not. Is this is an oral agent, we don’t have all the data yet in terms of drug-drug interaction, so I think I would still be careful with some of the agents that we’re using presently for advanced prostate cancer. But the data’s starting to come out in terms of safety.

DR ANTONARAKIS: Matthew?

DR SMITH: Yeah. So one of the attributes we heard from Dr Concepcion was that rapid on effect, rapid off effect, and that off effect is nice, I think, particularly for patients who are going to have short-term ADT. So I think the settings where we’re going to give ADT for 6 months is a good situation to use it there, particularly for patients who are concerned about the risk of persistent hypogonadism.

DR ANTONARAKIS: And then Raoul, following the data of the STAMPEDE M0 trial would you ever, in that context, use abiraterone 250 rather than 1,000? And more broadly, have you ever used abiraterone 250 instead of 1,000 mg?

DR CONCEPCION: Right. That always seems to be — yes, and obviously, as many know, the absorption and the bioavailability of abiraterone can be somewhat influenced by dietary habits. So I think that the answer is yes, I have used it, and usually though in conjunction with a change in diet to increase bioavailability.

DR ANTONARAKIS: Okay. Thanks very much. So to stay on time we will end there with Module 1, and we will pivot now to Module 2.

Role of Treatment Intensification in Metastatic Hormone-Sensitive Prostate Cancer — Matthew R Smith, MD, PhD

DR ANTONARAKIS: And let’s begin with a polling question. So “Regulatory and reimbursement issues aside, what systemic therapy would you typically employ for a 59-year-old man presenting with bulky high-volume metastatic hormone-sensitive prostate cancer?”

So an even split between ADT and enzalutamide or ADT with docetaxel and a secondary hormonal therapy. Great.

So now we’re going to hear the cases from Dr Markowski and Dr Morris.

DR LOVE: The next case was presented by Dr Paul Markowski, a 59-year-old man who presented with metastatic disease.

DR MARKOWSKI: This is a 59-year-old man who’s healthy, was found to have elevated PSA up to 15. His CT scan did show signs of osseous mets, and then the bone scan showed superscan pattern, so just diffuse osseous metastatic disease. He had Gleason 9 prostate cancer.

My first question is, is there still a role for up-front chemotherapy in patients with bulky disease, large-volume disease. What’s your selection criteria? And then the second question is patients who do get chemotherapy, what’s the best agents for continuing them on hormonal agents, newer agents? Enzalutamide, apalutamide, versus abiraterone?

DR LOVE: What do you tend to favor?

DR MARKOWSKI: I find enzalutamide and apalutamide tend to be better tolerable. Many of our patients have diabetes and have to be on the prednisone kind of more long term. Enzalutamide’s been my go-to, but I’m starting to use a little bit of apalutamide as well.

DR LOVE: Every case of hormone-sensitive metastatic disease is unique, as demonstrated by a 57-year-old man cared for by Dr Morris. The patient was found to have post-prostatectomy PSA elevation and positive perirectal nodes on PSMA PET scan.

DR MORRIS: This is his PET scan. So PSMA PET clearly lighting up. That’s kind of the bladder with contrast in it, but you can see that’s a perirectal lesion. He was starting ADT plus AR therapy on the front end. This is a lower-volume, with only a few pelvic nodes, and then I think the question on top of what agent is how long do you use the agent.

DR LOVE: If you could access darolutamide without having to give chemotherapy would you utilize it?

DR MORRIS: Yes. I think that darolutamide does offer some increased tolerability, potential benefits, versus some of the other AR agents. That’s playing the odds.

DR ANTONARAKIS: Right. So 2 cases there. I’ve written some notes so I don’t get confused. But the first case was a de novo high-volume patient with a so-called superscan, so a bone scan that shows too numerous to count metastatic lesions. So I’ll ask Matthew this question. How would you treat such a patient, and then when you answer that please tell us your role on chemotherapy for the metastatic hormone-sensitive patient?

DR SMITH: Sure. So this is a really important case. The clinicians in the audience have the opportunity to improve the survival of this patient. This is a patient who absolutely should not receive ADT alone. He should have intensified systemic treatment. That intensification should include the addition of an androgen receptor pathway inhibitor with or without docetaxel chemotherapy, as I’ll describe. But either 2 or 3 — excuse me, either 2 or 3 drugs: ADT, AR pathway inhibitor plus or minus chemotherapy.

DR ANTONARAKIS: Now let’s pivot to the second case. I think there’s a lot of learnings here in terms of how this was defined. So the second case was a gentleman with a single perirectal lymph node that some people might view as M1 disease, some people might view as a local recurrence, and it was only seen on the PSMA PET scan. So maybe I’ll ask Fred. In a patient with “metastatic hormone-sensitive” prostate cancer who only has a single PET-avid perirectal lymph node, let’s assume that he has not received primary therapy at all, what would be your approach?

DR SAAD: I would consider this patient a nonmetastatic patient. I think the definition is still based on conventional imaging. And we are doing a clinical trial where we randomize to getting a PSMA or not in this kind of high-risk patient, and then acting on what we see.

But this patient really deserves local therapy. Obviously, he’s already high risk with ADT. Now the question of adding abiraterone I think would be extremely irrelevant here. But I think if we did a PSMA on every very high-risk patient we would find a lot of these kind of findings, and so it should not diverge us from hoping to cure this patient.

DR ANTONARAKIS: And first I’ll review the criteria, then I’ll ask you, Raoul, how you’d handle this. So in the STAMPEDE M0 study they had to have 2 out of 3 high-risk features to be included. The first was T3 or T4 disease. The second was a PSA above 40, believe it or not. And the third was a clinical lymph node, N1 disease. There was also a subcategory that if they had a biochemical recurrence after local therapy with a PSA above 4 and a doubling time less than 6 months that was also included. So that was the composite definition of the M0 STAMPEDE.

Now this patient doesn’t have 2 out of 3, but yet they have a positive juicy lymph node. Would this be a patient, Raoul, that you would consider ADT plus 2 years of abiraterone?

DR CONCEPCION: And again, I couldn’t tell from the presentation, had this patient already been treated for his primary?

DR ANTONARAKIS: He had.

DR CONCEPCION: His primary had already been treated?

DR ANTONARAKIS: Yes.

DR CONCEPCION: I agree with — I mean I definitely agree with — this is actually a locoregional node. I would not consider this a metastatic lesion. This is locoregional. Depending on what his pathologic stage is, of the prostate, this gentleman I think should be — should be considered with radiotherapy to this area. Because as Fred said, I think he’s 57, assuming he has a great ECOG status, doesn’t have a lot of comorbidities, I think this patient can still be managed, can still be “cured” with radiation therapy to the pelvis and not necessarily immediately jumping to ADT plus an androgen receptor-targeting agent.

DR ANTONARAKIS: Okay, great. We’re going to move on here. So the next polling question. “Regulatory and reimbursement aside, what systemic therapy would you typically use for a 49-year-old man presenting with low-volume metastatic hormone-sensitive disease?”

So lots of different opinions. The majority was ADT plus enzalutamide, maybe followed by ADT plus abiraterone as a close second.

So the next case.

DR LOVE: The next case was presented by Dr David Taub, a 49-year-old man with high-risk disease in the prostate and a 1.3 cm right pelvic lymph node.

DR TAUB: First PSA is 16. He works in construction. He shows up a few months later. His PSA is 24. We did a biopsy, and it showed Gleason 7 and 8 disease in 11 of 12 cores. Metastatic workup was negative with the exception of a 1.3 cm right pelvic lymph node. And his MRI shows a PI-RADS 5 lesion involving right posterior lateral peripheral zone with capsular abutment and a 1.3 cm external iliac lymph node. And so very young guy.

He’s currently on ADT and apalutamide. Repeat scan showed that the lymph node is still present, but now 6 or 7 mm. And so the question is he should have some local therapy. Is prostatectomy reasonable? Any benefit to prostatectomy and radiation?

DR ANTONARAKIS: Great. So let me ask Matthew first here. So this is a de novo patient with locally-advanced prostate cancer, positive pelvic lymph node, has not received any primary treatment. And I will ask you 2 parts to that. First of all, what is the optimal systemic therapy for him? And secondly should he also receive a local therapy and which one?

DR SMITH: Sure. So this is NCCN regional risk prostate cancer, so he should receive intensified systemic treatment, ADT plus a second — plus an AR pathway inhibitor. Probably the best available data is with abiraterone acetate and prednisone. And he absolutely should receive local treatment to the prostate and nodes with either radiation therapy. I think given his young age surgery could be a consideration, but I think it’d be a hard case to make that surgery would be better than radiation in this case.

DR ANTONARAKIS: Now this was not something that came up in these cases, but it does come up with the STAMPEDE study Arm H, which is the treatment of the primary with radiotherapy in the context of oligometastatic disease defined in that trial as 3 or fewer metastases. So let’s take this case, and instead of having a single pelvic node he has 2 osseous metastases in the ribs.

DR SMITH: Great point because there’s really kind of convergence of these issues, oligometastatic, regional risk. We’re talking about the same thing. They need treatment of the primary, and they need intensified systemic treatment. So we can in some ways not get too caught up in the details of what you could — it’s really the priority of treating the primary and intensifying systemic treatment; true in both cases that were described here.

DR ANTONARAKIS: Raoul, we just heard from Matthew that the best evidence for this case would be ADT plus abiraterone for 2 years, according to STAMPEDE. But that’s the purist and maybe not the real-world scenario. Do you think in the real world any of the antiandrogens would be reasonable to combine with ADT and for how long?

DR SMITH: I think in the real-world setting in the independent practices the answer is yes, they would be considered. But I would think that for your typical — for your aggressive community urologists who have talented surgeons in place, this gentleman’s 49 years old, he’s young, assuming that he doesn’t have significant comorbidities, this guy needs the kitchen sink thrown at him. And obviously if a clinical trial is available to give him neoadjuvant or adjuvant novel hormonal therapies with prostatectomy I think obviously he would go down that road.

I think we talk about managing the primary. And again, I’m old enough to remember that when you don’t manage the primary, yes, it may not prolong their survival per se, but the local disease that you get, bilateral ureteral obstruction, urinary retention, clot retention, is a nightmare for some of these patients. And we remember the day when we weren’t aggressive with the primary.

Plus, there’s also some good molecular data that if you don’t manage the primary aggressively, with the seeding and branching of these clones they actually will come back and reseed the primary. So I would be very aggressive with his primary. I personally would probably move him towards radical prostatectomy followed by radiation followed by systemic therapy with treatment intensification.

DR ANTONARAKIS: So Fred, short answer, in a node-positive patient would you consider a radical?

DR SAAD: For most patients, no. Not for clinically-detectable metastases. Radiation would be our primary approach. The exception would be this kind of patient. And just a last word, test for genomic alterations in this high-risk patient at 49 years old.

DR ANTONARAKIS: Absolutely.

DR SAAD: It could be informative.

DR ANTONARAKIS: And we’ll get to that in your session as well. But with that, let’s move on. And now I’d like to ask Matthew to give his remarks.

DR SMITH: So what an outstanding introduction to my presentation, with these cases really illustrating the wide spectrum of situations where we should be considering intensification of systemic treatment. Very good evidence tells us that men receiving androgen deprivation therapy alone for metastatic prostate cancer have poor clinical outcomes. And if you take away anything from my presentation today it is the following: ADT alone is inadequate for the vast majority of patients with metastatic prostate cancer. I’m going to say that again, ADT alone is no longer an appropriate standard of care for most patients with metastatic prostate cancer. And the clinicians in the audience have the opportunity to make decisions that will improve survival for our patients.

Here’s the problem. This is the control data from the STAMPEDE trial looking at the control arm of patients with metastatic prostate cancer treated with ADT alone, about a thousand patients. Median overall survival was 42 months. Time to failure was less than a year. And risk for progression and death related to extent and sites of metastases with patients with bone and — bone and soft tissue metastases doing worse than patients with node-only disease, as this audience well knows.

I’m going to describe an extraordinary body of data of Level 1 evidence for improved overall survival. And most of the endpoints I’m talking about is overall survival. There’s lots of other supportive evidence from intermediate endpoints, but these are consistent observations for improved overall survival.

The first study’s looking at intensification of systemic treatment, meaning more than ADT alone, looked at docetaxel. This is a meta-analysis of before randomized controlled trials with about 3,000 patients showing a significant improvement in overall survival with the addition of docetaxel. There’s a 9% absolute improvement in survival at 4 years, so translated and an easier way to understand, for every 11 patients you’d treat with docetaxel for mHSPC you would prevent 1 death at 4 years. In our world that’s a pretty big treatment effect, but the treatment effects I’ll describe in the subsequent studies are even larger.

So this really set the stage for intensification of systemic treatment. This is one of those studies. This is CHAARTED, showing a significant improvement in OS by the addition of docetaxel in patients with mHSPC. This study included patients with so-called high volume and low volume. High volume being defined as 4 or more bone metastases or visceral metastases, low volume being the absence of those things.

And I think while this is an important subset of analysis it’s led to tremendous confusion in the field. And that is that somehow we only need to intensify systemic treatment for patients with high-volume metastatic disease. It is not true. It may be true for docetaxel, but it is not true for the AR pathway inhibitors, as I’ll describe in a few moments.

So we now have strong Level 1 evidence and consistent evidence across a whole bunch of randomized controlled trials that the addition of an AR pathway inhibitor to ADT alone also improves overall survival in mHSPC. These are data from the LATITUDE trial showing this marked improvement in radiographic progression-free survival and a significant 38% reduction in risk of death by the addition of abiraterone and prednisone to ADT in patients with high-risk mHSPC. These were patients with de novo high-risk metastatic disease, showing a big treatment effect.

And then you might ask, well if abiraterone and docetaxel work, like which is better. Well, there is no direct head-to-head comparison of those 2 approaches, but STAMPEDE investigators did the best they could, which was to look at contemporaneously randomized patients in 2 different arms of STAMPEDE and then compare those survival results and other outcomes.

So here’s what they found. So for the intermediate endpoints of failure-free survival and progression-free survival abiraterone performed better than docetaxel, although there was no difference in overall survival. It could be that abiraterone is simply better than docetaxel. There are other explanations, including the fact that docetaxel is given for a finite period of time, whereas abiraterone is continued to progression, so the improvement in the intermediate endpoints may reflect that it’s used continuously.

Other androgen receptor pathway inhibitors confer similar important survival benefits. This is data from the TITAN study showing meaningful improvements in rPFS and OS in favor of apalutamide and ADT compared to ADT alone.

The important addition of this study to the literature is that the study enrolled patients with both high- and low-volume disease, and the benefits in overall survival were the same between high- and low-volume patients. So said a different way, the benefits for intensification with an AR pathway inhibitor, here apalutamide, span the spectrum of both high- and low-volume metastatic disease. So intensification is not only for patients with high-volume disease.

Similar observations from the ARCHES study. This is enzalutamide again showing marked improvement in rPFS and a clinically and statistically significant improvement in overall survival in favor of the addition of enzalutamide. In ARCHES, too, the benefit was for both patients with high- and low-volume disease. Similar results from the ENZAMET trial, another study of enzalutamide showing meaningful improvements in progression-free and overall survival.

So the logical next question would be if either docetaxel or an AR pathway inhibitor improve overall survival how about both. And we attempted to address that question in ARASENS. So ARASENS is a global randomized controlled trial, included 1,300 patients with mHSPC who were candidates for treatment with ADT and docetaxel. All patients received ADT and docetaxel. Eligible patients were randomized to darolutamide or placebo, and they began that within 12 weeks of starting ADT, and then within 6 weeks were then treated with docetaxel for 6 cycles in both arms.

So the main difference here is our control group is not ADT alone, it’s ADT and docetaxel in both groups, and 1 group got darolutamide, the other got placebo, so triplet versus doublet in common terminology. Here’s the primary endpoint. There’s a large and statistically significant improvement in overall survival, a 32% reduction in risk of death in favor of the triplet. The magnitude of benefit we’re seeing here is similar to all of the other AR pathway inhibitor studies, the difference, again, being that the control group is ADT and docetaxel.

There were consistent benefits in overall survival across the prespecified subgroups, including according to sites and extent of disease, and it was true whether patients had recurrent or de novo metastatic disease. We also saw improvements in intermediate endpoints, including time to castration-resistant prostate cancer and time to pain progression.

The historical experience with darolutamide is it is well tolerated. We heard from Dr Concepcion about the nonmetastatic CRPC trials. In that setting darolutamide’s safety is similar to placebo. We saw a similar result here in ARASENS. The rates of any adverse events, serious adverse events, and adverse events leading to discontinuation of treatment were similar between the darolutamide and placebo groups.

There’s other data supporting intensification with 2 drugs. This is the data — this is the design of the PEACE study. It’s a little more complicated, so I’ll do my best to explain this. So PEACE1 included 1,173 patients. They were randomized to either standard of care, standard of care plus abiraterone, standard of care plus prostate radiation therapy, or both. And standard of care was initially ADT alone, and then about halfway through the course of the study it was changed to be ADT and docetaxel. So we have experience in that study with ADT as the control arm or ADT and docetaxel. And the primary endpoint for the trial was overall survival.

So the data regarding radiation therapy have not yet been reported so I’m going to describe the impact of abiraterone acetate addition on overall survival. In the overall study population abiraterone reduced the risk of death by 18%. And then if we look at the subgroup of patients who received docetaxel as part of standard of care the improvement in overall survival was even better, with a hazard ratio of 0.75, or a 25% reduction in risk of death.

There were no new safety signals with either docetaxel or abiraterone. There were somewhat higher rates of serious adverse events in the combination group, with the most commonly reported adverse events of patients receiving abiraterone being hypertension or liver function test abnormalities.

So in summary, ADT alone is no longer an appropriate standard of care for most patients with mHSPC. I’ve described this extraordinary series of large randomized controlled trials that collectively involved more than 10,000 patients that show the following: ADT plus docetaxel is better than ADT alone. ADT plus an AR pathway inhibitor, take your pick, is better than ADT alone. And then ADT plus docetaxel plus either darolutamide or abiraterone is better than the doublet of ADT and docetaxel.

So what does this mean for our patients? Most or all of our patients with metastatic hormone-sensitive prostate cancer should receive an AR pathway inhibitor, either ADT plus an AR pathway inhibitor or ADT and docetaxel plus an AR pathway inhibitor. The best data we have for the triplet is with darolutamide or abiraterone.

Thank you.

DR ANTONARAKIS: Great. Thanks very much. So now we’re going to get to some questions. We’ve had a lot from the audience. I may not be able to get through all of them in 5 minutes, but we will try to get through as many. So first case, let me begin with Raoul. A patient with de novo metastatic high-volume prostate cancer, PSA of 4,000. How would you treat him?

DR CONCEPCION: I would actually consult with my medical oncologist and based upon obviously the data that Matthew has presented very nicely and succinctly this is the high-volume disease 4,000. And despite the fact that there seems to be this movement away from cytotoxic chemotherapy it still is in play. And for this patient with high-volume disease, high PSA, definitely this patient needs ADT, docetaxel, and an additional androgen receptor-targeting agent.

DR ANTONARAKIS: Great. Thanks very much. Now one question which comes up often in my practice, and this particular person is asking the same thing, which is if you have a patient with high-volume disease that would have qualified for triplet therapy before the data came out, and they just received either ADT plus an antiandrogen or ADT plus docetaxel, so doublet, but now he’s in response. He’s currently — let’s say a complete response. Would you add in sequence the alternative agent to make it into a triplet or would you wait for CRPC, Matthew?

DR SMITH: Great question. So to clarify, in the PEACE1 and ARASENS this was concurrent therapy. In fact, in ARASENS patients — it’s ADT/darolutamide, and then they started docetaxel within 6 weeks. So it’s really concurrent overlapping treatment.

In the case of a patient who — that you’re describing, I would not add chemotherapy if their responding to their ADT plus AR pathway inhibitor. And if they had a spectacular response to ADT/docetaxel I’d probably wait. But I wouldn’t wait long. I mean at first PSA rise I would add the subsequent drug.

DR ANTONARAKIS: Question for Fred. A lot of these have this similar flavor, but they’re a little bit different. So a patient with metastatic castration-sensitive disease, high volume, has received 6 cycles of docetaxel, but unfortunately has not had much of a PSA response. PSA is not rising yet, but it was an incomplete PSA response. Would you hold off on adding further antiandrogens or would you jump into the antiandrogen there and then?

DR SAAD: Short answer, jump as quickly as possible. I mean I’m concerned with anybody that doesn’t go to undetectable PSA. So a nonresponsive patient on docetaxel and ADT is extremely worrisome. We’ve got data from 15 years that you’re PSA nadir on ADT alone is informative. It’s even more important if they don’t get to that nadir with an ADT and docetaxel approach. So…

DR ANTONARAKIS: Raoul?

DR CONCEPCION: For Fred and Matthew: so in those 2 patients that they’ve gone through their 6 cycles of docetaxel, and now you’re of thinking what to do next. What is the role of molecular imaging in those patients looking at whether some of these lesions are still avid and whether you should go after them because of that?

DR SMITH: I’ll try to answer that. It’s a great question. We don’t know. And I think the greatest controversy about PSMA PET/CT is going to be its role in response assessment because that is yet to be formally tested. But the questions that are being posed I hope are very temporary, meaning we shouldn’t be talking about next year the patient who got ADT and docetaxel and should they then later add an AR pathway inhibitor. That is not an appropriate form of treatment. If you’re going to use ADT and docetaxel, the patient should have already have started an AR pathway inhibitor.

So I’ll say it again, every — nearly every patient with metastatic hormone-sensitive prostate cancer should receive intensified AR pathway inhibition, ADT plus an AR pathway inhibitor, 1 of those 4 drugs we talked about. And then the next — to your question is should you also add chemotherapy.

DR ANTONARAKIS: All right. Let’s move on in the interest of time. Thanks, Matthew.

Selection and Sequencing of Therapy for Metastatic Castration-Resistant Prostate Cancer — Emmanuel S Antonarakis, MD

DR ANTONARAKIS: So the polling question for Module 3: 83-year-old man with metastatic CRPC to the bone, previously received ADT plus enzalutamide up front, now has developed CRPC, prefers not to receive chemotherapy. So radium-223 was the most popular choice, followed by abiraterone. Interestingly, this would be abi immediately following enza, so — and then a few people, one fifth, chose lutetium-PSMA, even though he has not yet had a chemotherapy. Great. Great discussion points there.

So let’s hear the 2 cases.

DR LOVE: The next case was presented by Dr Jason Hafron, an 83-year-old retired primary care physician with metastatic disease and prior treatment with ADT and enzalutamide who now has disease progression.

DR HAFRON: Here you see the images from the PSMA PET/CT, which shows osseous with pelvic activity concerning for metastatic lesions. You see those 3 bright spots. You see retroperitoneal lymphadenopathy designated by the arrow. What would you recommend for next line of therapy with this patient?

DR LOVE: So what are you thinking?

DR HAFRON: I’m thinking chemotherapy. I referred him to oncology.

DR LOVE: How about if you could give lutetium?

DR HAFRON: I would like to. My initial experience with a handful of patients I’ve treated with lutetium has been very impressive, quite remarkable. I think this is a very excited treatment option for our patients, but obviously clearly he hasn’t seen chemo yet. He wouldn’t qualify.

DR LOVE: So radium is an option in your patient now though, too, correct?

DR HAFRON: Yeah. Radium would be another option.

DR LOVE: How about your 67-year-old man, where you accessed lutetium through compassionate access?

DR HAFRON: He’s received already 5 out of 6, and on cycle 2 he actually developed thrombocytopenia and was dose lowered by 80% per the radiation oncologist. And his platelets returned to baseline by cycle 5.

This guy has made me a believer in lutetium. I mean this guy was essentially failing, with really no significant therapies to offer him. And the lutetium has lowered his PSA to 20 from over 100. His performance status has improved remarkably.

I’m just curious if anyone’s had experience with thrombocytopenia during treatment with lutetium, dose lowering. Also, how do I follow this patient?

DR ANTONARAKIS: Great. So 2 cases there. Let’s try not to get them confused. So the first case, I may begin by asking Fred. So the first case was the gentleman with metastatic CRPC who previously received doublet therapy with ADT plus enzalutamide. He’s got 3 bone lesions that are avid on PET scan and 1, I think it was a pelvic lymph node. How would you manage this patient?

DR SAAD: Yeah. So clearly the biggest area of research right now is what to do after failing an ARPI, and I think everybody’s looking for alternatives to what we consider the standard of care of chemotherapy. But when you think about it, there isn’t really Level 1 evidence that chemotherapy’s the best approach after failing an AR pathway inhibitor.

But having said that, I mean chemotherapy is not excluded from an 83-year-old patient, especially if they’re symptomatic. If they’re asymptomatic I think — or minimally symptomatic, I think it’s an opportunity. Radium, I think, is an excellent option. I think very soon when there’s going to be wider availability of lutetium it’s going to be a very attractive option for many of these patients, even right after an AR — because I think at 83 you can probably justify why you might not want to give chemotherapy to this patient and leave chemotherapy for after.

DR ANTONARAKIS: So Raoul, we’ve heard about the term oligometastatic disease, but there’s also another term, oligoprogressive disease, people that do progress with CRPC but only 1 or 2 lesions are lighting up. This case was not exactly that. It was a bit more extensive. But let’s say that he was progressing in 1 single bone lesion. He’s on ADT/enzalutamide. Would you switch therapy, or could you possibly entertain remaining on the same combination doublet and then doing something else?

DR CONCEPCION: I think that’s really the — it’s a great question because obviously we don’t know which clones are responding to his androgen receptor-targeting agent. So again there is this concept of treatment beyond progression. I think this is where genomic testing would also come into play. It looks like he’s got some mutations, so obviously if he has a positive mutation for homologous recombination repair gene that obviously then you’ve got PARP inhibitors that come into play, which I know Fred’s going to address. I think, again, these are — to me, having this — multiple arrows now in our quiver allows us to be able to direct therapies that needs to be more precision medicine guided, biomarker driven.

The worrisome thing about this gentleman, obviously, I think, and I would be curious if Matthew would take the same stance, he has already seen enza. Some of the tendencies, especially in bigger urology practices, is to switch them over to another androgen receptor-targeting agent, which I think you get very little benefit. But that seems to be a very commonplace practice. I personally would not do that. I think you check his genomic status, and I think as everybody said, chemotherapy’s still available out there. You still have radium assuming that he’s got limited pelvic lymph node disease and that he doesn’t have a lot of hematologic dysfunction.

But I think this concept of moving from one AR targeting agent to the next I think is very limited, and I would be curious if Matthew would be as strong as his commentary on no ADT monotherapy.

DR SMITH: Yeah. So we have good evidence that it’s inactive, right, very good evidence from large prospective clinical trials. So treat the patient not his anxiety or your anxiety by doing the AR pathway inhibitor switch. There’s very little in it for the patient.

I’ll very briefly add I think radium was also brought up. I think he had disease only on a PSMA PET/CT. So you’d really need to know he had technetium positive disease and a fair amount of it. I think radium still has an important role, but I wouldn’t have a lot of enthusiasm for someone with 3 bone metastases, where I’d really be involving my colleagues in radiation oncology to see if they could reasonable target those anatomic locations.

DR ANTONARAKIS: Yeah. That’s a great point. So the second case is about lutetium. I think we’ll get many of those questions at the end of my remarks, so I think we’ll save that and stay on time. So let’s hear 2 more cases.

And the polling question is in general do you offer sipuleucel-T to patients with asymptomatic metastatic CRPC.

So we are now 12 years out after the FDA approval of sip-T, and it seems like three quarters of people do not typically use it, and one fifth use it in select patients.

So let’s hear the 2 cases.

DR LOVE: The next case presented by Dr Markowski is a hearty octogenarian with metastatic disease and progression on cabazitaxel.

DR MARKOWSKI: A durable 81-year-old, even at 81 still, just treated with cabazitaxel with pretty rapid progression. Then, still a questionable performance status, 1 to 2. He’s doing good, still wants to get treatment, wants to try something. So the question was could we do the PSA targeted therapy that was just approved?

DR LOVE: So anything you’d like to hear the faculty discuss about lutetium?

DR MARKOWSKI: Yeah. The main thing would be the side effect profile, how well it’s tolerated. This is an 81-year-old who’s been through a lot of treatment. There’s going to be a lot of patients like this.

DR LOVE: We have noted many times the high fraction of millennial-aged physicians who attend our programs. And one strategy that docs new the field are not as tuned into is one of the first approved forms of immunotherapy.

What about this 62-year-old man who got sip-T before he got to you?

DR MARKOWSKI: Sip-T. It’s not something that I’ve used. I’m a little bit on the younger side, so it was kind of developed before. A lot of new agents came out since then, and it wasn’t kind of a homerun. So for patients with rising PSA but increasing asymptomatic bone mets is sip-T still a good option is my main question for the experts. Have people still been using it?

His PSA didn’t respond much, and we did end up — started him on enzalutamide, as well, afterwards. And he’s doing well on that now. His PSA’s coming down nicely.

DR ANTONARAKIS: Okay. So the first case was a gentleman with mCRPC, has progressed on cabazitaxel. We didn’t hear if he had received docetaxel in the past or not, but according to the FDA label he probably would have had to. And the question was would he be fit enough for lutetium-PSMA. So I’ll ask Matthew this question. If someone is fit enough to go through docetaxel and cabazitaxel A) is he fit enough for radioligand therapy and B) what particular side effects might you be looking for?

DR SMITH: Sure, yeah. So this is — the patient’s done well to tolerate all of that treatment. Not every 81-year-old man would get through all that treatment, including cabazitaxel. There are many patients like this included in the pivotal study of PSMA lutetium. And so when that drug is available I would be enthusiastic about considering him for that. That would require that he have a PSMA PET/CT to prove that he has PSMA-avid disease. And there’s good evidence that the greater intensity of — or greater PSMA avidity is associated with a better treatment response. So that is something to keep in mind in terms of prioritizing or selecting patients for that treatment.

Some of the side effects include hematologic side effects in an older individual who’s had a lot of prior treatments is something to keep in mind. Although most of those hematologic toxicities were not severe and requirements for dose reduction or treatment delays were in the range of like 5% to 10% in the VISION trial.

DR ANTONARAKIS: And Matt, just to go back to something that was mentioned in the previous case. The patient had thrombocytopenia, had to have a 20% dose reduction of the radioligand therapy. In your experience, when thrombocytopenia occurs, do you typically recommend reducing the dose or increasing the time between doses?

DR SMITH: I think either is an appropriate consideration. I don’t recall the explicit label instructions, and it would depend a little bit on where it happens in the course of their therapy. I think if it was — began at cycle 5 I would probably just delay cycle 6 if they were going to get that. If it happened early on, with cycle 1, I would be more inclined to dose reduce.

DR ANTONARAKIS: Thank you. I’m going to ask Raoul because sipuleucel-T is not available in Canada, so Fred you’re off the hook. Raoul, who is the ideal patient in your experience for sipuleucel-T?

DR CONCEPCION: I think it’s just like they’ve described it. It’s probably — it’s the newly diagnosed mPRPC patient that has not been heavily pretreated, and this was the patient that we saw a decade ago. Sip-T actually was the second drug approved, in April of 2010, after cabazitaxel, and there was nothing else. So those patients — it did not receive a lot of popularity because people didn’t understand really how it worked because it’s an autologous immunotherapy, and the biggest thing it think that bothered a lot of medical oncologists, there was no PSA reduction. So people were scratching their head.

In the urology world it’s still used quite extensively and even has NCCN recommendations for the asymptomatic patient with limited bony mets or soft tissue mets with an overall survival benefit, who you think can live 5 years. So it is actually still used quite a bit in the independent setting in urology.

DR ANTONARAKIS: Then the last question for you, Raoul, as well. Are you comfortable using sip-T concurrently with enzalutamide and abiraterone based on the Phase II randomized trials?

DR CONCEPCION: I would be comfortable using it. Again, I think that historically we’ve used — we’ve added an androgen receptor-targeting agent primarily because the patients, and even the providers, wanted to see that drop in PSA. It just made everybody feel better. But again, I think that the audience has to understand, Prostate Cancer Working Group, the recommendation is you should not necessarily change lines of therapy just because you have a rise in PSA. It should be actually clinical or radiographic progression. However, I think the combination, given the fact that you can get sip-T in within 5 weeks and immediately add an androgen receptor-targeting agent I think is very reasonable.

DR ANTONARAKIS: Great. Thank you. And with that I’m going to proceed with my talk and hope I can stay on time as well.

So the landscape for metastatic CRPC’s getting complicated. That’s a good thing for our patients, but it makes our jobs as oncologists or urological oncologists more and more difficult. We also have, in addition to the long list of genomically-unselected therapies, we have now 3 targeted therapies; 2 that have to do with PARP inhibition for the BRCA patients, pembrolizumab for the MSI high, but now also we have an imaging biomarker, the PSMA PET scan.

So what about selection and sequencing of therapies? There’s a paucity of evidence here, but there are a few key trials. Firstly, AR-V7 is still available. It’s not used that much by so many people, but this is a blood-based androgen receptor splice variant that can be detected from circulating tumor cells. It is commercially available, and it may help guide the use against an AR-targeted therapy and for chemotherapy if it is present.

We wrote this editorial in the New England Journal in 2019, and we were tasked to make it as simple as possible. This was as simple as we could make it. Long story short, it’s still very complicated. There are basically 7 or 8 ways that a patient can become metastatic castration resistant. And depending on the prior therapies that he has received that will influence the next line of therapy. The short version of this diagram is do your best to alternate between different classes of therapies, and in general don’t go from one class to another back to back.

I just want to show 1 important study looking at the sequence of abi to enza or enza to abi. This is something that we used to do a lot. I was guilty of that as well. And the Canadian trial led by Kim Chi, GUTG-001, really was the best level of evidence. These patients were first-line mPRPC that were randomized to receive abiraterone on progression they switched to enzalutamide, or the opposite, they began with enzalutamide on progression they switched to abiraterone.

And this trial, I think, is the best evidence for me that if you’re ever going to do this, which we don’t generally encourage, but if you are, it’s the sequence of abi followed by enza that seems to be more beneficial. In other words, enza can retain some efficacy in the post-abi situation, but abiraterone following enzalutamide has a very, very low response rate.

Now of course we have to talk about the CARD trial. Here, these patients — again, we often forget this. These were patients who had progressed on their AR-targeting therapy within less than 12 months. That’s only about a third of patients. If you think about the median time to CRPC in first-line abi/first-line enza it’s about a year and a half. So for that patient to progress you’re picking out the one third worst patients, the most androgen indifferent. They could have received docetaxel, as well, and then they were randomized to the alternative AR therapy or cabazitaxel.

And this study was positive for rPFS. That was not surprising. The thing that caught many of us, including me, by surprise was the overall survival advantage showing a clear and clinically significant survival advantage to cabazitaxel rather than the alternative AR therapy. This trial has been the one that people quote when they really say that we should not be using back-to-back AR-targeting therapies, especially not in those who have failed their first AR-targeting therapy in less than 12 months.

But cabazitaxel has slightly higher toxicity. It can be managed. Diarrhea, hematuria, neutropenia, thrombocytopenia were all statistically greater in the cabazitaxel arm. Many of us in the oncology field, and some urological oncologists, are now comfortable managing the side effects of cabazitaxel. Less neuropathy than with docetaxel.

There was a second, smaller Canadian trial. Interestingly, this trial showed no difference in PFS with cabazitaxel over AR-targeted therapy, but there was a numerical, though not statistically significant, overall survival trend with cabazitaxel. Smaller study, only about 90 patients, so perhaps it was the underpowered nature of the study that made this one “negative” and the CARD study positive, but for me this reinforces the same direction that cabazitaxel outperforms abi or enza in patients with high-risk mPRPC.

Of course what we really want are biomarkers. So in this trial patients with AR amplification had a relatively greater benefit with cabazitaxel. And interestingly enough, and this might be artefact, patients with PI3-kinase mutations had a preponderance for a better response to AR-targeting therapy.

What I think the field is in desperate need of are more biomarkers in addition to AR-V7, which is just 1, to help us select, with that patient in front of us, whether we should use a second AR-targeting therapy or chemotherapy. But without the biomarker most people would agree chemotherapy is the way to go.

Now a few words about radium. Of course this was the pivotal Phase III study. It’s hard to believe it’s already been 8 to 9 years ago, the ALSYMPCA study. This was radium-223, 6 doses given 4 weeks apart by an intravenous push. It’s an alpha radio particle, so this is a stronger particle at damaging DNA. It causes double-strand DNA breaks more so than beta particles like lutetium. And again, this trial was positive not just for skeletal-related prevention but also overall survival.

If you look at the forest plot you can see a consistent benefit favoring radium in multiple categories. The one that I want to attract your attention to is the extent of disease. It’s hard to see. It’s the second to last from the bottom. If you have too few bone metastases, 6 or less, or too many, the confidence intervals crossed 1. So when I look at this data, and this is my own personal belief, I think the ideal patient is someone who has between 5 and 10 bone mets. If you have 1 or 2 I would rather treat that patient with a stereotactic radiation approach. If I have 100 I worry that the disease may be too extensive for radium. That’s my personal preference.

But these are some guidelines about when to use radium. Of course the package insert says that the disease has to be symptomatic, typically that means bone pain. So with mild bone pain oftentimes, as long as you put that in your notes that there is some pain, as long as it’s not a score of 0, you can get that reimbursed. But with very severe bone pain it doesn’t tend to work quickly or rapidly.

Make sure that your patients don’t have any impending pathological fractures or cord compressions, again, because the drug doesn’t work rapidly. It can affect bone marrow function, so we do usually ask our patients to have adequate hemoglobin, ANC, and platelet counts. And of course because this is a bone-seeking radiopharmaceutical and does not attack anything outside the bone, people with visceral mets, maybe more than 1 cm, or bulky lymph nodes, more than 3 cm, that would be contraindicated.

And I’ll show you the data suggesting that this should not be combined with abiraterone, and if it is combined with enzalutamide concurrent denosumab should be used.

Now let’s talk about the PEACE III trial. Why is the PEACE III trial important? It’s important because of this study that Matthew led, the ERA-223, which caught everyone by surprise, at least it caught me by surprise. This was a study of abiraterone plus placebo versus abiraterone plus radium. And we can see that there is no difference. The hypothesis was that skeletal symptomatic events would be prevented, that was not the case, and overall survival was not improved. In fact, there was a numerical, although not statistical, worsening of survival. Again, not statistically worse. But the learning from this was that 60% of patients on this trial were not receiving a concurrent bone health agent.

And when that study was reported the European PEACE III trial was ongoing. This was a similar study with enzalutamide versus enzalutamide plus radium, and the trial was halted for an interim data safety monitoring board analysis. And the data safety monitoring board did in fact see that in this study, as well, there was an increased risk of fractures in the combination group. And they mandated, following this interim IDMC meeting, that the subsequent patients on this trial all had to have a bone health agent.

And this graph is a bit busy, but what it shows is it’s the pre and post experience, after the patients were mandated to add a bone-targeting agent such as denosumab, in both the enzalutamide alone and in the enzalutamide plus radium group there was a reduction in the risk of fractures. And this is shown numerically on this table. And importantly the use of denosumab, even in the control arm, the enzalutamide alone, reduced fractures and even to a greater degree, of course, in the combination.

So this study’s still ongoing, but the lesson is probably when you’re combining AR-targeting therapy plus radium, first of all don’t do it with abiraterone. Secondly, if you are doing it with enzalutamide please use a bone health agent.

Now there’s been a lot of excitement about lutetium-PSMA-617. This targets a cell surface protein called prostate-specific membrane antigen, and the goal here is to have a radioligand. What that means is a radioactive particle. In this case it’s a beta emitter, lutetium-177, which is linked to a ligand for the receptor. Remember, PSMA is a receptor, so in order to bind to it you need to have a ligand that binds to the receptor. And then this whole thing is internalized into the cancer cell, where the linker is cleaved, and the radioactive moiety, which is lutetium, is released into the cell causing double-strand DNA break and hopefully cell death and patient benefit.

So this was the VISION trial. This was a third-line mPRPC study. Patients had to have received and progressed after at least 1 androgen receptor-targeting therapy and 1 or up to 2 taxane therapies. The control arm was best standard of care, but that excluded chemotherapy; that excluded radium, and that excluded sipuleucel-T, so none of the life-prolonging therapies were in there. But things such as alternative antiandrogens, steroid use, and other supportive measures were permitted. And then in the interventional arm patients got lutetium-PSMA-617 every 6 weeks for 4 cycles, and if they had a response they were allowed to have up to 2 more, so up to 6 cycles given 6 weeks apart.

Big difference in radiographic progression-free survival and overall survival, with an overall survival hazard ratio of about 0.62, a pretty large relative benefit. And in the forest plots almost every group, except for the African American and Asian populations, which were very, very, very small, where favoring the use of lutetium-PSMA.

Now very importantly, and I may have glossed over this too quickly, these were all patients with positive PSMA PET scan. And the criteria for enrollment were not as strict as some of the Australian trials, where patients in those studies had to have an FDG PET and a PSMA without discordance. Here, just a positive PSMA expression was enough.

And the side effects. Dry mouth. Why? Because the salivary glands highly express PSMA, so do the lacrimal glands. So dry mouth, dry eyes are the most common side effect. And then, as you can see at the bottom, some diarrhea, some vomiting, and some cytopenias, including, as we heard from the case, thrombocytopenia. 17% of people had that, and 8% had Grade 3 or greater thrombocytopenia.

Now we did have an FDA approval in March, but last week we heard from Novartis, who is the maker of lutetium-PSMA-617, that there is a 6-week temporary hold in production because of manufacturing and delivery problems. We don’t know the exact details. So at this moment in time, even though this agent is FDA approved, no one in the world is able to get this on a clinical basis or in a clinical trial, for now. And we are told that this delay will be about 6 weeks.

I’m going to end with a few novel strategies for metastatic CRPC. Immune checkpoints have not worked very well. One exception is this Phase II study of cabozantinib plus atezolizumab. Many of us are used to using cabozantinib in the other urological cancers but not in prostate cancer. But there was this Phase II study performed by Neeraj Agarwal which showed quite compelling objective response rates and PSA response rates. And this has led to a Phase III trial where the interventional arm is cabozantinib plus atezolizumab, and the control arm is enzalutamide or abiraterone. These are patients with metastatic CRPC who have failed 1 and only 1 prior novel hormone therapy.

Two other things just to spend 30 seconds on. There are other ways to attack the androgen receptor. One is this PROTAC, which attaches to and degrades the androgen receptor by targeting it for proteasomal breakdown. And the initial study presented shows some activity with interestingly greater activity in those patients with AR-activating mutations and a second compound which blocks the most proximal enzyme in the steroid synthesis pathway, CYP11, which has interesting clinical activity. Again, it seems to be greater in the AR-activating mutations, but as a consequence causes complete aldosterone and corticosteroid reductions as well because of blocking the most, most proximal enzymes. So these patients did need fludrocortisone, hydrocortisone replacement.

So now let’s move into some questions here. I have the disadvantage of not seeing these as they came in because I was at the podium. So perhaps the first question for Matthew. “Have you ever seen a pain flare with radium?” Does radium, in your experience, cause pain reduction or can it cause a pain flare in the short term?

DR SMITH: It’s a great question, and it can be hard to know in an individual patient, right, whether they’re increased pain is a flare or actually represents progression of disease or the variability of their disease. Personally, I’ve not seen what I’d consider to be a true pain flare with radium.

I just wanted to briefly expand on one point that Emmanuel stated. I would say every patient receiving radium should be on a bone protective agent not just the patients who are going to receive it concurrently with enzalutamide. Why is that? Because all these patients are at risk for fractures. We saw that in data from the PEACE III trial, as well as the ARROW-223 trial. So these are very late patients, mPRPC, extensive bone mets. If you’re considering them for radium they should be on a bone protective agent. And if they’re not already on one, then you should begin one.

DR ANTONARAKIS: A question for Raoul since this is mainly a urology audience. Do you think at this point in time there’s any role for a urologist to be prescribing lutetium-PSMA, or do you think it’s more of a referral to the nuclear medicine colleagues?

DR CONCEPCION: I think the people that should manage these patients, whether it’s lutetium, whether it’s any of these agents that we’re describing, are the ones — is the provider that feels most comfortable. And it’s not necessarily disease specific, it is — as you know, it is a multidisciplinary approach. There are some urologists that are very comfortable and there are some that are not. And I think the bottom line is that whoever is most comfortable, is willing to manage the side effect profiles. I’m biased, obviously, because these patients obviously have been sitting in the urology practices for years. They enjoy that relationship. They want to maintain that relationship. But again, it’s whosever the most comfortable, but it should be overall a multidisciplinary approach.

DR ANTONARAKIS: Great. And with that we’ll move into Module 4 to stay on time here.

Current and Future Integration of PARP Inhibitors in the Management of Prostate Cancer — Fred Saad, MD

DR ANTONARAKIS: So the polling question. “Regulatory and reimbursement issues aside, which of the following patients with prostate cancer and no relevant family history should undergo germline testing?”

So most people thought that there were multiple indications for germline testing, and we’ll review those with Fred.

Okay, now we’ll hear the case of a germline-mutated patient.

DR LOVE: The next topic from our real-world treatment team was the emerging and very exciting data on the use of PARP inhibitors in prostate cancer, particularly the recently presented PROpel and MAGNITUDE trials. And I asked Dr Hafron what he believes urologists are most interested in knowing about these fascinating agents.

DR HAFRON: I think where urologists struggle is when is it appropriate to order germline testing. When should the urologist order somatic or next-gen sequencing? And then on top of that, when would they consider blood-based somatic testing in the circulating tumor cells?

DR LOVE: Any questions about the use of PARP inhibitors?

DR HAFRON: We have 2 approved PARPs in advanced prostate cancer. How do you decide which PARP to use in a patient? Do you choose the PARP based on the side effect profile? How do you follow a patient on a PARP? What do you recommend is the appropriate laboratory testing? How frequently, when we’re starting a PARP, should you be checking a CBC? Also, when you start a patient on a PARP one of the significant side effect is nausea. Do you routinely prescribe an antinausea medication with the PARP prescription?

DR ANTONARAKIS: So I think I counted 8 questions there. We’re not going to be able to address all of them. But first I’ll just ask one to Fred. Let’s just focus on the germline genetic testing component. Which patients with localized prostate cancer are eligible for germline testing?

DR SAAD: So I think that’s — in the ideal world we should be testing everybody, but it’s going to be impossible in the near future to be in the ideal world. But obviously a patient with localized high-risk disease, especially if they’re young, especially. And we have to think as urologists, family history is critically important. Personal and family history is extremely informative, and not just focusing on prostate cancer and not even just on breast cancer.

So I think, bottom line, germline testing, if accessible, should be done in patients with high-risk localized disease, and the other aspects that people voted on are clearly indications for thinking of germline.

DR ANTONARAKIS: And then Raoul, I’m going to pick on you again, my friend. If a patient has had germline testing, and the germline testing is negative, and then they subsequently develop metastatic disease, M1 disease, is there still a role for somatic testing, or can you forget about it because the germline was negative?

DR CONCEPCION: Clearly there’s a role. Clearly there’s a role for somatic testing, and obviously the question is what is the platform that you’re going to use. Again, I think — as we all know, the data suggests that only about 12% to 13% of lethal prostate cancer has a hereditary component. So obviously a lot of these high-risk patients who have progressed obviously because of — as we move into precision medicine, as Fred will address, obviously the utilization of PARP inhibitors, the mechanisms, how they work, somatic testing clearly is indicated. And again, I think to Jason’s comment, is what is the role of cell-free DNA, circulating tumor DNA, versus, as we discussed earlier, pre, is the role of metastatic biopsies. But clearly somatic testing, especially because it — because some of the mutations are clearly actionable.

DR ANTONARAKIS: And then I have 1 last question for Matthew. There were a lot of comments there about the side effect profile of PARP inhibitors. In your practice, what do you think are the 2 or 3 most common, and how do you counteract them?

DR SMITH: Nausea and hematologic toxicities. Most patients with nausea do not require antiemetics, but in selected patients they do. Sometimes it requires dose reduction. And then we’re going to be doing CBC a couple weeks after starting and then monthly, at least early on. And again, some patients will require either treatment interruptions or dose reductions. The way you’re going to help patients is to keep them on therapy for long periods of time, so you really — if you’re going to prescribe these drugs you have to be prepared to manage the side effects.

DR ANTONARAKIS: And then perhaps 1 question about, also for you, Matthew, choosing between olaparib versus rucaparib. Let’s make it easy, a BRCA2 germline patient who has metastatic CRPC, how would you choose between the 2? What’s your preference?

DR SMITH: I have to be careful how I say this, but the label for olaparib is broader. The evidence supporting olaparib, I’d say, is greater, probably because it’s just been more extensively studied. The safety between the 2 drugs is remarkably similar. In our practice, currently, we have the need for 1 PARP inhibitor, and we use olaparib.

DR ANTONARAKIS: Okay. Let’s move onto the next case. So “Regulatory and reimbursement issues aside, for which with mPRPC who are about to begin secondary hormonal therapy would you generally add a PARP inhibitor as well?”

So most people said germline BRCA or somatic BRCA. So basically any BRCA. Okay.

Let’s hear Dr Morris.

DR LOVE: The last case is another patient of Dr Morris, a 73-year-old man with progressive metastatic disease after receiving more than 5 years of abiraterone plus ADT. In spite of the lack of family history, at that point he had germline testing, which revealed a BRCA2 germline mutation.

DR MORRIS: As part of the guidelines changes he underwent germline testing, was found to be BRCA2 positive. We just found that information after he’d been on years of therapy. He then went on and had a great response to abiraterone for years before he started to have a PSA rise and now squarely fits in the label for what would be considered PARP inhibitor monotherapy.

I guess the questions for the panelists is number 1, I’d like them to comment on some of the combination studies with PARP inhibitors coupled with AR therapy looking at kind of first-line metastatic CRPC in all comers or in the HR-select population. And so if I’d had this information 5 years ago when he was BRCA2 positive, and I had just started abiraterone, is he the ideal patient that I should have considered adding in a PARP inhibitor? And then you look at he had a 5-year disease response to abiraterone. How much toxicity would I have added for what potential benefit?

I’d like the panelists to at least comment on their ideal candidate for a PARP inhibitor. Do they cast a wide net and see if it works and be quick to pull the trigger and withdraw the PARP if it’s not tolerated? Or do they really just try to push through only just the BRCA2 patients in particular?

And then in terms of combination treatment, is it worth added toxicity? Are they going to consider it in all comers? Are they going to try to focus it mainly on those who have some attributable mutation?

DR ANTONARAKIS: Okay, so a lot of questions in there. So just to recap, this was a germline BRCA2 carrier who received ADT plus abi, had a 5-year response, if I heard correctly, and then had a progression. So I’m going to ask Matthew the first question, which is going to be the easy one, and then I’m going to ask Fred the hard one.

So Matthew, let’s say this patient had only received ADT, which you have clearly stated was not adequate therapy. He now has progressed to first-line mPRPC, you know he has a germline BRCA mutation. Would you use combination therapy, assuming it’s FDA approved, with abiraterone and olaparib or sequential?

DR SMITH: This is a patient I would use the combination. I’m compelled by the data from the randomized trial, particularly in the BRCA-mutant patients. This is a patient who should receive a PARP inhibitor, whether in combination or as monotherapy, so why not just give them at the same time given the strength of the data from the randomized trial that you’re going to hear about in a moment.

This case is also fascinating because he did — it does send another message, which is a BRCA mutation doesn’t preclude response to an AR pathway inhibitor, as was illustrated in this case.

DR ANTONARAKIS: Yes. In fact, we had a study that we published when I was at Hopkins where we showed that the patients with BRCA2 and ATM mutations in our study had a longer response to ADT and greater time to castration resistance than the non-BRCA, which I think is a bit counterintuitive and has been refuted by other groups. But there’s some data these patients can respond for a long time.

Now I’m going to ask Fred this slightly unfair question, which is okay, this patient did receive ADT plus abiraterone, that was the decision his oncologist — his urologist made. Now they’ve progressed. They have mPRPC, and they have a known germline mutation. Would you switch to olaparib, or would you continue abiraterone and add olaparib?

DR SAAD: I base my decisions on where the evidence lies, and the evidence lies right now to switch. Even though it would have been nice to continue some patients on the AR pathway inhibitor and add on, but we just don’t have that data. So for now I would stop the abiraterone and go to the olaparib and then already start planning the next line of therapy. But some of these patients that go straight from AR pathway inhibitor to olaparib, we’ve had patients in complete response for 2 years. So this is really an opportunity where we’ll discuss a little bit where I would go straight to a PARP inhibitor rather than expose to a chemotherapy and leave the PARP inhibitor for third line.

DR ANTONARAKIS: Yeah. I would definitely agree with that. But let’s be reminded, this was a patient with a 5-year response to abi. Let’s say he had been on abi plus olaparib, he may have been on the combination for 7 1/2, 8 years. What have you seen as the cumulative toxicities of the combo, especially when patients have been on it for many 1, 2 or more years?

DR SAAD: So we’re still looking at it, and the cumulative toxicity is amazingly good in the first-line setting. It’s totally different than the third and fourth line that many of our clinical trials were on, where the bone marrow is pretty much beat up. But 5-year response on abi in a BRCA patient, the median in the trials, in both trials, was under 14 months of rPFS, not only PSA. So that is an exceptional response in a BRCA-mutated patient.

DR ANTONARAKIS: Yeah. Thanks for that reminder. Well, I think we can try to stay on time here, and I’m sure we’ll have many questions coming in through the chat. So Fred, why don’t you give us your remarks as well.

DR SAAD: So I’ll be very brief, in 10 minutes, to go over some of the current and future integration of PARP inhibitors in prostate cancer. And this is very much like the radioligands, an explosion of data and trials in this area. What I think we need to remind, and I think everybody knows, is metastatic prostate cancer is heterogeneous and why its heterogeneous and how resistance mechanisms sit in are multilayered. But importantly for this topic about a quarter of the mutations are really associated to DNA repair pathways that are relevant to our patients.

And so obviously when patients reach the mCRPC state we are enriched in patients with these mutations compared to patients that we diagnose initially with prostate cancer. And as we mentioned, at least in advanced metastatic CRPC, about 1 in 10 harbor a germline mutation. But if we stop there we would miss about half the patients with an HRR mutation if we limited ourselves to only germline mutations. And this is why we repeatedly come back to the somatic mutation testing.

And why is this important? And this was alluded to. The patients that harbor these mutations, especially BRCA2 mutations, have poorer outcomes in general. So their survivals for patients with mCRPC are in general, there are always exceptions, about half the survival of noncarriers. So in noncarriers the survivals are in the range of 3 years, like we would expect, but down to about 17, 18 months in carriers of BRCA2 mutations. And how quickly they progress on our standard of care therapies are clearly related to whether or not they harbor these mutations.

So as I said, I mean this is probably one of the areas where there’s the most amount of research and trials and new drugs coming in ever since the first report that maybe there is a role for PARP inhibition in prostate cancer, and already we have FDA approvals of olaparib and rucaparib in the States and olaparib around the world.

So this is one of the first, if not the first study, published looking at patients responding to olaparib that have biomarker-positive disease compared to biomarker-negative disease in patients heavily pretreated for mPRPC.

And since then Matthew led the GALAHAD study with niraparib monotherapy looking at patients with HRR mutations. This is a monotherapy study in patients who are at least in the third-line setting. They had to fail a taxane and an AHT, and you see the responses are quite good. Unfortunately, the colors didn’t show up the way they should, but the patients for BRCA versus non-BRCA disease clearly had an advantage in terms of measurable response and PSA response and radiographic progression response.

TALAPRO-1 was also recently reported with talazoparib as a monotherapy. Again, similar patient profiles and again the BRCA patients appeared to be getting the most benefit, although there are signals of benefit in other HRR mutations in these heavily pretreated patients.

TRITON2 with rucaparib monotherapy, again limited to patients with BRCA1 or BRCA2 mutations, again in the third-line setting. And this one of the differentiating factors between rucaparib FDA approval, it’s limited to patients who are at least in the third-line setting, where olaparib allows in the second line after ARPI inhibitor with or without docetaxel. And here, clearly, very impressive responses in terms of measurable response, PSA response, and radiographic progression-free survival. We don’t have a control arm, but these survivals compared to what we would have expected were quite impressive.

So the first Phase III randomized control trial of a PARP inhibitor is the PROfound study that I think everybody’s heard quite extensively about. And just to highlight a couple of points, these patients had had to fail at least 1 but could have had 2 prior NHAs, which is quite routine here in the States, and they could have had docetaxel, and they had to have at least 1 HRR mutation detectable on tissue. And this is important, and I won’t go into the details, but over 4,000 patients had to be screened to get about 400 patients into the study to be able to get — and these are the issues that we deal with in terms of tissue testing.

So main endpoint of the study was Cohort A looking at BRCA1/2 or ATM mutations. And the way it was done was there was a 2:1 randomization of olaparib versus the physician choice NHA. And what made this study ethically acceptable was that there was allowed to be a crossover when patients progressed on the physician-choice novel hormonal agent. And so clearly 66% reduction in the risk of progression or death with patients who started on olaparib versus those who started on the other NHA, and in terms of measurable response, very different measurable responses.

And this is some of the first prospective studies clearly addressing these issues in what happens when we go from NHA to NHA, which was part of the earlier discussions. And you see that less than 4 months to progression, to radiographic progression. This is going beyond simply PSA progression.

And if we look at patients in terms of overall survival in Cohort A there was a 31% reduction in the risk of death, and this is even though patients were allowed to crossover. So at least some indication that earlier appears to be better in terms of overall survival. If you delay the introduction of a PARP inhibitor in somebody who needs it you might be reducing the opportunity for further prolongation of life.

And so a mathematical evaluation of adjusting for crossover allowed us to calculate that if patients were not allowed to cross over there might have been a 58% reduction in the risk of death in patients on olaparib versus not. And these numbers are quite impressive. We’re in the range, even though we’re — in very aggressive patients, in the range of 4, 4 1/2 months improvement in overall survival as a primary endpoint.

I just wanted to at least deal with one of the topics that we did address, going from NHA to NHA. And this has been an interest of mine, and this study is to look at these NHA to NHA, and this is obviously in patients with HRR mutations. But if we look at patients who went from abi to enza or enza to abi, and this I reported at last year’s AUA, you look at the differences in rPFS, it’s a question of days. So taking a patient that you know has an HRR mutation and exposing them to a subsequent NHA, really you cannot expect any — regardless of which order, and with all the respect I have for Kim’s trial, which looked at an overall group and basing it on PSA, here we’re talking about days of difference, where the big difference is going straight to a PARP inhibitor.

And in terms of survival, we’re again talking about days of difference with survival, compared to going from about 14 1/2 months to over 19 months survival by going to the PARP inhibitor as early as possible. And again, this is even though patients did cross over, so really limited benefit of NHA to NHA.

In terms of tolerability, as was mentioned, anemia and nausea are the 2 most common adverse events. Fortunately the Grade 3/4 adverse events in terms of anemia were in the range of 23% in olaparib, but you see that anemia occurs even with an NHA. These patients are heavily pretreated in many of these situations, and these are manageable adverse events and occur relatively early in the use of PARP inhibitors. Again, nausea, the vast majority are Grade 1 or 2 nausea, not Grade 3/4. And we have to remember that we’re taking these adverse events even though patients were on olaparib almost twice as long as they were on the control arm.

In terms of quality of life, pain progression, there was an advantage to olaparib in this study. So even though there are adverse event risks in terms of quality of life there looks to be an advantage.

So just very quickly in terms of earlier introduction, the issues of combination therapies and whether all comer. So this is the rationale why we should consider the combination of PARP inhibitor and an NHA, is that there seems to be maybe a possibility of synergistic effects of a PARP inhibitor on the androgen receptor and an NHA inducing an HRR deficient kind of environment leading to more effective PARP inhibition.

And a Phase II trial actually showed that it looked like patients were getting benefit regardless of whether they harbored mutations or not. And this was published a couple of years ago in Lancet Oncology.

So this was the rationale behind 2 studies, and while PROpel is the study that really targeted the all-comer population using olaparib at full dose and abiraterone at full dose compared to placebo and abiraterone at full dose. And we just — I just want to mention that there is not a single Phase III study in mPRPC where there has been an effective life-prolonging control arm. Every one of the trials is either a placebo or a switch, something that is not proven to — so this is really a control arm that is far from being an inactive control in an all-comer population.

Primary endpoint rPFS because it’s an 800-patient study. Obviously multiple secondary endpoints. Bottom line, combining PARP inhibitor like olaparib with abiraterone led to significant improvement in rPFS. It went 16 months, the expected rPFS for abiraterone alone, up to 24 months based on investigator assessment and 11-month improvement based on independent central review.

And what is interesting is that in the study we found that 28% of patients harbored mutations, HRR mutations. And when we looked at the subgroups that benefitted in terms of rPFS you see that all the subgroups appeared to benefit from the combination over abiraterone alone, and that included patients with visceral metastases pretreated with docetaxel for hormone-sensitive disease, and whether or not they harbored a mutation. And all the other secondary endpoints point to the direction we hoped, still too early for survival results at this stage.

In terms of adverse events, very manageable, 15% Grade 3 anemia. All the rest were quite low.

MAGNITUDE, very similar design, but here the target was really looking at the biomarker-positive patients. So patients were screened with a panel prior to coming in and then put into the arms whether they were biomarker positive or negative. And in this study the biomarker-negative group was stopped early because it looked like there was going to be no advantage to treating these patients. However, the BRCA-mutated patients clearly had a clear improvement in RPFS, as well as the biomarker-positive group overall. And overall there seemed to be an advantage of the combination in almost every subgroup compared to the abiraterone alone.

Again, no toxicity profile that looked like it was worsened by the combination over each drug taken individually. Slightly more anemia and thrombocytopenia with niraparib, which was already known.

So the field is continuing to expand. There are multiple trials looking at PARP inhibition in earlier settings, even in hormone-sensitive disease, limiting it to patients with HRR mutations with talazoparib and with niraparib.

And so to conclude this whirlwind talk; so mPRPC patients are still living less than 3 years even with the best available treatments when we go with a sequential approach. And so we really need to do better in mPRPC in the first-line approach and do the very best we can because many patients will not go to second line. A significant proportion of patients who will die harbor mutations, so we need to improve progression and overall survival, but we especially need to identify these patients as early as possible because it’s critically important if we hope to improve their outcomes. And the future is probably going to be earlier introduction of PARP inhibition and possibly even going beyond patients with mutations with a combination approach.

Thank you very much.

DR ANTONARAKIS: Thank you, Fred. We’ve received about 10 questions. We have about 4 minutes. But one of them was from Neil, and since he’s my boss I have to do his question first. And this is a tough one. I might ask you, Fred, to try to answer this. “Assuming that both the combination of abiraterone and olaparib, as well as abiraterone and niraparib, are approved for a BRCA2 patient, which one would you use?”

DR SAAD: Well, that’s a pretty direct question. I would probably favor the olaparib. I think the adverse event profile, the fact that we can give the full-dose olaparib, I think, has a certain advantage. And we’re going to report at ESMO the results with the BRCA-specific mutations. They’re outstanding.

DR ANTONARAKIS: Well, I’d like to thank you for pointing out the dosing issue because many people may not have noticed that. So when abiraterone was combined with olaparib both agents could be given at their full dose, whereas in the niraparib/abiraterone combination the niraparib had to be reduced by 33%, from 300 mg to 200 mg, and even with that dose reduction the thrombocytopenia was quite significant. So I would agree with you that if your priority is maintaining the full doses — the full monotherapy doses of both agents, then the olaparib/abi combination might be better.

DR SAAD: But having said that, for the BRCA2 population especially, the 2 are extremely effective. It’s what we do with the non-BRCA-mutated patients or patients without mutations at all.

DR ANTONARAKIS: And then a question for Matthew from the audience. “If you have a patient with a BRCA2 mutation, and he has not received a PARP inhibitor or a PSMA radioligand therapy, which one would you use first?”

DR SMITH: Yeah, so I’d say PARP inhibitor — I mean it’s kind of the easy way out because it’s actually approved as an earlier line of therapy, right, so approved right after an AR pathway inhibitor and prior to chemotherapy if you chose olaparib as monotherapy for example. Whereas currently PSMA radioligand therapy would require prior chemotherapy. So that — but having said that I still would do it that way even if — even if the patient received an AR pathway inhibitor and docetaxel.

There will be future studies looking at the combination, as well, but it’ll take many years to have the results of such trials.

DR ANTONARAKIS: Question for Raoul. “In an mPRPC patient with a germline CHEK2 mutation could you use a PARP inhibitor and would you?”

DR CONCEPCION: I think you probably could. Obviously that was the cohort where they split out the cohorts as B1, B2, ATM, and then they looked at all the others. And I think that clearly the mechanism of action, how PARPs work in relation to homologous recombination mutations would suggest that you still could use in a CHEK2 mutation. But you probably, as we’ve discussed, B2 generally drives the day in a lot of these patients.

I think the other point that kind of goes missed here as we — is really for the audience is testing. And I think we have to test. I agree with Fred. I think every newly diagnosed prostate cancer patient should get germline testing. I think we should go the way of the breast cancer people. But I think also as these patients progress we should also understand yes we should do testing for homologous recombination mutations, but we also should look for mismatch repair because in a certain small percentage of the population you can use a checkpoint inhibitor, and patients will respond. So again, it’s not just looking for PARPs, but again, in some cases you can use immunotherapy.

DR ANTONARAKIS: Last question before we close. I’ll ask Matthew this one, and it’s about ATM mutations. “In a patient with an ATM mutation mPRPC who has not yet received chemotherapy would you use olaparib next or wait until after docetaxel?”

DR SMITH: I’d give docetaxel next. I think the evidence for responses with an ATM mutation is modest at best, more controversial. And I’ll just close by saying the response assessment with PARP inhibitors is more challenging than with AR pathway inhibitors, so you don’t see these — often don’t see these big PSA declines, and so it requires a lot more patience in keeping patients on treatment until confirmed radiographic progression.

DR ANTONARAKIS: So with that I’d like to thank the panelists, thank the audience for coming here this morning, and if you’re sticking around please check out Monty Pal and the urothelial bladder cancer session tonight at 6 pm. Thanks very much.