Introduction

DR ARMSTRONG: Good evening. Welcome to “What Clinicians Want to Know: Addressing Current Questions and Controversies in the Management of Prostate Cancer.” Due to unforeseen circumstances, Dr Neil Love will not be with us tonight. I’m fortunate enough to be the moderator in his stead. He wanted you to know that he’s sorry that he couldn’t be here.

I’m here — Dr Andrew Armstrong from Duke University. I’m here on behalf of an esteemed panel of experts. Here they are. Dr Tanya Dorff from City of Hope in Los Angeles, Dr Matthew Smith from Mass General Cancer Center in Boston, Massachusetts. We have Neeraj Agarwal from the Huntsman Cancer Institute in Salt Lake City. And of course, Dr Antonarakis from the University of Minnesota, today not wearing his turtleneck, which you all have known to love him dearly with that.

Our disclosures are all been displayed right before this session. We’ll go over those very quickly. We would like to thank commercial and educational grants from AstraZeneca, Bayer, Janssen, administered by Janssen Scientific Affairs, and Merck for their generous CME support of this program. Research To Practice CME Planning Committee members, staff and reviewers are all here to make sure that this program is both educational and entertaining. Planners, scientific and staff have put in tremendous amount of work to make this a really successful program with some amazing faculty. This is an educational activity. It contains discussion of emerging uses, non-FDA approved uses of agents and regimens. Please refer to the official prescribing information for the use of these approved indications.

I want to point out that Research To Practice is a very busy CME group. Just at ASCO, we have 9 programs that cover liver, lung cancer, ADCs, prostate cancer tonight, myeloma tomorrow morning first thing, ovarian and endometrial cancer, colorectal, metastatic breast cancer, and lymphoma. So a very active meeting here at ASCO to bring you up to date on all your CME needs. Tonight, we’ll be focused on prostate cancer.

Here’s some more details for the CME, both live webcast and online programs for you.

So here’s our program tonight. Again, we have about 2 hours to cover almost everything that’s impactful right now in advanced prostate cancer. We have — Neil has recruited a number of practicing oncologists from all over the country who have brought real-world cases and challenging discussions to our esteemed faculty who will challenge them to go outside of necessarily the clinical evidence and explore how they really practice. We have representation from Kentucky, Florida, California, St George, Utah, Miami, New Jersey, Illinois. And here’s our modules. So we’re going to be very comprehensive. We’re going to start with hormone-sensitive disease in the non-metastatic setting, Dr Dorff’s going to kick us off with this. Dr Smith is going to cover metastatic hormone-sensitive prostate cancer. Dr Agarwal will talk about the emerging and newly approved PARP inhibitors and PARP/AR combos in castration-resistant disease. I’ll be talking about novel radiopharmaceuticals in castration-resistant prostate cancer, and Dr Antonarakis will finish our evening with what’s new on the horizon for men with advanced castration-resistant prostate cancer.

Optimizing the Management of Nonmetastatic Prostate Cancer — Dr Dorff

DR ARMSTRONG: So we’re going to turn to Dr Dorff for Module 1, and we’re going to start — each module is going to start with a community-based oncologist posing a real-world question just from the last few weeks in their practice. So Dr Kimberly Ku will start us off.

DR LOVE: Good evening, everyone. I’m Neil Love from Research To Practice, this year participating in ASCO virtually. Over the last few weeks, I met with 10 general medical oncologists in community-based practice to help develop the plan for this program, and also to provide some questions and cases for the faculty on the stage to consider, beginning with 1 of the most important trends, the intensification of hormonal therapy and management of localized disease.

DR KU: I have had several patients in this very high-risk localized prostate cancer space, and we do talk about the usage of abiraterone in addition to ADT and having the abiraterone extend to about 2 years. There is also I believe a trial where it looks at using a Decipher score to further risk stratify whether someone really needs that second generation AR, or if maybe even they do a different duration of the ADT, or if maybe the radiation itself is a little bit different. But when I do have those conversations with patients, I think a lot of them tend to think that the second-generation AR antagonist is something they’re willing to do to go for a more definitive strategy.

DR ARMSTRONG: Alright, well, that was an important question to start with nonmetastatic localized or high-risk and very high-risk prostate cancer. So Dr Dorff, she brought up this important question of, who needs a potent AR inhibitor to enhance their chance of cure when they’re getting ADT and radiation for non-metastatic hormone-sensitive prostate cancer? What’s your brief approach to that and are you using the Decipher score? And maybe briefly mention the NRG trials testing that.

DR DORFF: Yeah. So the STAMPEDE trial included localized prostate cancer that was very high risk, and so that gives us some justification to use intensification, using abiraterone for 2 years as the physician mentioned. But probably not everyone needs it. And so the NRG trials, which are using Decipher to put even higher risk sort of patients into an intensification randomization adding an AR-targeted agent and then the lower risk to try to de-intensify the duration instead of 2 years to use 1 year of hormone therapy. This is a really important trial and may give us the first sort of precision medicine way of approaching these patients. So it’s a complex discussion. You look at comorbidities as well as the cancer characteristics.

DR ARMSTRONG: We’ll move down the road to Dr Smith. How do you define high-risk? Is it purely clinical, or also genomic?

DR SMITH: For the most part at the present time, it’s based on clinical and pathologic features, not genomic scores. But that’s coming soon. The data I find compelling in a variety of settings. I look forward to the NRG data. But Gerhardt Attard has beautiful data, like looking at this, that consistently shows that Decipher appears to be predictive or may be predictive. So I’m hopeful about that. And I too use like the STAMPEDE basically, criteria, which are very high-risk and regional risk, so it’s not for everybody. I mean a more typical patient with just NCCN high-risk disease actually has a very good clinical outcome with standard treatment. So I’m looking at it more for patients who would be NCCN very high-risk or regional risk.

DR ARMSTRONG: And Dr Agarwal, are you always using abi or for a patient where abi may be contraindicated, do you feel comfortable swapping out whatever ARPI you wish?

DR AGARWAL: Great question. I stick to the definition of the STAMPEDE trial, T3, T4, and the PSA level of 40 nanogram per mL or more or Gleason score 8 or plus. And I stick to abiraterone. And if patients cannot tolerate abiraterone, I have used enzalutamide or apalutamide in those patients who had PSMA positivity. And we can just keep discussing about this. It’s such a nuanced area. But I have switched therapy from abiraterone to 1 of the other AR inhibitors, but reimbursement has been a problem if they do not have metastatic disease.

DR ARMSTRONG: We’re going to go to some additional questions from Dr Spencer Bachow — I’m not sure I pronounced that right — from Boca Raton, Florida.

DR LOVE: Another critical and much discussed issue after the EMBARK trial presentation last year has been the management of patients with high-risk M0 disease, and in particular the use of intensified therapy with ADT plus androgen receptor inhibitors, and the potential consideration of the use of androgen receptor inhibitors alone.

DR BACHOW: I have a 72-year-old man who has a history of Gleason 7 adenocarcinoma of the prostate who had a prostatectomy. He now has a rising PSA, his Gallium-68 PSMA PET scan showed no evidence of metastatic disease. How do you choose among androgen deprivation therapy alone or enzalutamide monotherapy, or enzalutamide plus leuprolide based on recent clinical trial data? Are you giving patients treatment holidays, kind of like what we do with intermittent androgen deprivation therapy? Do people ever do intermittent enzalutamide monotherapy? We are about to start treating this patient. He elected, after going over everything, we are starting enzalutamide monotherapy.

DR LOVE: What about the patients on ADT for M0 disease who have disease progression but still remain M0?

DR BACHOW: I have an 82-year-old man with M0 castrate-resistant prostate cancer. He’s otherwise very healthy. There are multiple agents that are approved in combination with androgen deprivation therapy, including apalutamide, enzalutamide and darolutamide. How do you choose your agents, assuming that insurance will cover all 3 drugs and there’s not a high out of pocket cost? Do you like 1 better than the other, or is it strictly based on side effects? This patient is now on darolutamide.

DR KU: I would like to know what most physicians treating prostate cancer, what kind of second generation AR they prefer? There’s some affinity for darolutamide because it seems pretty tolerable and it has the preclinical data about CNS penetration being a little bit less toxic for patients. As a generalist, it’s important to see where we think that there are differences or if maybe there are some nuances where we need to be aware for certain patients.

DR ARMSTRONG: So Dr Antonarakis, before I get to the questions about EMBARK, you know, you’ve got a rising PSA post radical prostatectomy. What was not mentioned there at all was the context, the doubling time, the level of PSA, salvage radiation. Could you briefly talk about your approach in that circumstance?

DR ANTONARAKIS: Yeah. So the last thing we want to do is have an infatuation for EMBARK, that we’re reaching for enzalutamide, or ADT plus enzalutamide, without considering this patient as described is curable. And he’s only curable with salvage radiotherapy with or without a short course of ADT, in that context without any other ARPI. So that’s a teaching point for some of the fellows and trainees in the audience.

But let’s assume that he had also received salvage radiotherapy and had a subsequent rising PSA. The EMBARK study was high-risk patients defined as a PSA doubling time less than 9 months, but half of patients with BCR have a slower than that doubling time. So if you have a doubling time of 2 years, or 18 months, the natural history of those patients is very prolonged. The time to metastasis is 10 years or more. So we’re really talking about the 40% or 50% of patients who have exhausted their curative intent therapies and still have a recurrence with a PSA above 1 and doubling time less than 9 months.

DR ARMSTRONG: Let me go back to you. Is there a PSA level above which you would consider salvage radiotherapy to be futile?

DR ANTONARAKIS: Well, the data so far suggests that the higher the PSA, the worse. When you and I were in our fellowship Andy, you were a few years ahead of me, we used to say 0.5 or less was the sweet spot. Now we have evidence that 0.2 or less the chance of cure with salvage RT is higher. And I think many people on this panel would agree that the best time to offer salvage radiotherapy is with the first PSA that is either detectable or rises above 0, preferably before it goes to 0.20.

DR ARMSTRONG: So Dr Dorff, sometimes when I see patients in clinic and their PSA is rising and they’re debating with us whether to do salvage radiation, they’ve gotten a PSMA PET scan and it’s normal, which is a very common scenario. And sometimes they’re incredulous when I tell them that salvage radiation might still cure them, yet you see nothing. Could you explain that perhaps to the audience of how we can cure patients when you can’t see disease on a PET scan?

DR DORFF: Yeah I face that situation every day in clinic. And I tell patients, for decades we didn’t have the PET scan, and we radiated the most likely place where the residual or recurrent cancer cells are, and we cured the majority of people. So even with a negative PET scan, we still have some idea of where to target the beams. If it’s positive, then we can use that in our treatment planning and do a better job with our salvage radiation. But, I think most patients can wrap their head around that, especially if you cross apply other tumor types, like a breast cancer patient who gets lumpectomy and then radiation. Like there might be stuff in that area you want to sterilize the field.

DR ARMSTRONG: Dr Smith, do you agree that the PET scan doesn’t tell you the whole truth?

DR SMITH: Absolutely agree. First, there’s a small proportion of patients who are truly PSMA PET negative. But the PSMA PET’s been transformational. And the scenario that you’re describing is because now we’re now doing it at very low PSA. So I think the pearl I have is you advise the patient that the most likely outcome is we’ll find nothing.

DR ARMSTRONG: Right.

DR SMITH: And the reason we’re doing it is that if we do it could alter their therapy.

DR ARMSTRONG: So that you don’t someday see something. You know, if you’re cured it will never re-emerge. Your PSA will go to 0 and it’ll stay 0.

So Dr Agarwal, we have a few more minutes before we get to Dr Dorff. She’ll be discussing the EMBARK trial in great detail. But how have those findings changed your practice today?

DR AGARWAL: I like to, just I like to remind myself that EMBARK trial only allowed intermittent therapy once. So when patients had a PSA decline of less than, undetectable PSA, less than 0.2, they were able to allow to take a break. But when it returned, the PSA again went up. They were continued on enzalutamide or enzalutamide plus ADT. So I keep that in mind when I’m thinking about patients who may be candidate for enzalutamide. And I stick to the definition, like Dr Antonarakis mentioned. Patients who have a PSA doubling time of less than 9 months, I offer them enzalutamide or enzalutamide plus ADT. The question is, what do I do with patients who do not have PSMA PET scan positivity? We discussed about lower PSA threshold. Where should we give radiation therapy, 0.2, 0.5? But what if our patients with a PSA of say 4 nanogram per mL, just for the sake of discussion, and PSMA PET scan is negative? Should we rule out curative intent radiation therapy for those patients? And the answer is, I do not know.

DR ARMSTRONG: Right. Dr Antonarakis, before we get to Dr Dorff’s talk, you know we’re often doing PSMA PETs in this high-risk patient population. I think the EMBARK patient population’s predicted to be 80% positive on a PSMA PET. So we have good data from ORIOLE and STOMP and many of the metastasis-directed trials showing there is at least short term benefits to metastasis-directed therapy to avoid hormones. Do you ever mash up the approaches of metastasis-directed therapy and systemic therapy to allow that break to be perhaps longer?

DR ANTONARAKIS: We’ve all done that and it’s the art of medicine rather than the science. The 2 trials that you mentioned, their intention was to use some form of metastasis-directed radiotherapy to delay the start of ADT. So perhaps a treatment-free interval, which by the way, is a worthy goal. Patients do not particularly enjoy being on ADT. We heard a lot about quality of life today from PRESTO and EMBARK at the oral prostate session.

DR ARMSTRONG: Awesome. Great. So Dr Dorff, I’m going to turn this over to you so you can talk about EMBARK and PRESTO. And thanks for presenting tonight.

DR DORFF: Thank you all for spending your Saturday evening with us. I hope that it’ll be an engaging session. I’ll be covering EMBARK as well as comparing and contrasting that with PRESTO, and then just briefly touching on some updates from the non-metastatic CRPC trials as well as what’s ongoing.

But as we’ve just been discussing, the first thing we have to do is take into account the patient’s context and not forget that salvage radiation is our only curative modality for rising PSA after surgery. But we have to look at the patient’s comorbidities and life expectancy as well as how aggressive their prostate cancer is. What’s that PSA doubling time? What was the Gleason? And eventually, we’ll incorporate hopefully newer technologies, like Decipher and ArteraAI, in helping us choose the patients who really need treatment so we avoid overtreating.

So Neal Shore has this very nice graphic that kind of looks at the different options in the pre-radiation and postradiation setting.

So EMBARK and PRESTO were both for biochemically recurrent prostate cancer, but they were different trials. EMBARK allowed definitive radiation or prostatectomy whereas PRESTO was 100% post-prostatectomy. They both required high-risk features such as a PSA doubling time less than or equal to 9 months. And they both had 3 arms, but the 3 arms were different. EMBARK had LHRH alone, with placebo rather, versus LHRH with enzalutamide, and then the third arm was open-label monotherapy with enzalutamide, whereas PRESTO was single, double, triple. And initially they required degarelix, but then later on in the trial they allowed the other LHRH agonist to be used. So it was LHRH alone or with apalutamide, or with apalutamide and abiraterone. On EMBARK, as we heard, you could stop at 36 weeks if your PSA was less than 0.2. On PRESTO, you got a year of treatment and everyone stopped regardless. You can see there was a higher median PSA on EMBARK. And the primary endpoint is probably the most significant difference. So metastasis-free survival is an endpoint that correlates with overall survival. It’s an FDA approvable endpoint which is why the EMBARK trial has made more impact on practice. You can see that it was improved from 71% with monotherapy LHRH to 87% with doublet using enzalutamide.

PRESTO used PSA progression-free survival which is not as strong an endpoint. And so although the hazard ratio was strong and there was a 5 month improvement in time to PSA recurrence between the doublet and triplet versus the monotherapy, it has not been as clinically impactful.

So also very important to note, EMBARK used conventional imaging, right, CT and bone scan for that metastasis-free survival endpoint. So we have no idea what we would do with PSMA PET data. And as Dr Armstrong mentioned, probably most of these patients would’ve had PSMA PET positivity.

So all of the secondary endpoints in EMBARK were also favoring doublet. If you look at the top forest plot across the board favors doublet. The 1 that didn’t was first deterioration to FACT-P and we did hear a lot about quality of life tonight. And it makes sense, 2 drugs are going to have more side effects than 1 most of the time and that’s what we see here. More surprising I think, if you look at the bottom, that’s comparing the enzalutamide monotherapy versus leuprolide. And again, the leuprolide monotherapy does a bit better in time to deterioration of quality of life. So a lot of people think that enzalutamide monotherapy is better quality of life, but this is kind of an interesting nugget from the trial.

In terms of success of PSA decline, 91% on the doublet got that treatment break after 36 weeks compared to 68% with the monotherapy LHRH and 86% enza. But what’s notable is those enza patients had the shortest time off treatment. So again, if you look at that bottom forest plot kind of floating in the middle, way to the right, the leuprolide alone patients actually had a longer time off treatment.

In terms of adverse events, they’re definitely different as well. Hot flashes are definitely less with enzalutamide monotherapy than either of the LHRH. But interestingly, fatigue is fairly similar whether you’re on enza monotherapy or the enza doublet. And then there’s of course much more breast symptomatology as a lot of people have been talking about.

Okay, so looking at PRESTO, PRESTO also compared everything to the LHRH monotherapy arm. A is the doublet. B is the triplet. You can see they’re not so different. They importantly had to look at testosterone recovery because that impacts PSA rising, and it was slightly longer with the triplet. And based on my own personal experience, there really were more side effects with the triplet therapy, so we’re really not finding that CYP17 and AR antagonists give us an advantage when used together.

Alright, so now briefly looking at nonmetastatic CRPC, these were the 3 big registrational trials, SPARTAN, PROSPER, and ARAMIS. Very similar designs, also high-risk in terms of doubling times of PSA less than 10 months, and you can see really strong hazard ratios favoring adding this AR pathway inhibitor with fairly low discontinuation rates suggesting it’s tolerable.

So what have we learned in the years since those trials all reported out? We saw some long-term updates from SPARTAN in terms of quality of life, showing a delay in time to deterioration because these patients have no symptoms from their cancer until the cancer progresses. And yet, we all found it very controversial during the oral abstracts today to say that patients have no decrement in quality of life. I think that’s indicating that the instruments maybe don’t truly capture the day-to-day experience of a patient and maybe we need even better quality of life instruments. But it is reassuring that we can tell our patients, generally speaking, they can live a good quality of life.

In terms of long-term safety, although there are very small numbers out at 2 and 4 years from the ARAMIS trial, it is reassuring to see we don’t have any new side effects popping up and you don’t see fatigue rates going up. So that’s nice to know that fatigue is not a cumulative exposure kind of toxicity.

But what we didn’t see are dexa data. Now fortunately, on the ARAMIS trial there was not really an increase in falls and fractures with darolutamide compared to placebo, but there was with apalutamide and enzalutamide. And so, it’s very important. These patients are on really intensive androgen suppression for a really long time. We must look at their bone density. We must offer support. And you can look at the slide later. On the right is a very nice summary of some of the different agents that can be used to support bone density.

From PROSPER, we recently saw a long-term analysis that looked at PSA nadir predicting outcomes. We see a similar trend emerging from all the metastatic hormone-sensitive trials. The 1 thing we don’t know or have is what do we do? We see the guy that doesn’t have a good PSA nadir. We know he’s not going to do well but we don’t yet know how to help him and raise that survival curve up.

Elephant in the room, PSMA PET. So we can do metastasis-directed therapy when we see it on a PSMA PET. And most of the trials like ORIOLE and STOMP have done it in the absence of ADT with a goal of delaying time to ADT, which may be some patients’ goals. However, as Bertrand Tombal pointed out this year at GU ASCO, there’s no known survival benefit for this, whereas, we have at least a metastasis-free survival benefit with intensified therapy doublet on the EMBARK trial. And so we shouldn’t always be rushing to this. There are lots of ongoing trials that are going to combine ADT with metastasis-directed therapy that will be very informative, including ARASTEP.

So I’ll end on this slide but just to say, this is a trial that actually looks at PSMA PET positive biochemically recurrent patients and it gives them either 2 years of ADT with placebo or with darolutamide and allows the physician and the patient to choose whether or not they get metastasis-directed therapy. They are stratified based on this. And hopefully we will learn a lot. This is going to be a large international Phase III study. There was a Trials in Progress poster from my colleague Alexander Chehrazi-Raffle this morning. If you didn’t see it you could look for it online and I encourage people to support these kinds of important trials.

DR ARMSTRONG: Thank you, Dr Dorff. There is a great audience question that I’d like to pose to you. It was, in a patient that’s PSMA PET negative and you’re considering salvage therapy, is there a role for ctDNA testing? I think the audience is becoming increasingly familiar with bladder cancer and colorectal cancer, MRD testing, and is there a role for liquid biopsy in this very early disease setting to guide therapy?

DR DORFF: I would say not yet. I would love it if there were. But first of all, we have trouble with sensitivity of our assays. In a low-volume patient we may not find enough ctDNA. And then we have that PSA that sort of tells us something’s there. So if you had a PSA that’s rising but a negative ctDNA, would you not treat that patient? I think — we’re not there yet. We need more data.

DR ARMSTRONG: I completely agree. The MRD assays are something that’s emerging, but the PSA in a way is a very good MRD assay already.

Evidence-Based Selection of Treatment for Metastatic Hormone-Sensitive Prostate Cancer — Dr Smith

DR ARMSTRONG: Alright, we’re on to metastatic hormone-sensitive prostate cancer. So we’re going to have questions from 3 different community-based physicians and cases on the integration of triplet or doublet therapy.

DR LOVE: The management of hormone-sensitive metastatic prostate cancer has evolved rapidly from the pandemic considerations of intensified ADT versus ADT plus docetaxel to a new position where intensified ADT is standard. And the challenging issue is who should receive an ARASENS-like approach of triplet treatment with chemotherapy?

DR GUPTA: 55-years-old male, he presented with severe back pain and he was noted to have widespread osseous metastases in his spine, retroperitoneal lymphadenopathy, and other disease, but not technically visceral disease I would say. And his pain just literally disappeared once he started on leuprolide right away, which is typically what we use to get them started. But eventually I put him on apalutamide as a combination with leuprolide, antiandrogen. But my question was, he’s such a young individual, there’s extensive disease although you wouldn’t qualify for visceral disease. Would this be an ideal candidate to give that triplet therapy which everyone has been talking about in combination with darolutamide and docetaxel?

DR LOVE: How’s he doing on the apalutamide?

DR GUPTA: Great. He’s symptom free. He’s not using any pain meds. He has absolutely no fatigue. He’s doing very well.

DR MORGANSTEIN: The biggest practice-changing thing that we’ve seen now is using triplet therapy up front on patients. And I guess the question for the investigators is, who gets triplet therapy, meaning darolutamide, docetaxel and ADT? And how aggressive should we be in utilization of it, of course in people who can tolerate it?

DR CHEN: 71-year-old male, presents with new metastatic prostate cancer, Gleason score 4 plus 4, initial PSA was 702. He underwent PSMA PET scan which shows some multifocal tumor infiltration of the prostate gland as well as multiple intensely radiotracer-avid bone metastasis. So in this patient what would be the best up-front therapy? He does have hyperlipidemia and he was also borderline diabetic as well. So I was deciding on the different choices of the agents and was trying to avoid steroid use. I would definitely be interested in the decision-making from the faculty in terms of how to choose between the up-front agents in newly diagnosed metastatic hormone-sensitive prostate cancer.

DR ARMSTRONG: So Dr Smith, in that first case, the physician was wondering if she could get away without docetaxel in a high-volume patient with widespread bony metastases. Is a risk adaptive approach reasonable or would you consider all high-volume patients who are chemo fit to be suitable for it?

DR SMITH: Yeah, I mean, that’s really, of course, the high-volume, low volume oversimplification and then the last case also raises the issue of what do you call that ‘cause we don’t know because the risk classification was not based on PSMA PET but that’s where we are. So I think a risk adapted approach makes a lot of sense. I think about the patient in front of me, as what is his chance of dying of this disease, right? And so it’s a very different scenario for a younger, healthier patient with high grade disease, maybe even if they don’t meet the criteria for high-volume, versus an older patient who has many comorbidities, not the third case but much older patient with many comorbidities. But the priority is doublet therapy, ADT and an AR pathway inhibitor for de novo metastatic disease. I start both of those drugs on the day I meet the patient. It shouldn’t be much of a conversation other than this is what we recommend. And then, the subsequent decision is whether to add docetaxel. I would add docetaxel. I would do triplet therapy for the first and third cases. The first case is high volume. The absence of visceral metastases does not make him otherwise. And we didn’t have a Gleason grade but he would also probably be high risk based on that description.

DR ARMSTRONG: Dr Agarwal, sometimes I hear from the community that the PSA is dropping, I don’t need to give a doublet or a triplet. Is it reasonable to use that PSA to withhold a Level 1 evidence-based life prolonging therapy? That’s kind of what I was getting at with the risk adapted approaches. You treat the patient, see a response, and now can you make a decision about intensification or should you do that up front not based on a response?

DR AGARWAL: That was one of the most common reasons for withholding doublet or triplet therapies by many of the physicians on a survey, that PSA is going down, why should I start anything else? So answering the first question, we have Level 1 evidence to use androgen intensification therapy for patients with metastatic hormone-sensitive prostate cancer. So they have to get doublet or triplet. The question is whether we use triplet for all or whether we should use doublet for all, and that is not settled. We don’t have a trial showing that triplet was better than ADT plus an ARPI and we need that trial, or at least we need a trial which is going to add docetaxel based on some kind of response adapted strategy. So Dr Dorff and other doctors in SWOG are leading a trial where patients start ADT plus ARPI, they are newly diagnosed metastatic prostate cancer. And if PSA doesn’t drop to less than 0.2, those patients are then randomized to triplet versus continuation of doublet. So I think we need some data before deciding where triplet is good for all or doublet is good for all.

So far, I’m sticking to ADT plus doublet in all patients except those patients who are really young men. Patient is a 42-year-old man I saw just last week, high-volume disease, cord compression, I will not hesitate using triplet therapy. Second scenario, patients with liver metastasis who come with newly diagnosed metastatic hormone-sensitive prostate cancer. And then sometimes we all do genomic sequencing, sometimes I see really bad players such as RB1 loss. I do triplet therapy. So overall, 20% of my patients receive triplet therapy with ADT with ARPI plus docetaxel and 80% of my patients with newly diagnosed hormone-sensitive prostate cancer get ADT plus ARPI.

DR ARMSTRONG: Thank you. You answered both questions on the slides so we’re going to keep going. So one of the questions that came up is when using ADT in combination with an ARPI in the hormone-sensitive, which agent, Dr Antonarakis, are you most frequently utilizing and why?

DR ANTONARAKIS: Yeah, I’ll answer that in a second Andy. I think 1 of the educational missions here is to make some very clear statements and Neeraj, you were talking very fast and you mentioned some gold nuggets in there that I want to repeat. And 1 is that the use of ADT plus docetaxel alone is no longer sufficient as a first-line treatment. That used to be in the NCCN guidelines. It has been removed. So ADT plus docetaxel alone is no longer sufficient therapy for metastatic hormone-sensitive disease. You said that Neeraj, but you kind of went quickly.

The second thing, which is a bit contrary and then Matthew’s on stage and he probably will agree with me. You will never be wrong if you want to give triplet therapy. You can always justify giving triplet therapy if you wish, because there were low risk and low volume patients in the triplet study. You will also never be wrong if you wish to give doublet that contains ADT plus ARPI alone, because that ADT plus ARPI alone has never been the control arm in any study on which you add subsequently the taxane agent. So in a court of law, in litigation cases, if you have ADT/ARPI as your choice, you will not be wrong either on that 1. So then it becomes a question of preference, art of medicine and importantly patients’ preference. And the age comes into it, all of us, we talk about age. Age was never really, if you look at the forest plots, we all talk about young age. Young age was never a factor that predicted that you must give triplet over doublet, although I myself do it.

So sorry about that Andy, but the choice for me is first, am I going to give doublet or triplet? And then if you decide to give triplet, you only have 2 options for the ARPI. You’ve got darolutamide plus 6 cycles of docetaxel or you’ve abiraterone plus 6 cycles of docetaxel. If I have made the decision with my patient that chemotherapy is not necessary or wanted, then I like to use ADT plus abiraterone. I’m very comfortable with that. I see less fatigue with that than with apalutamide and enzalutamide. And the prednisone in the first 1 to 2 years actually helps the patient’s energy level, sense of well-being. So ADT/abi is my choice, for me, if I have to use a doublet.

DR ARMSTRONG: Dr Dorff, let me push you on this last question. Would you use ADT/darolutamide without having that ARON note data which may be coming out later this year in the absence of docetaxel?

DR DORFF: Well, first, I just want to push back on something Emmanuel said.

DR ARMSTRONG: You may.

DR DORFF: To not use — you wouldn’t use enzalutamide with docetaxel. I mean both ENZAMET and your study, ARCHES, had some docetaxel.

DR ANTONARAKIS: I wouldn’t. I wouldn’t. I would not.

DR DORFF: I don’t think —

DR ARMSTRONG: Not concurrently.

DR ANTONARAKIS: Yeah.

DR DORFF: Well, true. So you’re saying starting at the same time.

DR ANTONARAKIS: Yeah.

DR DORFF: Okay, got it. So I agree that I often had been using abiraterone preferentially because of fatigue. But there is a very compelling paper from the VA showing that there might be increased cardiovascular morbidity with abiraterone compared to the AR antagonist. So that’s really making me rethink that. And I think we need more data to help us choose for this patient with their comorbidities, is there a right choice? I was more concerned about frailty with drugs like enzalutamide. But the more we can learn how to select patients for the right drug, the better. I am comfortable using ADT/darolutamide without docetaxel. As we mentioned or someone mentioned, I guess one of the question askers, darolutamide does seem to have a little bit better toxicity profile in terms of CNS and fatigue. And I don’t know, I think —

DR ARMSTRONG: Yeah, I agree. I mean enzalutamide is appropriate for younger patients who don’t have a lot of drug-drug interactions. It’s a notorious CYP inducer. Patients who may not tolerate prednisone at all due to metabolic syndrome, diabetes, obesity, those who wish to avoid prednisone entirely due to an adverse reaction, so it’s really personalized. These are all winners. We don’t want to portray 1 as necessarily superior in terms of efficacy. They’re all efficacious.

So we’re going to move on to Dr Erik Rupard, who’s a physician who has treated many patients in the Amish community and he is going to — you know, one thing that we have for you is a very nice video. You’re going to have to watch it after the symposium because he spends about 5 minutes talking about what it’s like to care for the Amish patients in his practice, where the values are very distinct. They’re a very tight-knit community. They value quality of life rather than necessarily doing everything to eke out several extra months of life. They have a community-based insurance program where they pay out of pocket in cash. They’re still driving up their horse-drawn carriages into the clinical practice. And so, it’s a really unique perspective. I’d encourage you to watch Dr Rupard’s message to you after this.

https://www.ResearchToPractice.com/ASCO24Clip

DR LOVE: An important consideration in the management of patients with hormone-sensitive metastatic disease is the patients’ age and comorbidities as exemplified by a challenging case from Dr Erik Rupard.

DR RUPARD: This 92-year-old gentleman was admitted to the hospital with flank pain and he’s a Plain community gentleman. This was here in Pennsylvania. And he was ultimately found to have hydronephrosis nephrosis bilaterally and they checked the PSA and it was 28. So the question I have for the group is considering the fact that this is not an elderly man, this is a very elderly man, what do your investigators use first-line treatment for prostate cancer in an elderly man? Is it just leuprolide/abiraterone or is there some optimal combination that’s going to sort of hit that sweet spot between tolerability and efficacy? Again, as a Plain community man, in other words an Amish gentleman, he was fine with dying of his prostate cancer. He was happy if there’s something we could do that would make his prostate cancer better and keep him from having to have a stent forever but he was not willing to deal with a whole lot of side effects. I gave him bicalutamide and said, hey, we’ll see you in 3 weeks in my clinic. When I saw him in my clinic, his PSA was less than 1 on just the solo bicalutamide. Now I know that that’s unlikely to be durable response, but I’m curious where your investigators are with the durability, efficacy of the stronger drugs, drugs like apalutamide, enzalutamide. I’m curious how your investigators are using the oral GnRH, relugolix, because I understand that there may be — there’s certainly an advantage in that the patients don’t have to come to the infusion center to get their treatment. And there may be some durability advantage if I’ve read the literature correctly. I’m very interested in what they have to say about that. He tolerated the bicalutamide well and he kept asking me the question, why do you need to switch it? If my PSA went from 28 to 0.7, why do we need to switch it? And my answer was, well, we don’t necessarily need to switch it. I just think that this is probably a better agent.

DR ARMSTRONG: So I personally have had many patients in their 90s doing well with oral therapies and maybe, Dr Smith, I’ll call on you given that you’ve actually studied this prospectively in trials both with darolutamide as well as other AR antagonists as monotherapies.

DR SMITH: Enzalutamide and bicalutamide.

DR ARMSTRONG: All the “lutamides,” yes.

DR SMITH: So I think we do know though that bicalutamide monotherapy is inferior to standard androgen deprivation therapy. So that wouldn’t be my first choice in this case. I understand the practical considerations that may have led to that decision. I absolutely would not give a generic agonist because of risk for flare in a patient who already has bilateral hydronephrosis. So this is a patient where I would use, in my practice, either degarelix or relugolix. I realize the financial considerations could be problematic in this particular case but that would be my approach. And also, before you make other decisions about like whether you’re going to intensify beyond that, probably like some more information. And in this case we don’t actually even have a biopsy. But I presume there was other information that supported a clinical diagnosis of prostate cancer in addition to the elevated PSA.

DR ARMSTRONG: I agree. I think we’ve covered these topics very well and now it’s your turn Dr Smith to talk to us more about metastatic castrate-sensitive prostate cancer.

DR SMITH: Happy to do it. Good evening, and this has been an area of extraordinary progress in our field. And while in most cases we talk about moving drugs from a later stage to an earlier clinical setting, that may not be the most glamorous thing, but the impact on patient outcomes has been extraordinary as I hope to show you.

We all know that patients with metastatic disease treated with androgen deprivation therapy alone have relatively poor clinical outcomes. This is data from STAMPEDE showing survival of less than 4 years for patients treated with ADT alone. And clinical outcomes are related to the anatomic sites of disease with patients with bone and bone and soft tissue disease doing worse than patients, for example, with lymph node only metastases.

This slide summarizes an extraordinary body of data. I will describe many of these trials in the slides that follow. But the key takeaway message isn’t that a trial has shown improved overall survival in mCSPC, it’s that almost every trial has shown improvement in overall survival of mCSPC, first with docetaxel, then with 4 different AR pathway inhibitors and in combination with docetaxel. And it’s the consistency across trials, across different agents and across different risk groups that really makes this an extraordinarily compelling case to intervene in the appropriate way with our patients.

This is a meta-analysis of the docetaxel/RCTs, making the point that the addition of docetaxel to ADT improves overall survival, again consistency for the most part across those 4 trials. This meta-analysis showed about a 9% absolute improvement in overall survival at 4 years. The lure about docetaxel and mCSPC is that it only works in high-risk disease. That conclusion has been mostly supported by meta-analyses that have looked at subgroups, although it’s not completely black and white. It’s just that most of the benefit appears to be conferred in patients at greater risk for prostate cancer specific mortality. And just to be sure that I make the case at least twice, I’ll repeat what Dr Antonarakis said and that is that ADT/docetaxel is no longer a standard of care for reasons that I’ll show you in a few moments.

Consistent evidence has also shown that intensification with AR pathway inhibitors improves progression-free and overall survival. This is data from the LATITUDE trial of abiraterone in patients with what was defined as high-risk metastatic disease showing this early separation of curves for RPFS in a clinically meaningful and statistically significant improvement in overall survival, but this was in patients with high-risk disease.

So which is better, ARPI or docetaxel? There has not been a direct head-to-head comparison but we have the next best thing in the STAMPEDE experience where it’s a contemporaneous comparison of patients randomized to different arms of STAMPEDE to other ADT/docetaxel or ADT plus abiraterone. And you can look at outcomes. While there’s no difference in overall survival discernable in this contemporaneous comparison, abiraterone is the winner for a variety of intermediate endpoints including failure free survival, progression-free survival, and metastasis-free survival. That improvement in intermediate endpoints could represent better efficacy. It also could represent the simple fact that abiraterone is continued until progression whereas docetaxel, as you all know, was administered for only 6 cycles. And most of these events occurred after completion of that treatment.

The TITAN study looked at the addition of apalutamide, excuse me, to ADT in mCSPC. Again, marked improvement in RPFS, similar beautiful reduction in overall mortality. Hazard ratio about 0.65, repeated over and over and over again in all the studies of ARPIs. The important innovation here was that this benefit was observed in patients defined as both high and low risk. You see the point estimates looking very similar. In fact, the magnitude of the benefit, the effect size is somewhat larger in patients with low-risk disease, making the case that this is really the go-to treatment for patients regardless of their risk stratification. And 1 of the historical problems with CHAARTED, I think for many clinicians, they have locked in their mind this idea that intensification is only for high-risk or high-volume patients. It’s simply not true. And that’s consistently been demonstrated in all of the ARPI studies.

This is the ARCHES study of enzalutamide, again showing a marked improvement in RPFS and that same, about 35% reduction in risk of death in favor of doublet therapy compared to ADT alone. Similar benefit shown in the ENZAMET study of enzalutamide. Again, nearly identical hazard ratio for overall survival.

ARASENS addressed the question of triplet therapy. And it’s important to note historically that this study was designed at a time soon after there was confirmation that docetaxel improved overall survival, but before we knew that ARPI doublets improve survival. Accordingly, we did the difficult thing, which was to say the right — and what we thought the right thing at the time, and that was to go with the winning arm of the previous trials, ADT and docetaxel, and use that as the control group. So eligible patients were randomized to darolutamide or placebo. Patients in both groups received ADT and docetaxel, docetaxel for a total of 6 cycles. And it’s important to note this was concurrent therapy. Patients began their ADT and darolutamide and then were subsequently treated with docetaxel in the weeks that followed. When we designed the trial, we also thought that the only way that it would make a difference is if we improved overall survival, as that benefit had been shown in the prior studies of docetaxel, so that was the primary study endpoint. In fact, we did not measure RPFS in this trial.

Here's the data showing that the addition of darolutamide to ADT/docetaxel significantly improved overall survival. Hazard ratio 0.68. So very similar magnitude of benefit compared to the ARPI/ADT doublet trials. This benefit was seen in both, across a whole spectrum of disease states, high volume, low volume, high risk, low risk, de novo versus recurrent. I do have a slight disagreement with Dr Antonarakis though, is that doesn’t prove that triplet therapy works in low volume or low risk disease. In ARASENS, we asked a darolutamide question, not a docetaxel question. So it is an unanswered question as to whether we need to add docetaxel to the ADT doublet in ARPI and whether benefit to triplet therapy extends to patients at lower risk for progression. PEACE-1 served to confirm the results of the ARASENS study. This is a 4 arm, 2 x 2 factorial design, so much more difficult to explain and to interpret.

There are, again, 4 arms, standard of care, standard of care plus abiraterone, standard of care plus prostate radiation, or standard of care plus abiraterone and prostate radiation. Originally the standard of care was ADT plus docetaxel at the discretion of the treating physician. About halfway through the trial, standard of care was changed to require the addition of docetaxel, and so the triplet therapy question was really done as a subgroup analysis of this 4-armed trial. So you see in the overall population there's a benefit in favor of triplet therapy, or excuse me, in favor of addition of abiraterone. And in the docetaxel population there's also benefit to adding abiraterone, making the case for triplet therapy.

A number of studies are looking at this question of intensification further. Two studies will look at PARP inhibitors. The AMPLITUDE study will look at niraparib in biomarker-positive patients. The TALAPRO-3 study will look at the addition of talazoparib in biomarker-positive patients. And then lastly, PSMAddition is looking at lutetium-PSMA-617 in mCSPC, again, moving that therapy further up the line to look to see whether it has a role in that disease state. So I'll briefly conclude. ADT alone is no longer the standard of care, nor is ADT plus docetaxel. Most or all patients with mCSPC should receive an AR pathway inhibitor, either ADT plus ARPI or triplet therapy. Thank you.

DR ARMSTRONG: We've got 3 great questions. Thanks, Dr Smith. And I'll pose the first one to you since you've been so involved with bone health and antiresorptive therapies. If you could briefly mention your approach in the hormone-sensitive bone metastatic setting, whether you're using denosumab or zoledronic acid, or whether you should wait ’til castration resistance.

DR SMITH: So you have to ask the question, what's your therapeutic intention? Are you trying to prevent osteoporotic fractures in which all patients, older men on ADT are at risk? Are you trying to prevent disease-related skeletal complications? If it's the latter, we only have evidence in castration-resistant disease. Why is that? Because if you control the disease with your current therapy, they're at low risk for disease-related skeletal complications. And it's about the drug dose and schedule. So if you're preventing osteoporotic fractures, then you use a drug dose and schedule that's appropriate for osteoporosis. If you're looking at SRE prevention, then you use a different approach.

DR ARMSTRONG: Another question, Dr Antonarakis, was about AR-V7 testing in the hormone-sensitive setting. Is there any utility, and do you find any AR alterations in this pre-ARSi setting?

DR ANTONARAKIS: I would say there is not a role, and it's extremely, extremely uncommon. It's a selection pressure mutation, which does not occur before ADT is given.

DR ARMSTRONG: It's a late event.

DR ANTONARAKIS: Yeah.

DR ARMSTRONG: Thank you for that great answer. And then, Dr Agarwal, what's your approach to using relugolix in this combo, you know, dual or triplet therapy? Do you often use the oral GnRH antagonist or are you mostly using the injectables?

DR AGARWAL: I don't use relugolix when I'm using combination therapies for multiple reasons. There is no reason to switch patient to an oral medicine when they will have to deal with copay issues, when we already have injections which do a perfect job. Relugolix is used by us once in a while when patients really want to pursue intermittent therapy, and relugolix allows testosterone recovery pretty rapidly. So I rarely use relugolix when I'm pursuing intermittent androgen deprivation therapy in patients who have biochemically recurrent disease, slowly rising PSA level, and who really want to do something.

DR ARMSTRONG: Thanks for that. I agree. I think the value of relugolix is the rapid on and rapid off, so you can get back to castration-free existence.

New Considerations with the Use of PARP Inhibitors for Metastatic Castration-Resistant Prostate Cancer (mCRPC) — Dr Agarwal

DR ARMSTRONG: So Dr Agarwal’s now going to turn our attention to the newly approved therapies using PARP inhibitors and AR/PARP combos. We're going to start with some case discussions. We have three community-based oncologists who have brought up some key questions about risks and benefits of the use of these PARP inhibitors.

DR LOVE: General medical oncologists have a lot of experience using PARP inhibitors in ovarian and breast cancer, but in prostate cancer these fascinating agents have become equally important, and there are many questions about the genetic and genomic evaluation of these patients and the use of PARP inhibitors in the management of these patients.

DR MORGANSTEIN: The first question is, is it now standard of care to both get germline testing and somatic testing with next-generation sequencing? And then, more so than other tumor types, I think we're often stuck with we don't have availability of tissue. I have a case right now, he had prostate cancer 10 years ago, with surgery somewhere in Oregon. So legit, I'm not going to be able to get that initial diagnosis and many of these people have bone-only disease, which may be a little bit more difficult to get NGS on.

So what is the now role for liquid biopsies in this setting and how much can we rely on it in people who don't have lung or liver metastases?

And then, what genes do we look at, and how far down the road can you go? I think if somebody had a BRCA gene, how quickly would PARP inhibitors be instituted, and would it be with hormonal therapies or by itself?

DR KU: I'm very curious about trying to get a sense of the different PARP inhibitors. Even in the community setting where we treat a lot of different cancers, we don't always get to get that sense of how does a patient do on certain PARP inhibitors? So being able to review what are the different side effects, the unique ones that we should consider, and also the approved indications, because some of them have certain HRR mutations that they were studied with and other ones not.

DR GANDHI: One of the issues I have is duration. And the question is myelodysplasia. I went to whatever research I could do myself, and my feeling was if patients don't develop in the first 2 years, subsequent risk of myelodysplasia is not much more, and so you can continue it. But I don't know whether I'm 100% right or wrong, you know. I would like faculty to answer that.

DR ARMSTRONG: Alright, Dr Agarwal, since you're giving this lecture, we're going to start with you. You know, how do you explain the synergy between these 2 combinations? And how do you make a choice between which combination to use?

DR AGARWAL: I think we may want to tackle these questions after my presentation. Is that okay?

DR ARMSTRONG: One minute.

DR AGARWAL: You are giving me 1 minute for my presentation? I thought I'll get 8 minutes.

DR SMITH: Clock is running.

DR AGARWAL: Yeah.

DR SMITH: I'm just kidding.

DR AGARWAL: Alright. So synergy, I think they cooperate with each other. I'd like to show you some data in a moment. And then very recently we presented BRCAAway trial. Dr Antonarakis, Dr Hussain, all of us are involved. And I think after looking at those results, for the first time, I think there may be some synergy, which was also seen in large Phase III trials. And the second question is, is combination therapy really better than sequential? Again, same trial showed that combination therapy up front is likely better than sequencing of these agents. So answer is, yes.

DR ARMSTRONG: I think the answer is pretty clearly yes. We have now BRCAAway to proclaim that. You know, the progression-free survival of the combination just blew either olaparib or an AR inhibitor out of the water in a relatively small study, and that was already addressed in PROpel and TALAPRO as you're about to approach.

So you're going to talk about this. But Dr Antonarakis, maybe since we're not going to hear from you in the lecture, maybe you could talk about your approach. Do you start with which AR inhibitor is appropriate for the patient and then move to the PARP or do you think about it more? Which combination is appropriate?

DR ANTONARAKIS: You know, I wish there was an easy answer. It has become complicated because of the regulatory approval of the 2 combinations. They're both approved in the first line, mCRPC setting. The abiraterone/olaparib combination is only approved in the US for BRCA1 and BRCA2 germline or somatic alterations. And the enzalutamide/talazoparib combination is approved for 12 HRR genes, 1 of which is not an HRR gene, it's a mismatch repair gene. So that snuck in there. I'm not going to blame Neeraj for that one but it should only be 11 genes in that panel. And again, even in that scenario, BRCA1 and 2 patients derive the greatest benefit.

We don't have evidence that if you have received a doublet up front for metastatic hormone-sensitive disease and you subsequently develop CRPC first line that you should be getting a combination. In fact, the purest evidence in that scenario would be, even with a BRCA2 mutation, olaparib monotherapy.

Now, have I ever done it where I've had a patient on ADT/abiraterone progresses? I don't think they need chemotherapy quite yet. So the ARPI switch idea does not seem unethical to me. Many of the patients, by the way, they want to delay chemotherapy. And in such a scenario, if I knew that this gentleman had a BRCA2 mutation, I would consider enzalutamide plus talazoparib. The very reasonable alternative with Level 1 evidence would be olaparib monotherapy.

DR ARMSTRONG: We have one more case to go through from the oncologists in the community.

DR LOVE: While the use of PARP inhibitor seems very understandable in patients with BRCA, somatic and germline mutations, oncologists have many questions about the use of these agents in patients with other abnormalities and to what extent these predict benefit from treatment.

DR KU: I think there's a lot of curiosity about PARP inhibitors, especially with data now about doing the second-generation AR with PARP with ADT, and should we be doing that on all patients who have HRR mutations? Or are there certain mutations that we think of as more likely to benefit that we're taking to be applicable for this kind of triple therapy up front?

DR BACHOW: Have you ever used a PARP inhibitor with NHT and ADT in a patient with metastatic castrate-resistant prostate cancer that does not have BRCA or HRR mutations? Because I know 1 of those studies, there was a radiographic progression-free survival benefit in patients that did not have HRR mutations or BRCA mutations. So I wanted to know the experts' experience in using this combination off-label in patients that are not HRR mutated and not BRCA mutated.

DR ARMSTRONG: So Dr Dorff, if we lived in Europe you could have the liberty of choosing AR/PARP inhibitors in unselected patients. That's not where we live. The regulatory authorities looked at the same datasets and made opposite decisions. Let's say in an ideal world, you could use an AR/PARP inhibitor in the US and you don't detect a BRCA alteration or an HRR alteration. Is there a patient phenotype genotype characteristic that would compel you to use that combination?

DR DORFF: Well, I would just like to emphasize the importance of the genetic and somatic testing. Because the 1 thing that was clear across the studies is that while there may have been a benefit seen in some cases in the intention-to-treat population, which included those without an HRR alteration, the strongest benefit is for BRCA1 and 2. The other HRR alterations had the next greatest benefit, and it's clearly smaller. So would you ever discuss it if I were in Europe, if it weren't off label in the United States? You could but the risk-benefit discussion is going to look different for those patients. They don't get as much out of it and they're still exposed to the same toxicities.

And the earlier question about germline and somatic testing, germline is indicated across the board, but in localized prostate cancer we're not yet doing somatic testing, right? And I think it's also very important for people to know that you can qualify a patient for PARP inhibitor therapy based on ctDNA. So the case he posed, 10-year-old prostate tissue, bone-only mets, liquid biopsy can really be used to select patients. It's a little more nuanced in the interpretation, but it's still valid.

DR ARMSTRONG: Yeah, like, this reminds me of a case of mine where the Foundation test on a prostatectomy specimen showed an ATM mutation, not very PARP-sensitive alteration. But on the third liquid biopsy assay, as the patient has progressed on both an ARPI, docetaxel, cabazitaxel, we finally repeated another ctDNA assay, and he had a BRCA2 copy loss that was found. And this was not found on 2 other liquid biopsies. He's now gotten olaparib for 2 years and attained a complete remission.

So we published his case along with, you know, the PROMISE Registry that we're leading with 2,000 patients, multicenter, retrospective study of 2,000 patients who have had next-gen sequencing. And these serial assays can sometimes be of value. There's about 10 to 15% of patients in this study that had new actionable alterations, BRCA, MSI-high disease, that could help that patient live longer.

DR DORFF: And I don't know if we can put a link to the FDA pooled analysis, but showing things like the fact that ATM is not as good a predictor and then certain other mutations that could be helpful for the audience.

DR ARMSTRONG: Alright, Dr Agarwal, take it away.

DR AGARWAL: So we have these 4 topics to cover in the next 8 minutes. What is the incidence of these mutations in patients with prostate cancer? And let’s see the data.

So this was a seminal publication in, almost 10 years ago showing for the first time, unlike many papers that had come out before that, but I think this was one of the most impactful papers showing that 11% of patients with metastatic prostate cancer had germline mutations in DNA repair genes.

And then we also looked at the real-world dataset, so Foundation Medicine, this is a database from Foundation Medicine. We can see more than 3,000 patients were looked at. And these patients underwent comprehensive genomic profiling through Foundation Medicine testing. And we found that about 25% of patients have homologous recombination repair mutations. So, of course, these 2 studies, without any doubt, and many more studies after that have established that these patients are common. Patients who have metastatic prostate cancer, one-quarter of these patients have DNA repair gene mutations.

So now, let’s look at the long-term data with PARP inhibitor monotherapy in patients with metastatic CRPC. This will answer one of those questions by one of the community oncology colleagues about the long-term side effects of these PARP inhibitors.

So we decided to look at these 4 trials which have relatively long-term data available. And, of course, these trials have been presented in the last 4 years, so the long-term meaning 4 years at the most. So these are the 4 PARP inhibitors which are approved as monotherapy in patients with metastatic prostate cancer who harbor homologous recombination or DNA repair gene mutations.

This was the PROfound trial. I won’t go into the detail of the design of this trial. But if you look at the recent publication we had, which is a 22-month follow-up. This showed that efficacy of olaparib was maintained in these patients who had BRCA1 and BRCA2 alterations. So efficacy in this patient population was maintained. And this paper just focused on BRCA1 and BRCA2 mutation patients who were enrolled on the PROfound trial.

If you look at the safety, we did not see any other safety issues with a follow-up duration of about 22 months.

If you look at long-term data from rucaparib, this is a monotherapy PARP inhibitor approved based on a Phase II trial, efficacy-wise, efficacy continues to be maintained in patients who are BRCA1 and BRCA2 mutations, and somewhat less efficacious in patients who have ATM mutations. But we did not see any difference in efficacy with the longer follow-up.

Now if you look at the long-term safety data with rucaparib, again, there was no new safety signal. We are not seeing any myelodysplasia or any higher risk of AML, so far. Again, this is 24 months of follow-up duration.

If you look at the long-term data from talazoparib, although talazoparib was not approved based on the Phase I trial, it was approved based on the TALAPRO-2 Phase III trial. But still, we have some long-term data available. And this is 16-month follow-up. This was the longest I could find. So ideally, we want to look at 4 or 5 years of follow-up, but this is what we have so far. And we did not see any higher risk of anemia or any long-term concerns of myelodysplasia or AML being established by this long-term follow-up.

So now, let’s look at the third question which was also raised by one of the community oncology colleagues, which is biological rationale for combining PARP inhibitor with ARPI in patients with prostate cancer.

This is a summary of all the data, many of the data which have been published since 2008. And we recently published this paper. This is an open access in the European Journal of Cancer. If somebody wants to have, see all these data put together, so we have summarized all those data in this open-access paper. But this is how I explain to my patients. When prostate cancer cells are targeted with AR pathway inhibitors such as enzalutamide or abiraterone, those cells are rescued, or at least partly rescued, by PARP enzyme, poly-ADP ribose polymerase, which gets upregulated and tries to rescue the cell from the targeting by AR inhibitors. Vice versa also happens when PARP inhibitor — when PARP is inhibited, that leads to downregulation of AR. So this is mostly preclinical data which led to a Phase II trial, I’m not going to talk about that Phase II trial, which led to ultimately these large Phase III trials.

And these are PROpel trial, MAGNITUDE trial and the TALAPRO-2 trial. The last trial was not completed for multiple reasons. So let’s look at these Phase III trials.

I put all these designs together. To me, these trials are more similar than different. There are some nuances. In some trials, there was prospective tissue testing. In the PROpel trial led by Dr Armstrong and colleagues, there was no prospective tissue testing. They got all-comer patient population, and found that 27% of those patients had DNA repair gene mutations. Again, supporting the previous observations that about one-quarter of these patients have HRR mutations. So these are the 3 trials. Now, let’s look at the results of these 3 trials which I’ve complied in 1 single table.

And I would like to bring your attention to the all-comer patient population because this was the question which was also raised. So in the PROpel trial, if you look at the ADT/abiraterone plus olaparib, ARPI plus PARP inhibitor, the hazard ratio was 0.66 in all-comers, 0.50 in HRR positive patients, favoring the combination. And even in HRR, like, homologous recombination repair negative patients, there was a hazard ratio favor with a 25% reduction in the risk of progression. In TALAPRO-2 trial, we saw very similar data. Again, those benefits are most pronounced in patients with BRCA1 and BRCA2 mutations, but they’re also present in patients who have homologous recombination repair mutations overall. And we see some benefit although efficacy, the level of efficacy, if you look at magnitude of efficacy, is different, is lower in all-comer patient population but there is efficacy. Now there are other differences within PARP inhibitors. Niraparib seems to have lower efficacy compared to olaparib or talazoparib, but these are cross-trial comparisons. So at this point, I will say they are very similarly efficacious. And efficacy is most pronounced in BRCA1 and BRCA2 positive patients, but also present, like Dr Dorff said, based on the recent FDA analysis. We clearly see efficacy in patients with CDK12 mutation, PALB2 mutations, and there are other patients who have RAD51 mutations. We clearly see efficacy. There are such a small number of patients that it’s almost impossible to have power for all those small cohorts of patients.

I’ll quickly go through the BRCAAway data. To me, these are very impactful data despite the small size of the trial, 20 patients in each arm. They were randomized to abiraterone versus olaparib versus abiraterone plus olaparib. First time any randomized trial answered the question of whether olaparib can be used for these patients who have disease progression on androgen deprivation therapy plus or minus docetaxel in metastatic castration-sensitive prostate cancer setting.

This is the efficacy data. I’d like to bring your attention to the median PFS in the abiraterone arm, 8.4 months. We know these patients who have HRR mutations, they don’t do very well on ARPIs alone. Then let’s look at the olaparib arm, 14 months. And now, let’s look at abiraterone plus olaparib arm, 39 months. These patients were allowed to be crossed over to the other side if they had disease progression or when they had disease progression.

The first thing, only half of the patients could cross over, which is consistent with the real-world data that we lose half of the patients when they have disease progression, at least in metastatic prostate cancer setting. But let’s look at these data. If you combine the rPFS, or progression free survival, of both sequencing arms, abiraterone followed by olaparib, 16 months. Olaparib followed by abiraterone, 16 months. And abiraterone plus olaparib, 39 months.

These trials have already changed my practice. I go with up-front combination rather than sequencing. So my take on this subject, about 34% of patients in the US with newly diagnosed mCRPC were not exposed to any ARPI prior to development of mCRPC. So we have a significant number of patients out there who are developing new mCRPC without prior exposure to ARPI. How I select combination? Purely on FDA approval. Abiraterone plus PARP inhibitor are approved for BRCA1 and BRCA2 mutation positive patients. Talazoparib and enzalutamide is approved for patients in first-line mCRPC regardless of type of HRR mutation. So all HRR mutation patients, positive patients can get this combination. Based on the results of the BRCAAway trial, I combine the treatment rather than sequence them. And as Dr Dorff said, all patients with advanced prostate cancer should have genomic profiling done, somatic and germline testing done. And the next steps are to figure out who are those patients who are responding who do not have HRR mutations. And ultimately, all these patients will progress. So let’s find out, let’s work on mechanism of resistance to PARP inhibitors. Thank you.

DR ARMSTRONG: Dr Agarwal, thank you. We have time for 1 audience question. And I think the data around BRCA and olaparib and AR combinations are so compelling. The audience was wondering whether you would be compelled, Dr Antonarakis, to give this combination in the hormone-sensitive setting in the absence of our AMPLITUDE, TALAPRO-3 and EvoPAR trial data, and whether you would do it without an AR inhibitor as you’ve done in clinical trials.

DR ANTONARAKIS: I would not do that yet outside of a trial.

DR ARMSTRONG: Thank you. That was a nice, short and sweet answer.

Role of Novel Radiopharmaceuticals for mCRPC — Dr Armstrong

DR ARMSTRONG: Alright. So we’re going to move on to my session which is on radiopharmaceuticals. Certainly, this meeting at ASCO, we’re going to see some new radiopharmaceuticals on Monday. But we’re going to talk about some of the older radiopharmaceuticals and the emerging newer ones that are already approved with some community-based cases to kick us off.

DR LOVE: Two approved radiopharmaceuticals available in the treatment of prostate cancer, general medical oncologists have a number of questions about the selection, use and timing of use of these important agents, and also key considerations in following and in managing patients receiving these therapies.

How about your 70-year-old man with bone metastases on the ARASENS triplet?

DR CHEN: I would be interested in seeing how the faculty would integrate lutetium in his treatment, which line to use and how to also perhaps combine it with other treatment modalities.

In this patient, given that he has PSMA-positive disease and multiple bone metastases, upon progression, how would the faculty sequence additional treatment such as the radium-223 or the lutetium treatment in the future?

DR KU: In our community, we have a nuclear medicine department that will give the medicine, but then it’s medical oncology that follows the patients in between. So should we just be checking blood work or are there other new side effects that we need to also be thinking about? At what point should we be expecting a PSA change? Or should we be getting interim imaging and expecting imaging to show some changes, especially when it’s bone-only? Should we be following with PSMA PETs? And then also the bone marrow implications for patients who get so heavily pretreated. They have had chemo and then put in a PARP inhibitor and have these nuclear targets, these theranostic agents.

DR BACHOW: In a patient with metastatic castrate-resistant prostate cancer who’s receiving lutetium-177 PSMA therapy, do you ever add enzalutamide to augment the expression of PSMA on the cell surface? How about using other NHTs? I know there are some preclinical data and some early clinical data on using enzalutamide specifically to increase PSMA expression. Are you doing that in all patients that you’re placing on lutetium-177 PSMA? Or are you putting them on monotherapy lutetium-177 PSMA and if they’re not having an adequate response, are you adding that later on?

DR ARMSTRONG: So those are some really important and complex questions that I’m going to get to in my talk. But my approach to these radioligand therapies is to obviously get blood work, PSAs, but I’m interested in our faculty’s approach to imaging. Obviously, with PSMA lutetium, you have to get a PSMA PET to qualify your patient. But after treatment, the PSA, when it goes down, that’s very reassuring. But my approach is after about 2 or 3 cycles to repeat conventional imaging to document response, remission and whether the patient is benefiting, and then to continue with the second component of the therapy. There are some patients where I may take a break from therapy if they obtain a complete remission. There’s this phenomenon of the tumor sync. Or maybe if there’s no more disease seen on imaging, what are you actually treating with the PSMA lutetium? Are you just treating their salivary glands at this point? So that’s the extraordinary responder. But maybe, Dr Dorff, you could comment on whether you follow that same kind of approach. Do you treat all your patients with 6 cycles or do you sometimes take breaks?

DR DORFF: So I do very similarly follow the PSA. I look at the patient, and I actually repeat PSMA PET because if I really want to know, do they still have PSMA expressing disease, conventional imaging won’t tell me that. Now in VISION, that’s not how they followed the patients, so your answer is correct to do conventional imaging. But we’re able to get PSMA PET. It’s a better apples to apples comparison. But it does create some tricky situations where PSA is going down, but the PET scan looks worse, and you really don’t know what to do with that. But I’m using it more, as you suggest, to see if someone’s PSA is all the way down and they’ve had 3 doses and they’re already having some anorexia from their dry mouth. If there’s no PSMA left to target, I think adaptive dosing makes sense. It’s totally off-label. We don’t have data yet. But I think it just feels like the right thing to do in certain really extreme responder cases.

DR ARMSTRONG: Dr Smith, do you want to add?

DR SMITH: I take a similar approach, I think, to what you described, taking the break in the extreme responders. It’s also very practical because at the present time, we can’t re-treat patients with another 6 cycles.

DR ARMSTRONG: You get 6 doses.

DR SMITH: So you want to save the therapy. It’s a good news problem. I’d like to briefly comment, if I could, on the enzalutamide question. So I took a deep dive into that data. The effect is very small. It appears to be transient. And it’s a tiny fraction of the interpatient variation in PSMA PET expression. So I can’t really make a good case to prime someone with an ARPI to increase PSMA PET expression.

DR ARMSTRONG: Dr Agarwal, would you use an ARPI with PSMA lutetium if they’ve only had 1 prior therapy? That was allowed in the VISION study. We don’t actually have much data to go with.

DR AGARWAL: Right now, I’m using lutetium therapy by itself. I’m not combining with anything.

DR ARMSTRONG: Dr Antonarakis, do you agree?

DR ANTONARAKIS: If I have a patient who is on an ARPI already and progressing slowly and their PSMA scan is positive, I would often continue the ARPI and add lutetium.

DR ARMSTRONG: So there’s a lot of heterogeneity even among experts, I think you’ll hear. And there’s emerging data, as I think you’ll hear me talk about. And I’m going to start with, what’s going on with radium and why haven’t we heard anything recently? We’ve covered this, and I’m going to get right to my talk.

So let’s see. Yeah, I’m going to just jump right to this. So I’m honored to be here. I’m going to talk about radiopharmaceuticals and where we are in the current landscape.

But let’s not forget the very first life-prolonging radiopharmaceutical that came out with the ALSYMPCA trial, now over a decade ago, in the New England Journal. Radium is an alpha particle. That is basically a large cannonball of radiopharmaceutical decay that is bone-targeted. It’s actually in the chemical periodic table right underneath calcium, so it’s considered a calcium mimetic that’s bone tropic. And offering this to patients with symptomatic bone-predominant metastatic CRPC was superior to best supportive care in terms of overall survival and delaying really important events like pain and spinal cord compression. And there were patients that had greater benefit. Those that had high alkaline phosphatase, for example, was a suggestion of one of the subgroups. But all of these subgroups tended to benefit regardless of the number of bone metastases, the symptoms of the patient and the prior docetaxel use.

This trial was one of the few trials where the overall adverse event rate was actually greater in the placebo group where the patients had a better quality of life. There were some notable adverse events that were increased with radium, and this was largely GI side effects, mild anemia, and mild thrombocytopenia. But you can see where the arrows are that the reductions in pathologic fractures, spinal cord compressions were very compelling as a bone-targeting therapy. Now radium does not make your PSA go down. It does not work in soft tissue disease. It does not leave the bone. So there’s very easy ways for prostate cancer to evade radium. And that’s why it’s really important halfway done — halfway through with radium to do imaging to understand if there is escape of the bone disease into soft tissue disease, particularly visceral metastases.

There has been some work to move radium from a post-docetaxel setting into a first-line setting. This is called the ERA-223 trial where abiraterone plus prednisone was studied as a first-line therapy plus or minus radium 223. This trial was stopped early because of inferior outcomes which I’ll talk to you about. But the intent was to see in this asymptomatic population whether we could delay symptomatic skeletal-free survival and whether that would translate into a benefit by preventing these bone metastatic complications.

I’ll point out the Kaplan-Meier curve on the left here is the time to first fracture. And if you look carefully, the radium group was in blue. That’s the lower group. There were actually much more fractures and occurred much more frequently. Now these were not necessarily pathologic fractures. These were often insufficiency fractures distant from the sites of disease. And if you look at overall survival, again, the placebo group, or just abi alone, did better with a hazard ratio above 1. So this led to a black box warning, this study was stopped, and it’s now strongly not encouraged to give radium as a first-line therapy in conjunction with an ARPI.

Now we have learned from both this study and the PEACE III study that when you’re using a potent AR inhibitor, ADT, enzalutamide or abi, and combining that with radium, that it’s really important to pay attention to bone health. So not only imaging for bone density loss, but also preemptively using our bone health antiresorptive therapies, denosumab or zoledronic acid, to reduce the risk of these insufficiency fractures.

From the PEACE III trial, as you’ll see in this table that’s been reported to date, that on the left, we have the fracture rate without the use of a bisphosphonate. And on the right, we have the fracture rate with the bisphosphonate. And you see really dramatic reductions from the table when the protocol was done without the mandated bisphosphonate on the left where the 18-month, for example, fracture rate was almost half in the enza plus radium group, 21% with enza. But on the right, when the bisphosphonate was mandated as part of this protocol, there’s a really dramatic 10-fold reduction in fracture rates. Still higher with radium, but much more reduced and lower risk in this patient population. So that is really a word of caution to the audience. Don’t forget bone health in this castration-resistant setting, to image with bone density if you’re using it to prevent insufficiency fractures, but also to preemptively use denosumab or zoledronic acid to reduce the risk of skeletal-related events.

There is work going on about radium. And this is one of the few remaining docetaxel combination trials that we have. I think there have been 25 and counting negative Phase III studies testing whether a novel agent can improve upon docetaxel. The only success has been in the hormone-sensitive setting where we have Dr Smith and his ARASENS trial now building on that with an ARPI, abiraterone, in ARASENS, with darolutamide. The DORA trial is attempting to build on this, mashing up 2 combinations that have been successful individually. So Dr Morris is leading this. This is a multicenter Phase III study testing docetaxel at standard of care dosing versus a lower dose of docetaxel every 3 weeks in combination with radium for patients with bone-predominant disease, but soft tissue disease allowed because now, you’re targeting both compartments with both microtubule therapy as well as bone-targeting radiotherapy. This trial is nearly complete. I would expect probably within 1 to 2 years for us to have an answer to this.

In general, the field has moved beyond targeting the bone to targeting the tumor. Our ability to see the tumor with PSMA imaging has really been transformed in the past 2 to 3 years with the FDA approval of multiple radioligands that allow us to more precisely and sensitively see PSMA expression.

We have many radioligand binding agents, small molecules as well as antibodies, PSMA-617, PSMA-11, PSMA I&T. These are different urea-based analogs that stick to PSMA on the cell surface, allow either gallium-68 or fluorine imaging to capture the presence of PSMA positive disease.

The VISION study really has transformed my practice personally. I think we’ve now treated about 300 patients postapproval. I feel like sometimes I’m a Jiffy Lube for PSMA lutetium because we’re a referral center for all of our Southeastern United States. And we’re very busy with this approach. This is a very popular approach. Patients are coming for this because it’s not only a life-prolonging therapy, but as you saw in the PSMAfore data at the oral session just before this, quality-of-life is dramatically improved and maintained in more patients.

And the VISION study really demonstrated that overall survival could be improved by targeting PSMA with PSMA lutetium with up to 6 doses every 6 weeks while delaying progression. Now I think there was some initial disappointment that this was not a more robust survival benefit, that this was not a more robust progression free survival benefit. Even though these survival curves separate, we do unfortunately see that most patients develop fairly rapid resistance within about 9 to 12 months in this post-docetaxel setting and within about 12 to 13 months in the pre-docetaxel setting. So I think we need to do more. This is a beta emitter. This is inducing some DNA damage, not a lot of DNA damage. It’s not a perfect targeted therapy. There’s a lot of normal tissues that can be targeted with this. But it is a huge step forward and a new mechanism of attack against the cancer.

Now as you’re deciding in a post-ARPI, postdocetaxel setting, should you use a second taxane or should you use PSMA lutetium? The Australian group has done the TheraP study where they just did that randomization. Overall, the overall survival was no different, so they’re both winners. But there were differences in PSA-based outcomes where the PSA waterfall plot favors the PSMA targeted therapy. Objective response data favors this and progression free survival favors this. And if you look at different PSA quartiles and PSMA uptake, the patients that had the brightest PSMA uptake seem to have a greater benefit with PSMA lutetium.

Now, there was a lot of crossover in this study. This study was not powered for overall survival. And you can see in the lower left that really, both treatment arms did equally well in terms of overall survival. So the sequence may not matter as much as long as you’re offering both therapies and following patients carefully.

We do have some data in press that does suggest that there may be some strong prognostic and selection factors. Now all the patients in the VISION study had a PSMA PET scan. They had to have positive lesions on the PSMA PET scan. They could not have the absence — they could not have the presence of PSMA negative lesions. But there’s a lot more that you can do with a PSMA PET scan. You can quantify the whole-body burden of PSMA uptake. That’s called the SUV mean. You can look at individual lesions. And we did show that the whole-body uptake, the brightness of the PET scan is strongly associated with better survival in this context. This was not a predictive factor, meaning you can’t use this to identify patients that don’t benefit from PSMA lutetium. But within PSMA lutetium context, the patients who seem to benefit the most are those with the brightest tumors, and thus the more radiation delivered to those tumors.

A very cheap and easy test is the post-treatment PSA decline. So as the PSA goes down, as you target PSMA, you expect the PSA to report on the outcomes of this. And these are some plots showing that the very cheap and easy way to identify a changing prognosis and deliver that prognosis to your patient is based on that PSA decline which usually tends to correlate with the imaging that you see afterwards.

As we heard about the PSMAfore data earlier today, the quality of life is maintained and improved. PSMAfore is not yet published and continually gets updated. The PSMAfore is now moving PSMA lutetium into the pre-chemotherapy setting. Again, PSMA-positive disease and post-ARPI.

The data from this study has been presented at ESMO and then just updated literally about, what now, 3 hours ago where the progression free survival was substantially delayed suggesting that you don’t have to give docetaxel to see the benefits of PSMA lutetium. This was a, by design, crossover trial where 80% of the patients treated with PSMA lutetium, treated with a second ARPI were offered PSMA lutetium at progression. And so we don’t expect overall survival to be majorly affected. And the progression free survival is really reporting on the real clinical benefit of this approach.

Therefore, overall survival did not show an advantage. And the hazard ratio updated about 3 hours ago was 0.98, suggesting there’s no harm to early use of PSMA lutetium. But not necessarily, when separated by a 6-month crossover, a major difference.

I’m just going to spend 2 minutes talking about a couple of the other new kids on the block when targeting PSMA lutetium. PSMA I&T, this is a separate PSMA binding agent, a separate radioligand therapy. There’s an ongoing and now completed Phase III study that, again, looked at every 6-week dosing for up to 6 doses in the ECLIPSE trial versus a second ARPI. So stay tuned for this.

We have another trial called the SPLASH trial that also looked at a chemo naïve, post-ARPI, CRPC, PET positive population. This met its primary endpoint. All we’ve seen is a press release, not a presentation yet. But a more modest impact of this approach with maybe a 3 to 4-month improvement in progression free survival. No yet data on overall survival which is still maturing.

This was mentioned earlier in the hormone-sensitive lecture, but we’re now starting to move PSMA radioligand therapies into the hormone-sensitive setting, both in nonmetastatic PSMA-only disease but also in the metastatic hormone-sensitive disease. This might someday be a new triplet therapy with the PSMAddition trial.

I think I’m over time, but there are many combinations that are being looked at. We heard about earlier whether ARPIs can sensitize to PSMA lutetium. Dr Sandhu has looked at PARP inhibitors as radiosensitization. I think this data is way too immature to take to your real-world practice.

The ENZA-p study used a risk adapted approach. The idea here is you can use maybe 2 or 3 cycles, get rid of the PSMA avid disease, maybe take a break and save some of the PSMA lutetium for later.

This approach, when added to enzalutamide, built on top of enzalutamide and was superior to enzalutamide itself in a high-risk patient population in delaying PSA and radiographic progression free survival. Again, Phase II data, very suggestive that this approach may translate into earlier settings.

I just want to finish with talking about alpha particles, started by talking about radium. I’m going to finish by talking about newer alpha particles. And I think if you tune in on Monday, you’re going to hear about a new radioligand therapy from Dr Morris. Actinium is an alpha particle. It’s a larger radioligand therapy that induces more DNA double strand breaks. In preliminary data, this has shown some success in rescuing patients and inducing responses even in patients who have failed prior PSMA lutetium, as shown in this case example.

There’s a number of CRPC alpha programs out there. And I think in future ASCOs, you’re going to see this data mature. Whether it’s Monday’s anti-HK2 actinium 2235 trial, that’ll be the first-in-human report, as well as a number of other really interesting compounds.

These all differ in their toxicities and their decays and their daughter molecules. And I don’t have time to go into all the details of this.

I do want to just finish with 1 slide on neuroendocrine prostate cancer. We’ve spent this whole meeting not talking about it. But it is important to realize that about 25% of men, when they die of prostate cancer, do so with treatment emergent neuroendocrine or small cell prostate cancer. There’s actually an audience question about this. And there are a number of markers that are absent in typical adenocarcinoma of the prostate that then re-emerge on small cell neuroendocrine prostate cancer. I think on Monday, you’ll hear Dr Agarwal talk about targeting DLL3, for example, with bispecific antibodies. We’re now developing, along with the group in Australia, new radioligand therapies using alpha particles to target neuroendocrine markers. GPC3 is a really good candidate for that.

Promising Investigational Approaches for Patients with Prostate Cancer — Dr Antonarakis

DR ARMSTRONG: Alright. So we’re on to our final module. So please stay with us until the final end. So Dr Antonarakis is going to give us a sneak preview of everything that’s new and coming in castration-resistant prostate cancer. We’ll start with a case.

DR LOVE: One of the key issues in the management of patients with solid tumors is the use of local therapeutic modalities in patients with metastatic disease, both for symptom relief as well as oligometastatic disease for long-term tumor control. Dr Spencer Bachow has an interesting case where he has questions about using this type of integrated strategy in one of his patients.

DR BACHOW: A 77-year-old man with metastatic hormone-sensitive prostate cancer. He had external beam radiation therapy into the prostate.

He has 2 lung metastases. Biopsy of 1 of the lung metastases shows adenocarcinoma of the prostate.

My question is, would you start this patient just on androgen deprivation therapy with an NHT? Would you give them SBRT alone despite being non-osseous or non-lymph node metastases and kind of delay the time until the patient has to go on androgen deprivation therapy? Or would you plan to combine androgen deprivation therapy with or without an NHT with external beam radiation therapy or SBRT?

Have any of the experts ever used NHT alone in patients with metastatic hormone-sensitive prostate cancer without ADT? I have a few patients that just really can’t tolerate the androgen deprivation therapy. The hot flashes for some of them are just too problematic despite treating them with agents such as venlafaxine. Some patients say I’ll just take my abiraterone acetate with prednisone. I’ll just take my darolutamide alone. I would like to know are the experts experience at using novel hormonal therapy without androgen deprivation therapy.

Anybody ever using the NHT alone in the castrate-resistant setting? You’re taking them off, and their testosterone is still very low, just using an NHT alone.

DR ARMSTRONG: Alright. Dr Antonarakis, you’ve actually published, I believe, on lung-only metastatic prostate cancer. And maybe you could talk to us about the pattern of spread, its prognostic importance and how that might change your management.

DR ANTONARAKIS: So not all visceral is the same, and pulmonary visceral is very, very indolent. It almost always responds to ADTs +/- ARPI. It’s enriched in a favorable genomic profile consistent with SPOP mutations which themselves further sensitize to ADT. The paradox is it technically counts as “high-volume disease” because it’s a visceral site. None of the panelist on this stage would consider pulmonary visceral the same as liver visceral, very, very different. And so in that particular case, those things are going to disappear within the first 3 months with ADT/abiraterone. I would not offer SBRT in addition to that. And I would send genomics, of course. And I would likely not personally add docetaxel.

DR ARMSTRONG: There was another great question about using ARSI alone. And Dr Smith, again, you’ve published extensively on this ARSI alone topic. What kind of patients in your practice are you using ARSI alone therapy?

DR SMITH: Well, you have to be — ARSI, so antiandrogen monotherapy, we’re talking about enza, daro, apa, really have different side effects. They’re not necessarily better, right? So you have less hot flashes and more breast symptoms. We saw data in nonmetastatic CSPC today that there’s a lot of fatigue. So you have different side effects. I wouldn’t classify it as better side effects. So I think you’ve really got to look carefully at what the goal of doing that is. And in the mCRPC setting, the time to recovery of testosterone is very long, so I don’t really see the benefit of discontinuing the ADT because the patient’s not going to have a symptomatic benefit. And if they do recover, it can be at a very inconvenient time and cause disease progression, so I’m not enthusiastic about that.

DR ARMSTRONG: Dr Dorff, we’re going to go with you on this question here. And you’ve been a pioneer in the development of CAR T-cells for prostate cancer. So I know Dr Antonarakis may not have time to get to that. But I was on NPR a few weeks ago, and that was a call-in question. People want to know, when can I be cured with that CAR T-cell therapy?

DR DORFF: Yeah. All of the CAR T-cells that have been tried in prostate cancer have shown some ability to achieve very, very good, deep remissions but in a very, very small number of patients. So CAR T-cells can have a lot more modifications that can make them more effective. And it’s possible we’ll need to study them in combination. But I still believe we can get to cure with CAR T-cell therapy. It’s just we didn’t in the first-generation of trials, but we saw proof of principle that it can work. And it’s about navigating that therapeutic index, getting it to a point where we can have robust, deep, long-lasting remissions but without excessive toxicity.

DR ARMSTRONG: Thank you. Dr Antonarakis, you’ve helped lead some of the monotherapy trials with pembrolizumab. And I think we’ve now seen 4 negative Phase III trials of PD1 blockade costing hundreds of millions of dollars. So in which patients do you consider PD1 inhibitor therapy in prostate cancer in 2024?

DR ANTONARAKIS: Unfortunately, it’s the 3% with microsatellite instability high or mismatch repair deficient prostate cancer. And a few years ago, there was some enthusiasm which I think has died down about CDK12 deficiency also potentially being an immunotherapy sensitivity biomarker. I think the present data do not support that as much as we initially thought. And yes, there have been 3 negative mCRPC studies and also 1 negative mHSPC study with pembrolizumab as a monotherapy as well as a negative Phase III study of pembrolizumab plus olaparib compared to RP switch. So we’ve had 5 graveyards with pembrolizumab-based therapies except for the MSI-high.

DR ARMSTRONG: Yeah, prostate cancer evades the immune system in unique and different ways much like luminal positive breast cancer. It doesn’t tend to respond to the traditional PD1 therapy. And many labs around the country are trying to develop and identify new immune checkpoints that could be overcome. Myeloid checkpoints is emerging as an area, other prostate-specific checkpoints. So I think we still need to work on this. Now cabozantinib can actually inhibit myeloid suppressor cells. So I was not going to ask Dr Agarwal this question since he’s the leader of this trial, but maybe we’ll have Dr Smith play FDA today.

DR SMITH: Happy to wear that hat.

DR ARMSTRONG: Yeah. Make a decision for us. Is the atezo/cabo data that’s been presented so far sufficient for FDA approval?

DR SMITH: My speculation is no. It is a positive trial. I’ll admit it’s prespecified boundaries for rPFS improvement, so it is a technically positive trial. And my view is that it’s not a clinically meaningful risk/benefit calculation based on current information. I’m more than happy to have my opinion changed by new data, but I would need new data to alter that view.

DR ARMSTRONG: We’re going to talk about some of the other exciting compounds. Dr Dorff, maybe you can talk a little bit about PTEN null prostate cancer and whether you believe inhibiting that pathway by itself is going to be sufficient to change the needle.

DR DORFF: It’s been tantalizing, right? We know 60% of our CRPC patients have PTEN deletion. And the PI3 kinase AKT pathway clearly drives progression. And we have agents that can target that. But the IPATential trial with ipatasertib, a Phase III trial adding that to abiraterone, was negative. But when they looked at the NGS, it looked like had they molecularly selected, maybe it could have been positive. So I still have hope and I do think hormone-sensitive is different than castration-resistant when you’re looking at synergistic pathways and bypass pathways. So the capivasertib trial which is being done in metastatic hormone-sensitive, with that NGS selection for a molecularly enriched subgroup, I think could be positive.

DR ARMSTRONG: Dr Smith, you presented today about CDK4/6 inhibition. And maybe for the audience that may not have been at the oral session right before us, you could summarize those results and maybe what you think of that whole approach that’s been so successful in breast cancer and what you think of that approach and how we could do it better.

DR SMITH: Yeah. Our discussant today, Professor Sandhu, did a spectacular job of sort of highlighting the biologic differences between breast and prostate cancer. So while there are many overlapping parts of the biology, and leading up to the design of this Phase III trial, there was good, I’d say, very solid nonclinical evidence for this approach, the study was ultimately negative. It was sort of particularly disappointing because the study also had this adaptive design with early stopping rules that just missed sort of being stopped earlier when you look back at the data blinded to the investigators and the research team. So clearly, the biology doesn’t carry forward to prostate cancer. And I think that particular approach, CDK4/6 inhibition, you have to have a very long, hard look at that as to whether there’s a path forward there. I would say based on current information, no.

DR ARMSTRONG: Great. I think we have time now to finish up with Dr Antonarakis talking about all the promising new therapies that are coming.

DR ANTONARAKIS: So it won’t be all of them. And if there are people on this stage or in the audience that are working on something that I didn’t discuss, please forgive me. And this also reflects my own practice and experience.

So I’ll talk about these 6 topics, and I’ll hit the highlights in the next 7 minutes, 50 seconds.

So first, Tanya paved the way to talk about PI3 kinase pathway and its inhibition. We have 2 drugs, ipatasertib and capivasertib. Both of them are AKT inhibitors. And there’s been this longstanding understanding of reciprocal feedback between the androgen receptor pathway and PI3 kinase pathway. I remember about a decade ago when we started to do the AKT inhibitor trials alone without combining with ARPI, we were all surprised that the PSA levels would go up. So you’re relieving a negative inhibition on AR when you block AKT which accelerates, enhances the AR pathway. Well now, we might be able to overcome that by using an AR pathway inhibitor and an AKT inhibitor.

And this was done in the IPATential150, abiraterone plus or minus ipatasertib. And on the left, you’ll see the overall intention to treat biomarker agnostic improvement which was numerically there if you squint hard enough, but not clinically significant and the side effects did not justify FDA approval or even seeking FDA approval. But on the righthand side, as Tanya mentioned, you’re setting me up for success, Tanya, in the genomically defined PI3 kinase activated scenario which was either a PTEN deletion or inactivation, PIK3CA activation or AKT activation at the genetic level, there clearly was a separation of the curves. This was not a preplanned primary analysis and did not lead to an FDA approval of this agent.

But now we have capivasertib, also an AKT inhibitor. And the choice here in the CAPItello-281 is to move this into metastatic hormone-sensitive state. And this is for PTEN deficient patients. So here, with prior learnings and experiences, the decision was made to go into PTEN. And I believe in this trial, it’s being done by immunohistochemistry which is looking for the protein itself. This does not encompass PIK3CA or AKT1 activating mutations, just PTEN, has to be deleted or lost. And, again, this is a metastatic doublet trial, ADT/abiraterone plus or minus capivasertib. No results yet.

And Andy mentioned the DORA trial. I think the DORA trial is probably going to be the second to last docetaxel-based combination because we have the capivasertib combination as well. And this Phase II study published already showed an overall survival trend when you add capivasertib, AKT inhibitor, to docetaxel in an unselected, genomically unselected population. And whether this is an artifact or not, I’m not sure. In the patients that had received a prior ARPI, the response seemed to be accentuated, but not in those who had not received an ARPI.

So here, this is a metastatic CRPC population that is docetaxel eligible. I’m not involved in this trial, but I don’t believe this is a biomarker selected trial. I think they’re enrolling patients irrespective of PTEN status. And if you look at those bars in the middle, they’re getting the docetaxel every 21 days. And then on the second, third, fourth and fifth day, they’re getting the oral AKT inhibitor. And then 4 days in the second week and 4 days in the third week. So they’re calling this 4 days on, 3 days off. And I think the biomarkers are built-in, but it’s not the prespecified primary endpoint. So this may be the 27^th negative docetaxel trial, but let’s — I hope there’s no one from the company in the audience.

The next one, my friend Neeraj, has led this for about 5, 6 years now, a TKI combination. In this case, cabozantinib plus atezolizumab. Again, we had a spoiler alert a few minutes ago. And the rationale here is that cabozantinib, which is a multi-TKI inhibitor that inhibits multiple aspects, VEGF, R2, MET, AXL, TAM kinase, might actually eliminate or reduce myeloid derived suppressor cells, might increase CD8 effect or T-cell immunity, might actually skew microphages away from an M2 and into an M1 state.

And in the published COSMIC-021 trial, there were quite impressive, I don’t think anybody would argue with the impressive activity here. These were mCRPC patients that have predominantly soft tissue diseases, so you can measure objective response rates as well as PSA response rates.

And this exciting data led to the Phase III trial. So here, this was, I believe, one of the first or only studies where measurable disease was actually a requirement for enrollment. So these were mCRPC patients. They had received 1 prior ARPI. They had to have measurable disease which could have been a lymph node disease. And then they were randomized, as you can see, to the AR switch, as we now call it, or the combination of cabo/atezo. PFS, primary endpoint, with coprimary of OS, and a bunch of key secondary endpoints.

So as Matthew mentioned, again, spoiler alert, now you have the data. The PFS endpoint was equivocally met — was unequivocally met. The forest plot shows that most of those dots are on the left side of 1, favoring the combination of cabozantinib and atezolizumab. And the ones highlighted in red, I believe, Neeraj, this might be your slide because I don’t think I made that myself, the liver metastasis group appeared to benefit, the prior docetaxel group appeared to benefit, and the bone metastasis group. All these patients had soft tissue, but the ones that also had bone appeared to benefit. So it looks good. What’s the problem with this one? The problem is that the OS in immature. And the other problem is that the cabozantinib alone, when it was compared against placebo, and the study that was almost a decade old now was Matthew’s study, also showed a PFS advantage of this magnitude with no OS advantage. So the doubters in the audience, and I might be one of them, Neeraj, might wonder whether the atezolizumab is adding anything other than toxicity and expense. So we would love to see the updated overall survival, and I think the FDA will probably request that as well.

Moving on to hormonal agents. There is a new target, CYP11. We’re all familiar with CYP17, the target of abiraterone. And as many of you know, ADT is sometimes called medical castration. Well, this is a medical adrenalectomy.

It’s an adrenal ablation by inhibiting the most proximal adrenal enzyme that converts cholesterol, which is the backbone to all adrenal steroids, into pregnenolone. And by inhibiting that step, you’re inhibiting all glucocorticoid production, mineralocorticoid production, and yes, sex steroid production including androgens as well. Why would this even make sense? The drug has gone through a number of names. Orion was the first developer, ODM-208. Then Merck took it over. Now, it’s called opevesostat. Since I’m Greek, I’m just going to call it ope for short. And the way that this works, or at least the rationale, is that there are promiscuous steroidal ligands other than androgen that can stimulate mutated forms of the androgen receptor. And those promiscuous ligands could be corticosteroids, progestins, estrogens, which will be suppressed by the drug.

Interesting data presented in a new journal called NEJM Evidence, it’s not that new anymore, but the patients that had activating AR ligand binding domain mutations, as would have been predicted based on the mechanism of action, have the greatest benefit. And while there is some modest benefit in the AR mutation negative patients, those are the ones that don’t have activating mutations, the response is more modest.

This is moving into 2 Phase III studies. This is the first one. This is the advanced disease postchemotherapy trial, metastatic CRPC, postdocetaxel where the control arm is the AR switch in patients that have received 1, but not 2 ARPIs, and the interventional arm is the CYP11 inhibitor. These patients have to undergo hormone replacement therapy, that’s very important, with a glucocorticoid supplementation, in this case, dexamethasone. The dose is fixed. And we learned a lot in the Phase I and Phase II about adrenal insufficiency. And, of course, a mineralocorticoid such as fludrocortisone. So it’s a triple therapy. With abi, we have to add steroid. With ope, we have to add dex and fludrocortisone. There’s also a pre-chemotherapy mCRPC trial.

I want to talk a little bit about proteolytic chimeric AR degraders, also known as PROTACs. These were initially developed by Arvinas. ARV-110 which is now called bavdegalutamide. I’m not going to say that a second time. ARV-776 is the next-generation. And then there’s one from Bristol Myers Squibb/Celgene.

And these are drugs that target the proteasome degradation pathway. They basically use ubiquitin ligase, E3 ligase, to target the androgen receptor protein to the proteasome for degradation. So they break down the androgen receptor. The important thing is these do bind to the ligand binding domain of the AR. They are not capable of binding to splicing variants. So if you wanted a solution for ARV7-positive prostate cancer, this is not the one because it still requires the LBD.

The Phase I and Phase II trials showed activity. And it’s hard to read the blue, green and purple bars on the right, but in the mutation positive patients, again, these are AR activating ligand binding domain mutations, especially the T878A and the H875Y, in those particular mutational groups, the efficacy was greater. For financial and commercial reasons, this drug was replaced and will not be moving into Phase III.

But the next-generation ARV-766, which was presented at this meeting, I didn’t have those slides in advance of this meeting, so this is just the study design. And this is another oral PROTAC, again, AR degrader, binds to the ligand binding domain.

And then there’s a third agent, BMS-986365, being developed by Dana Rathkopf and Andy Armstrong, which is both a proteolytic AR degrader, again, using the cereblon E3 ubiquitin ligase targeting mechanism plus an AR antagonist. So again, this binds to the LBD, it induces degradation to the proteasome, and at the same time, functions as an antiandrogen. And while the data, again, are preliminary, there does appear to be, at least in my eye, a slight numerical enhancement of the efficacy in the AR LBD mutated patients, perhaps due to similar mechanisms. We will see if that pans out.

Now if you were attending any other oncology sessions throughout this meeting, you would have heard a lot about antibody-drug conjugates. The one that I want to focus on is antibody drug conjugate, vobramitamab duocarmazine. I’m not saying that a second time.

But this is targeting a novel, although not so novel anymore, supposedly immune checkpoint B7-H3, also known as CD276, also known as PD-L3. And this is in the same family as the other B7 ligands such as PD-L1, also known B7-H1, PD-L2, also known as B7-H2. So this is a ligand, not a receptor. And in fact, the receptor for B7-H3 is unresolved. If you want to become famous in the field, you should discover the receptor for B7-H3 and figure out how to block it. But we can block the ligand, which is B7-H3 itself, and we can also use the expression of this, which is 85% to 90% of prostate cancers, as a target for a chemotherapy payload to enter the cell of a B7-H3 expressing cancer cell.

And this is the design of the vobra duo, as I’m going to call it. So it’s a B7-H3 antibody-drug conjugate targeting using a payload of duocarmazine.

Interesting data from a Phase II. Andy’s standing up. I don’t know quite what that means, but it’s making me nervous.

And the TAMARACK trial is going to be reported soon. This was a randomized study, but both arms had the ADC in there. And what was being tested here are 2 different doses. This is intravenously administered once every 4 weeks. And the doses here were 2 mg/kg every 4 weeks or 2.7. Again, this will be presented at a future meeting.

And the last one is, I’m not going to talk about CAR T because I would feel like an imposter in front of Tanya, but I do want to talk about bispecific immune engagers. We may not be allowed to call them BiTEs because that’s a copyrighted term, but AMG. It’s now called xaluritamig. All these drugs, you have to practice ahead of time before you come to these sessions.

So STEAP is the target of this one. It’s a 6 transmembrane protein that is expressed in prostate cancer and Ewing sarcoma. I’m not going to say much about Ewing’s. But in prostate, it’s expressed in 80 to 90%. It appears to be slightly higher expressed in the mCRPC compared to the hormone-sensitive. And it’s expressed even in patients with PSA low or negative cancers. So this provides an alternative, an additional target.

And this is the compound. It used to be called AMG-509. It’s a bispecific antibody. It targets STEAP1 and it engages, like many of these, the CD3 T-cells.

And these data were very surprising to all of us when they first came out in Cancer Discovery, Kevin Kelly. For a bispecific engager, this level of clinical efficacy was pretty eye opening, at least to me. And of course, there is a cytokine release syndrome risk. And there has to be careful monitoring of these patients, at least for the first dose. And many institutions require inpatient admissions for CRS and mitigation strategies and treatment strategies. But I have not seen any CAR T or any other immune engagers in the prostate space with that level of efficacy.

And by the way, this was not limited to bone disease. There was unequivocal efficacy in liver mets, and quite large ones at that. And on the right, you can see a PSMA PET scan with, again, in this trial, they were not using this in conjunction with any other antitumor therapy, just the STEAP1 ADC — the STEAP1 bispecific.

So with that, I will end and leave you with a summary slide. And thanks for sticking around until the bitter end.

DR ARMSTRONG: Thank you, Emmanuel. I mean, particularly your pronunciation of those complex words. I think you could all see that the field of prostate cancer is getting increasingly complicated.

We’re now at 9:00. I do have a list of your questions, but we’re at the time. And what I would encourage you, if you have a burning question, to come up to us after the presentation and we’ll be happy to field your questions. I think for the sake of time and respect for all of your time, it’s late. I would like to thank you for your attention. If you’re really interested, you can wake up early and join Neil Love and his crew at 6:45 for a free breakfast and hear about myeloma.

I’d like to thank all of our faculty for presenting, for you for being here, for the staff for putting together a great program. And thanks for your attention tonight.