Introduction: Evolution of the Prostate Cancer Model; Prostate Cancer Working Group 4 (PCWG4)

DR LOVE: Good afternoon, everyone. I’m Neil Love from Research To Practice, and welcome back to Year in Review, as today we talk about some of the key papers and presentations from the past year in prostate cancer. We have a great faculty today: Dr Andy Armstrong, the Duke Blue Devil about to play St John Red Storm. I don’t know, Scott, whether you’re into the St John’s. You guys are playing on Friday night. But Andy’s at Duke in Durham, North Carolina; Scott is at the Meyer Cancer Center in New York from Weill Cornell Medicine.

Today we’re here to talk about prostate cancer. And as is always the case for our Year in Review programs I met individually with each faculty member in the last couple weeks to record a presentation reviewing in detail the papers that we’re going to be referencing today, if you want to check that out, and then when we send this webinar out we’ll put that out as well.

We will be talking about the use of unapproved agents and regimens, so check out the package inserts for various products for more information.

Here’s where we’re heading today. We’re going to start out, before we kind of get into the papers, and talk about a really interesting paper that Andy was — chaired. I was actually working — when I was working with Scott he was starting to use different terminology to me. APM — androgen pathway modulator-resistant and -naïve, and I’m like where did this come from, and he said well, Andy just wrote this big paper. So we’re going to just briefly talk about that and see if I can get this straight in my mind. It took me a couple years to kind of get ARPi in my head, and now I’m going to try to figure out — well, at least we get rid of the word “castration resistant.”

And you know, faculty, I’ve got to say, just sitting back thinking about the 2 incredible sessions I had with each one of you individually, I was thinking about what’s going to happen tomorrow night with Eunice and Amir, really incredible. Such an amazing privilege and an opportunity for me to talk.

When I woke up this morning, I don’t know, this happens sometimes, I had this vision — and probably less than half the audience has ever heard of Ed Sullivan, but when I woke up and I thought about the great faculty I was going to work with this week I was thinking I’m kind of becoming the Ed Sullivan of oncology. But anyhow, for those of you who don’t know, Ed had a live program on Sunday night. You can see he actually was the first one to have the Beatles. He had — the first one to have Elvis on his show. The Supremes there. He began in black-and-white days, so to speak. So he was able to work with the great entertainers, and I feel so privileged to be able to work with the great oncology leaders that we talk about here today.

So here are the titles of the 2 talks that they both gave. We’re really not going to go through in detail all of that. Go to their talks to get the details of all these papers and what their thoughts are about that.

Today we’re really going to try to take it to the next level in terms of clinical implications and particularly research implications, which really was the focus, Andy, of this amazing — talk about great figures in oncology. Look at the people who were involved in this working group. Really incredible teachers, incredible researchers, including the 2 of you.

And for those of you who are into GU oncology, if you’re a fellow in GU, or you’re an assistant professor, you probably need to read every word of this thing and digest this. But for those out there in the real world the one thing that I talked about that I wanted to get Andy to comment on, again, is this new terminology, I guess with the idea — that wasn’t the main point of the paper. The main point, as you can see, was really to focus on where things should be heading in terms of trial design.

But Andy, all of a sudden we now have this new approach. I’m really happy to get rid of the word “castration.” I know that you’re very patient oriented. But can you just give us a little bit of a briefing on what the Prostate Working Group is, I know this is the fourth time you all have met, bottom line in terms of how you’re — what you’re calling these different states nowadays? APMN and APMS for example.

DR ARMSTRONG: Yeah. Thank you, Neil. Yes. This is the fourth iteration, and it’s kind of an every-10-year iterative function. We had 65 coauthors, international kind of dream team of investigators that came up with this terminology, and it’s something that will now be layered into new clinical protocols, hopefully FDA and regulatory labels.

We’re jettisoning the term “castration” because we all recognize we’re not using that term in clinic, patients don’t want to be labeled as such, and we’re creating a new basket term, androgen pathway modulator, which encompasses androgen deprivation therapy, these AR pathway inhibitors like enzalutamide, abiraterone, darolutamide, apalutamide; a lot of new drugs coming in the next 10 years, AR degraders, AR RIPTACs, cofactor inhibitors, cytochrome 11 inhibitors, which are going to be in that basket.

So we’ve kind of provided this little appendix here for translating the old term to the new term. We also have PSMA PET, which didn’t exist 10 years ago for the last guideline, so we’ve redefined metastatic disease using very sensitive imaging techniques. And so the guidelines kind of are soup to nuts on eligibility endpoints, ctDNA, circulating tumor cells, PSMA PET endpoints, progression, response, so a great treatise for protocols and writing.

DR LOVE: So for the Talmudic scholars of oncology, you can check out the details of this.

Hormonal Therapy

DR LOVE: But I want to move on and start talking about some of the papers that came out this year and kind of what they mean and where things are heading. And Scott, I’m calling this the year — I would have called it the year of the — until I talked to you 2 I was going to call it the year of the hormone-sensitive metastatic disease, but now I’m going to call it the year of the androgen pathway modulator-naïve or -sensitive, right, “S” also, breakthroughs.

DR ARMSTRONG: Yeah.

DR LOVE: Because I know you can say well maybe they were a long time coming, but to me we have 3 Phase III trials that were positive, 2 we don’t know whether we’re going to see an approval or not, 1 we have, of really new therapies in this space, new triplets, I guess instead of docetaxel. We’re going to talk a little bit about it, but obviously we saw PARP with niraparib in this space, we saw an AKT inhibitor, we just did a CME program at the GU symposium on capivasertib, an AKT, and then of course lutetium also in the same space with the PSMAAddition study.

So Scott, I just want to start out, before we get into some of these trials and what you all think they mean, a little bit about how you think through when you know that you’re about to deal with a patient who fits into this APMN situation. And a couple things I want to know about how it affects the way you think: (A) Whether the patient’s de novo or metachronous, Scott, (B) Whether or not they have PSMA-positive but conventional imaging negative state, or are they conventional positive. As Andy said, that’s kind of a newer thing. And then also biomarker implications, and that we’re going to get into more with some of the clinical trials, but also in terms of prognosis in terms of PTEN. So Scott, want to take a shot at how you think about this?

DR TAGAWA: Sure. Well, first of all, I would say that the first point in terms of de novo versus metachronous, number 1, there’s prognostic implications. It’s a worse prognosis if it’s de novo. But the other part of the equation in terms of treatment in de novo settings is should we directly treat the prostate or not. Officially that is — with modern-day therapy that is a clinical trial that we’re all paying for in the United States, a cooperative group trial, but there is some evidence that treating, especially in lower-volume disease settings, is something to do.

The other thing that I really want to emphasize is that for essentially all of these when we have what I think of as true metastasis on CT and bone scan the standard of care is at least 2 drugs, so I have to think — I need to have an excuse why I’m not going to give at least ADT plus an AR pathway inhibitor. It’s not 100%, but it should be the vast majority, and still not everyone in the community is getting these for a number of different reasons. There’s a lot of reasons why it’s not all the time, but it’s something to kind of think about.

The PET only, I think that is an emerging subset, where someone is diagnosed with prostate cancer, and the scan that we get is a PET scan, many of those we’d also see on a CT and bone scan, but we’re not always getting a CT and bone scan. I will call out that right — literally right now ASCO has guidelines in development that are out there for public comment, and I will tell you that one of the initial questions is should you get another scan. Should you get a CT and/or bone scan if you start off with a PET with metastatic disease? I don’t know what the answer is going to be, but it is an unknown situation because all of these Phase III trials, going back more than a decade, going back to CHAARTED 2014 readout, so it started way before that, used CT and bone scan. So applying Level 1 evidence is difficult, and we just need to extrapolate and consider what it really means with the individual patient’s goals.

DR LOVE: So we’ve got some slides in the deck here that we’re not necessarily going to talk about, but they’re there if you want to look at them. I’m going to flip through them. We’ve got some really cool algorithm slides. But I just want to — focusing still on these questions, Andy, anything you want to add to it?

And one other thing in general, whether or not you’re going to use AKT — or capivasertib, what are your thoughts in terms of PTEN as a prognostic marker? We’ll talk about the CAPItello study, but one of the things about it was these people really had a poor — very short disease-free interval. You didn’t always see the PSA go up, and they might have had positive imaging. So even from following a patient point of view do you think PTEN is something you want to know? And anything else you want to add to what Scott just said?

DR ARMSTRONG: Yeah, thanks, Neil. So PTEN loss is associated with a worse relapse risk and a poor prognosis on doublet therapy. So ADT/ARPi patients don’t do as well, and they have less durable responses when they have PTEN loss. And that was the basis for the capivasertib trial, and it did meet its primary endpoint of delaying progression-free survival with added toxicities and not yet a mature survival slide deck. We don’t yet know if that’ll get approved.

Likewise, BRCA2 mutation carriers have a worse prognosis with ADT/ARPi doublet therapy, and we do know that we can rescue some of those patients with a PARP inhibitor like niraparib, and that was just FDA approved.

PSMA positivity, however, only, is a good prognostic finding. So if you have PET-only disease without conventional metastases that’s kind of an EMBARK-type patient population, I think we’re going to talk about that a little bit later, and that’s where I might offer intermittent therapy just like you have on the slide here.

DR LOVE: And so I’ll point out, too, this is the NCCN algorithm. They haven’t quite caught up to your terminology yet. They’re still calling it hormone-sensitive prostate cancer, so hopefully when they meet — your paper just got published I think a couple weeks ago.

DR ARMSTRONG: Yes.

DR LOVE: But I’m sure the principles will stay the same, but maybe the wording will be a little bit — and there’s yours with more —

So Scott, again, drilling a little bit more down into this APMN situation, we’re going to talk — Andy was mentioning EMBARK. And one of the things that’s really striking to me about the EMBARK STUDY is the fact that they used intermittent therapy in all 3 arms, including enzalutamide monotherapy. And prior to that it kind of — I was hearing you all say well, I don’t use intermittent therapy in metastatic disease, I use it in PSA-only disease. Of course that all blew up when we saw most of the EMBARK patients really probably had metastatic, at least on PSMA.

So I’m curious. Now, how do you decide, Scott, whether you’re going to use intermittent endocrine therapy. Are you looking at bulk? Disease bulk? How do you make that decision? And when you use intermittent therapy what do you observe? Do you see people actually improving symptomatology when they come off therapy, which of course we’ll flip through and Andy goes through in his talk. You see a longer period of time off therapy if they get combination. But Scott, how do you think about intermittent endocrine therapy right now in the APMN situation?

DR TAGAWA: So my attitude hasn’t changed very much in the setting of biochemical recurrence, so some therapy to the prostate. It could have been 1 or 2. I do think we need to keep in mind that some patients can be cured with salvage therapy, so we don’t want to ignore that, with a local therapy. But in the biochemical recurrent setting if I’m going to employ hormonal therapy, which is generally for a higher-risk or shorter doubling time patient population, my practice has forever been to administer intermittent therapy.

Keep in mind the entry criteria for studies such as EMBARK or PRESTO, knowing that some of these would have had lower volume, and that’s why I think it’s mostly a volume issue with something that’s PET-positive and not positive on CT and bone scan. And it may be a little bit having to do with the AR pathway being intact because there’s an association there, but overall I think it’s a volume issue, so for low-volume disease I am generally employing an intermittent schedule. I’ve kind of always looked at around 9 months, as little as 6, as much as 12, but because of EMBARK that went in weeks rather than months, but I think it’s easier to say 9 months to a patient, whether it’s 1 or 2 drugs, and then pause.

That being said, when we look at the data, when we go back to true bone metastatic disease in SWOG 9346 or EMBARK, the patient-reported outcomes are actually that different in those overall patient populations. A little bit of differences in sexual function, and actually in 9346 their testosterone was still low, so I think it was they knew they were on a break.

But anyway, it’s not everything that automatically gets better, but many of my patients do at least subjectively feel better. And I can say even for metastatic APMR disease, when someone’s on say an oral drug, I say are you having any side effects, no, and I stop it because they have progression sometimes they actually feel better. So some of the things are kind of in the background that they may not notice.

DR LOVE: So Andy, our audience may know that I immediately fell in love when I first saw the EMBARK study. It’s one of my favorite studies in all of oncology. I love it. We just saw survival benefit. It got a standing ovation, I think, at the ESMO meeting. One of the things I really loved about it was enza by itself looked like it was about as effective as ADT alone, which has been our standard for 20 years. Now, obviously, I think most people would rather go for the combination.

But I am curious whether or not — first, if you want to add anything to what Scott said about intermittent therapy and also how you approach the issue of enza monotherapy, how often you use it, what do you do to prevent gynecomastia. Any thoughts about how to use it?

DR ARMSTRONG: Yeah. Thank you. I agree with what Scott said. I would just add that patients with low-volume conventional metastasis I would offer — also offer intermittent therapy to if I’m employing metastasis-directed radiotherapy for example. We’re now doing PSMA PET on so many patients it’s hard to imagine that situation, but using MDT to extend that duration off gives patients a chance to have a more durable quality of life.

With ADT/enza the median time off therapy was about a year and a half. With enza monotherapy it was relatively short, 11 months. And with leuprolide alone it was about a year. So you can enjoy intermittent therapy. You see that data right here. With enza monotherapy that was kind of a tie with leuprolide, but the combination was more of the winner. That had the survival benefit, that had the metastasis-free survival benefit, and it had the longer treatment suspension period, so talk about more durable quality of life benefits.

There was no MDT in EMBARK, so my hope is that when we start to mash up these 2 approaches, we’ll get longer treatment suspensions. And there was only 1 treatment break in EMBARK. I would like to see more data on second, third and fourth holidays.

DR LOVE: That’s a great point. And again, you can check out Andy’s presentation for more. He goes into this really great paper looking at EMBARK-like patients showing that really most of them do have metastatic disease. This great algorithm he goes through in terms of a model of prostate cancer.

But Scott, I was curious about — I was excited when I first saw relugolix came out. It was an oral agent. It’s interesting what they initiated reported in terms of cardiovascular morbidity. Where are you today, Scott, in terms of utilization of relugolix versus systemic therapy or intramuscular therapy with leuprolide acetate or other agents?

DR TAGAWA: So I believe in the totality of the data plus a little of the mechanistic data that the GnRH antagonists have a little bit less cardiovascular toxicity than the agonists. I say a little bit less because the main trial that we have results on was aborted early, but that we have results on didn’t show a major effect, but that one mandated a cardiologist. So I think that we want to work in a multidisciplinary situation that includes our internal medicine colleagues. I think most of the people listening are medical oncologists. So adding a cardiologist I think does help. But I do think that there is — the trend is for less cardiovascular toxicity or less MACE (major adverse cardiovascular events) with an antagonist.

Many of us treat metastatic disease, and they’re on ADT, in my mind, in the background as we’re marching through these other therapies, and I think it matters a little bit less. I would comment that I like having all the options, but it is an extra pill when they’re on some other pills. But the off in terms of testosterone recovery, even head-to-head against the other — the injectable antagonist, appears to be faster testosterone recovery. So when I want — let’s say with unfavorable intermediates, when I’m giving a short course of hormonal therapy, or intermittent therapy if it’s a GnRH alone, which we do less now because of EMBARK, that’s when I really favor the oral version.

DR LOVE: So Andy, any comments? I know you’re more likely to use relugolix if the patient’s going to be in short-term therapy, but what do you see when you stop the relugolix, and the other agents, too, but I’m particularly interested in terms of what you observe clinically, how long it takes people to regain their testosterone and they start reporting feeling better.

DR ARMSTRONG: Exactly. It’s about 1to 2 months for testosterone recovery after cessation of relugolix, and it’s about 3to 6 months from when the expected leuprolide is supposed to wear off, so that’s a big advantage if you don’t need to be on the ADT. It’s a little bit of a double-edged sword because if there’s testosterone recovery, and you haven’t cured the patient, there may be a more rapid PSA rise. So if you’re using it intermittently in a metastatic setting or an EMBARK-like setting I do worry that the off period might be a little shorter with relugolix, but in a curative intent setting, intermediate high-risk patients getting radiation, I like relugolix because the goal is cure and get back to life without side effects from the ADT.

DR LOVE: I was mentioning a program we did with Dr McKay, and she had a great paper at the GU symposium, a real-world report on the use of relugolix. Has a lot of interesting data.

So we’re talking about medical oncologists, but also we have urologists who are dealing with prostate cancer. And I mentioned we had a program on AKT at the GU symposium. We also had one last year at AUA ,where we were talking to urologists about AKT inhibition for the first time, and we were — we just had an entire webinar just on hyperglycemia with AKT inhibitors. Of course, AKT inhibitors, including capivasertib, inavolisib and previously alpelisib that kind of got pushed away because in terms of toxicity, but their kind of eyes were wide open. It was kind of a new world. We talked a little bit about what was seen there just in terms of reproducing the fact that the control arm had a pretty poor prognosis.

So Scott, this is still, I guess, making its way into or through the FDA. We’ll see whether or not it actually gets approved. We did see a PFS advantage, it did reach that endpoint, but there’s a debate about whether or not it’s time to use it, if and when we see a survival advantage. Also, Dr Fizazi reported more benefit with higher levels of PTEN depletion. If you go from — you needed 90% to get in the study, but if you went up to 95 or 100, I guess worse prognosis, as well as better efficacy.

So Scott, anything you want to say about the data that was presented there, where you think things are heading in terms of AKT inhibition, and also just in general — and here’s some quality-of-life data that was presented, but also just in general where you see things heading in terms of targeting this pathway and using capivasertib, which also is given 4 days on, 3 days off, which is kind of a different approach? But Scott, any thoughts?

DR TAGAWA: Yeah. I like the approach. There’s a lot of scientific rationale. So one of the mechanisms of resistance to AR targeting is the PI3 kinase pathway, and that’s really hard to target in solid tumors because it’s a different isoform. But indirectly targeting it is more possible, AKT or mTOR, et cetera. I would say that all the 3 trials that you mentioned are positively designed because they’re all trials for rPFS. How much does that mean in the setting of a lack of OS, it’s an individual kind of decision, and I think having the agency weigh in will be important, especially in terms of availability.

I would have loved mentioning the kind of intent to the biomarker, let’s say with 99 or 100% loss, if that was worse for the control arm and better for the interventional arm, but it wasn’t. It was basically the control arm was worse, worse prognosis. It wasn’t necessarily any better for the addition of the AKT inhibitor. So it did improve the therapeutic index but not as much. I suspect that this — if this is approved it may be like — this is my opinion, it may be like niraparib, that it’s a subset of the overall trial, at least at an early timepoint had a bigger benefit. To me, comparing across trials maybe is not quite as good, but I do like the idea of a biomarker-selected, scientifically driven type of a therapy.

DR LOVE: So Andy, again, we spent an hour and a half talking about this topic at GU ASCO. These are some of the issues that came up. I’m curious to see if there’s anything you want to add to what Scott said but also these issues. One is how are you going to — if it gets approved and becomes accessible how are you going to test for it? Is it going to be NGS or IHC where you see quantitation, which the trial required 90%, you would need IHC?

Another thing, and this came out in our diabetes webinar. We had a diabetologist from Mass General there talking about hemoglobin A1c levels. I think it could be up to 8 to get into the trial. We actually presented a case like this, who had a hemoglobin A1c of 7.4, and Dr Fizazi was like oh, yeah, we treated those patients. But how are you thinking about that, Andy, I don’t know if you’ve been talking to your breast cancer colleagues, and where do you see things heading with AKT inhibition and capivasertib in general in prostate cancer, Andy?

DR ARMSTRONG: All great questions. I think IHC is certainly easy. Our pathologists can do that in house, and they developed the IHC assay around 90% to correlate with homozygous PTEN deletion on NGS testing. So I think if you have homozygous depletion that’s really going to be an adverse prognostic indicator and would indicate the patients most likely to benefit if it’s approved.

I would have liked to have seen survival data, and I think more mature survival data will really tell us whether this will get approved. It is a new entity. It is more toxic. There is a detriment in quality of life early on, and there’s some real toxicities. PI3 kinase is important in insulin resistance, so understanding how to manage the rash, the diarrhea, the hyperglycemia is really important if it does get approved.

So I would like more biomarker data to understand who’s benefitting the most from this population. I think it’s probably the 100% population, but even those patients are still progressing, and they’re not living longer, so I would like to see us add more to this and take novel approaches.

DR LOVE: And I guess one — we had another — we had actually — actually, Rayna presented a case at the GU of a patient who was on a docetaxel triplet with — who had PTEN deficiency who did not have a very good response to it, and she was like I wonder if I’m going to be adding capivasertib to patients like this in the future. I don’t know if replacing docetaxel or adding to it.

Also, I know it’s a different disease, but I’ll tell you, the hazard rates for AKT inhibition in breast cancer are pretty impressive. This can be an effective therapy. We’ll see if that’s going to be the case here with prostate cancer as well.

And then we’ve got the AR degraders coming along. There’s BTK degraders, ER degraders, but now you’ve got AR degraders.

Chemotherapy (Docetaxel)

DR LOVE: But going back to the old days, so to speak, Scott, also I had some questions about chemotherapy because we saw a paper looking at Q2 week docetaxel. This was really more for, supposedly, more frail patients, although it looked like certainly it’s better tolerated. It looked like the efficacy was pretty effective there.

But I’m just curious. With all these crazy things going on in the APMN space, Scott, right now how are you deciding whether to use a docetaxel triplet? We’ve been hearing for a while younger patients who can tolerate it who are higher risk or higher bulk. I’m also curious. Do you ever use the strategy being looked at in the so-called TRIPLE-SWITCH trial, where you just start out with ADT and an AP blocker or APM blocker or ARPi, and then switch if they don’t have a good response? And what about Q2 week docetaxel? Sorry for answering so many — asking so many questions, but is that just going to be for the older, frail patients, Scott, or would you give it to a younger patient?

DR TAGAWA: So I would say at a high level de novo high-volume disease in a patient who’s a chemo candidate. That’s kind of my, I think, the minimum that is there. Going back to the — part of the prior conversation it’s interesting that the — when we look at the genomic classifier background, the PTEN signature, that at least in STAMPEDE, which didn’t have the concurrent ARPi, there’s a signature that may indicate that’s when docetaxel may add there.

When I think about the old-fashioned CRPC metastatic patient population and all the trials we did looking to beat docetaxel 75 mg/m2 the only one that arguably did is Q2 week docetaxel. Actually, it was — the primary endpoint safety, but actually the overall survival was better in the Q2 week, and there are multiple reasons. That was in Lancet a long time ago, but —

So anyway, I have not used Q2 week docetaxel in this particular situation. For someone I was worried about right now, because I don’t know how much docetaxel adds, I would probably do the ARPi doublet, but I do think it’s a reasonable option when we want to do it.

I think the TRIPLE-SWITCH approach is reasonable. There are 2 not exactly competing but 2 trials in the same disease state. So ASPIRE is the other cooperative group trial right now that’s ADT/ARPi with or without docetaxel because the additional of docetaxel has never been proven. I’m biased by our preclinical scientists that it’s the synergy together that is more than kind of getting the residual other cells. But anyway, it hasn’t been proven that docetaxel adds to the ARPi doublet, so I would enroll them in a trial if I could.

DR LOVE: So Andy, again, all these topics are discussed in much more detail in the presentation. This is kind of a tasting menu just to bring up some of the key issues.

PARP Inhibition

DR LOVE: And again, Andy, we can talk a long time about PARP inhibition, but certainly one of the issues that came out is this, again, in the APMN setting we now have PARP as a consideration with the niraparib study. We already had it available, and I still — I want you to again clarify what the 2 other studies with olaparib and tala in the later-line disease represent kind of an unusual scenario of people who are getting ADT without an ARPi and then need treatment so you can add abiraterone with or without — with or without a PARP. But also now we’re seeing it in the — I’m sorry, I’ve got to say it — in the hormone-sensitive situation.

So bottom line, Andy, you’re on rounds, and a fellow says when do you use a PARP inhibitor in prostate cancer, how do you test for it, what type of alterations do you need to see. The approval now with niraparib is just BRCA2. Later line you have a lot more options. Any thoughts about the BRCAAway study that we go into a great deal? And then, again, what kind of alterations are you using for it in later-line disease? Do you use it for BRCA2? What about BRCA1, ATM, CDK12, et cetera?

DR ARMSTRONG: So there’s 3 main settings that you would use a PARP inhibitor. The first is the oldest, monotherapy with olaparib. The PROfound study showed improvements in survival, particularly for BRCA1/2 carriers, but there was also benefits in delaying progression in other patients with homologous repair deficiency. So when I’m seeing a patient who’s already had an ARPi, maybe chemo, maybe PSMA lutetium, and I detect that homologous repair deficiency, that adds olaparib to the menu.

The second indication is a doublet, so abiraterone/olaparib, talazoparib/enza, niraparib/abi. Those doublets were based on hormone-resistant patient populations that had not had an ARPi, and we don’t see those patients anymore, but those were positive studies leading to FDA approval.

What you’re showing up here is 2026. We now have approvals in hormone-sensitive or APMN settings, and that’s based on niraparib/abi showing a delay in progression-free survival and not yet survival for BRCA2-mutated patients, so selectively effective in that group. Not as much efficacy outside of the BRCA2 carriers. Talazoparib, this is a press release literally last week, that showed that it met its endpoint for delaying radiographic progression-free survival. Again, we don’t have the details about the subsets of HRR patients that benefited the most, but we expect to see that at a coming meeting.

We also have the EvoPAR-01, which is testing a PARP1 selective inhibitor in combination with all sorts of other ARPis. This will read out in the coming year or 2. And so hopefully in the hormone-sensitive setting we’re going to have another selection of choices of different triplets, most likely to be most effective in the BRCA carriers and then second most in the non-BRCA but HRR-positive patients. And whether it’s effective in non-HRR entirely, that’s going to be the test of the EvoPAR study.

DR LOVE: So we also have, as you were mentioning, this new PARP inhibitor, as yet unapproved, saruparib.

DR ARMSTRONG: Yup.

DR LOVE: I think it’s PARP1, I think it is.

DR ARMSTRONG: PARP1, yeah.

DR LOVE: And interestingly, too, this press release, this is now PARP with ARPi, with enzalutamide. The other one before niraparib was with abiraterone. Am I remembering that correctly?

DR ARMSTRONG: Yes.

DR LOVE: Okay. So now we’re going to see another study, but now with enzalutamide.

So Scott, any thoughts? Would you like to? I mean, I feel like using PARP in a patient with BRCA2 in the APMN setting is something I think people would have been wanting to do for a long time, but how are you thinking through the data? Is that something you something you think you might want to do? And what do you think about this new PARP inhibitor? Any hints of whether or not it might be more efficacious or better tolerated than the ones we already have? And also, it looks like they’re also looking at it in earlier-stage disease, as well, and as Andy said, in non-HRR patients. Any thoughts about these — this new agent and where you are today with APMN and PARP?

DR TAGAWA: So the nice thing about BRCA2 is I think it is both poor prognostic for not using PARP but also predictive for using a PARP inhibitor, whether it’s a nonselective or probably a selective one. So that’s, I think, the little bit of a difference between, at least what I’ve seen so far, with the capi data. So yes, I would be interested.

I’d say the nicest thing about, not that I know it’s going to be approved, but assuming that the TALAPRO-3 study leads to approval is that will have — I mean, preclinically maybe there’s differences with niraparib and talazoparib, but I’m going to say clinically they’re the same, but I’ll have the choice, as you kind of alluded to, on ARPi. I won’t be stuck with abi. I could use an ARI and enza. I think that’ll be the nicest thing for this patient population, but of course I have no idea what — I don’t know the data. And of course I don’t know what the FDA’s going to say in terms of the overall population or a subset.

I haven’t seen any head-to-head data of PARP1 selective versus an unselective PARP, but the initial Phase I single agent across tumor types had some efficacy post nonselective PARP inhibition, and there was a hint that the toxicity, and scientifically it’s supposed to be less toxicity, so we’ll see. So I was a little bit disappointed in what I saw in terms of the toxicity profile, meaning there still is toxicity, but we’ll see.

The study that you’re showing of the combinations with all the different ARPi agents, that I take as feasible and safety. Very hard to interpret the efficacy because most of them were ARPi naïve and some were actually ADT naïve or sensitive. So that’s difficult, but that set the stage for the initial studies for AMPLITUDE/TALAPRO, that setting, just positive biomarker and without, and then the even earlier one as an adjuvant with radiation. We’ll see. That one, I think, because it’s so early, I think really needs to be biomarker selected. None of these — we all said for all of these studies we don’t have the longer-term efficacy data, for all of these drugs, including PARP inhibitors, we also don’t have the long-term toxicity data, so that’ll be important to kind of see what happens there too.

DR LOVE: So again, I know breast cancer is different than prostate cancer, but we are using PARP inhibitors in the adjuvant setting with breast cancer. We’ll see how low we go with prostate cancer, and I think this study with this new agent is going to be very interesting in that regard.

Radioligand Therapy

DR LOVE: So I want to move on now and talk about radioligand therapy, including a new radioligand agent I just heard about. Talking about abbreviations, you’re going to explain to me about what’s called the WARMTH Act trial, which I can’t figure out where they got these letters from, but pretty cool-looking radioligand.

But let’s start with what we have and some updates on that, as well as, of course, one of the big papers of the year, again in the APMN setting, the PSMAAddition trial. So Andy, can you kind of summarize where we are and what we learned about lutetium this year, both in terms of later-line use and now in the APMN setting.

DR ARMSTRONG: Sure. So right now I’m utilizing PSMA-lutetium in men who have progressed on ADT and an ARPi and have PSMA PET-positive disease using the kind of older VISION criteria, and that’s where it’s most population, FDA approved. We don’t have an FDA approval in earlier settings. But the PSMAAddition trial is the first Phase III to test the idea that early use of PSMA-lutetium in conjunction with that doublet ADT/ARPi regimen could extend progression-free and overall survival.

And as you see here, it met its primary endpoint for delaying progression-free survival by about 28%. The overall survival had a favorable trend but not yet significant, and more data will be needed because this data is very immature for event rates for survival. The expected side effects you see here: a lot of dry mouth, fatigue, nausea, anemia, thrombocytopenia. We worry about myelodysplasia, clonal hematopoiesis, that that could predispose to marrow toxicity later.

I’m also not sure, and I’d be interested to hear Scott’s talk — thinking about this, about whether patients need all 6 doses right up front, or in this hormone-sensitive setting maybe you could do a sandwich approach of giving a few doses, reimage, if they’re getting a complete remission reserve other doses for later.

DR LOVE: So again, Scott, any thoughts about PSMAAddition? Is that something you’d like to do right now? Do you want to see more data? If you could, would you actually do it in select patients?

And then let’s talk a little bit, too, about this other radioligand actinium-225-PSMA radioligand therapy, another agent. It looks pretty interesting/exciting. Let’s start out with lutetium. Any thoughts about PSMAAddition, Scott?

DR TAGAWA: I’m biased, but — so overall for my patients I would like to have as many options as possible and then talk them through, even if it’s not a clinical trial. It’s actually an informed consent of these are I think what the benefits are, these are the risks. And I mean I know what the risks are, but I don’t know the data for long term, and we think that in that PSMAAddition patient population we don’t know what the median’s going to be, but 8-plus years, meaning there’s going to be a significant proportion, hopefully, that are alive past 10 years and alive and possibly at risk for other long-term toxicity.

So anyway, I would love to have that as an option, just like I’d love to have capi and an expanded option, niraparib, talazoparib, kind of et cetera, to have that as an option available.

So for the listeners that don’t know, I think anyone who treats prostate cancer should know an alpha and a beta because prostate cancer is the only disease to have an approved alpha. It’s radium-223. And there’s 2 general differences between an alpha and a beta. One is officially the linear energy transfer, you can think of it as much higher potency, and the range is much shorter.

So the way I explain that to patients is having that in the right place, ie tumor, that’s good and probably better than a less potent type of a warhead, and in the wrong place it’s bad. So in the tumor probably good, in the salivary glands probably bad. Although we have very little comparative data we believe, especially with the small molecules, that the risk of dry mouth, for instance, might be higher.

On the flipside, the risk of myelosuppression and probably longer-term toxicity, whether we’re talking about the kidney, acknowledging there’s some … the kidney or the marrow or anything else, it’s probably a lower risk with alphas because the range is shorter, as well as the potency, where if it’s going to kill a cell rather than just damaging a cell.

DR LOVE: So Andy, any thoughts? I mean, the waterfall plot looks really interesting. Fifty seven percent had significant drops in their PSMA. I don’t know if we’re calling this ACT or Act, but we also see that now in a Phase III. I think this is 1 Phase III trial. You see there on the bottom there are several Phase III trials. Any comment on this new radioligand, Andy? Do you think there’s going to be more salivary gland/mouth dryness with this? And when I hear alpha I think or radium, so that paradigm that Scott just talked about, I kind of remember hearing about that with radium. Any thoughts about where this is heading? What about after lutetium, Andy?

DR ARMSTRONG: So actinium-225 is an alpha emitter much like radium-223, and so it’s more potent, which is both, like Scott said, a good and a bad thing, and we have seen more salivary toxicity. Losing your saliva can really impair quality of life in terms of chewing, nutrition and satisfaction with taste. And so we would like to have targets that are not expressed in your salivary glands, and there are a number of cell-surface targets that are under development right now.

PSMA, unfortunately, is not prostate specific. It’s actually expressed in your lacrimal glands, your salivary glands, your kidneys, your nephrons, your small bowel, and so it’s not a perfect target. But we do see responses to actinium-PSMA after lutetium-PSMA, so it suggests that PSMA is still important, still a good cell surface marker, but we see that limitation of the durability. We’d like to see durability beyond 6, 12 months, and we see on-target toxicity with salivary toxicity.

So I’m excited about it. Again, like Scott, I hope this works for my patients so I have other options, but I also think we should be investing in other cell surface targets.

DR LOVE: I don’t know why maybe I’m the last person to realize that, but when you said you see PSMA in other tissues I actually didn’t realize that. But now it makes a lot of sense, although I don’t know what PSMA is doing there from a normal perspective. But anyhow, it looks like we’re going to find out a lot more about this new agent.

New Agents

DR LOVE: And speaking of new agents, as is the case all throughout oncology, there’s a lot of new agents to think about here. Just to give you a little bit of a — I think oncologists in practice know it can be very short between the time we start talking about things and they wake up and check their phones and they see that it’s approved. And certainly that seems like that happens almost every day with ADCs. I think you guys have been a little bit behind, but it sounds like you’re catching up.

So Scott, let’s talk about B7-H3 ADCs being looked at in a variety of cancers. Ifinatamab deruxtecan, obviously the same payload as T-DXd. So Scott, what do we know about these ADCs in terms of efficacy, as well as tolerability? We certainly learned that ADCs are not necessarily going to be without toxicity, but what do we know about ifinatamab deruxtecan, Scott?

DR TAGAWA: So B7-H3, I would say, is — there are a number of different promising cell surface targets, many of which might actually have even more homogeneous expression compared to PSMA. It’s just that PSMA is the first, and the bias has an imaging agent that’s there, so we see it, and we say oh, well let’s go after it. But B7-H3, TROP2, STEAP1 and 2, a lot of other things that are out there, HK-2, that look to be very good, especially in this AR-positive patient population.

And so there’s several ADCs that are out there. One of them that was I think already started, it was … a Phase III trial. It was kind of abandoned, but that doesn’t mean the target is necessarily bad. So this is one of them. The platform, as you mentioned, is well known, good and bad, with a potent warhead that has some bystander effect. And this makes sense.

I think of all ADCs as chemo. I say that to patients. I say targeted chemo, but many of these are actually going head-to-head against taxane chemotherapy, and I think that’s the proper space. Something we’re also going after is a faster pathway towards approval, but I think of these as a target chemo, so I think that there could be, and this essentially never happens, trials that are noninferior trials just showing less toxicity but really what they’re going after is superiority trials, and the toxicity will just be different.

DR LOVE: So Andy, curious about your thoughts about B7-H3 and ifinatamab. A lot of people see that deruxtecan. We have Dato-DXd, which is another target where you use the same payload. You don’t necessarily see as much ILD there. I’ve heard people say that maybe the ILD with T-DXd is maybe because there’s a lot of HER2 receptors in the lung. But what do we know about tolerability of I guess you could say Id, but also efficacy, and what have you observed yourself?

DR ARMSTRONG: So B7-H3 is a great target. It’s overexpressed in 90% of all prostate cancer cells, and it’s not expressed in a lot of normal tissue, so I do like it as a target. You do get chemo toxicity. If you’re a patient receiving Id you experience some risk of marrow suppression, neutropenic fever, nausea, vomiting, diarrhea, so you feel like you’re getting chemo. So whether it’s better than dumb chemo, docetaxel or cabazitaxel, you really need to see the survival data. And so I’m hopeful. Like Scott, again, I would hope to have combinations that don’t cause neuropathy. This agent would not be expected to cause peripheral neuropathy, and so I would like to have alternatives and new targets.

DR LOVE: And again, we’re seeing in breast cancer ADCs moving into first-line therapy often combined with immunotherapy but always. And I’ve got a big surprise talking to Scott. I don’t know what — how this came up because I just asked him have you ever seen HER2-positive prostate cancer, I’d never heard about it, and he said yeah. And in fact, you actually have a patient who responded to T-DXd, Scott, so what’s the deal with HER2-positive prostate cancer? Again, that’s kind of new in my book, so to speak.

DR TAGAWA: Well, I would say that if we think of this as analogous to AKT we don’t — we rarely do a bunch of protein staining in immunohistochemistry, but we usually get a panel, next-generation sequencing, and so that might pick up amplification or mutations. So that’s how we would often find these in other diseases. And I happened to participate in the ETCTN trial of this in non-breast, and I had a patient with prostate cancer with a not fully neuroendocrine but neuroendocrine-ish type of cancer and had a CR on T-DXd with toxicity, so as I would expect from that particular drug.

There was a poster at ASCO GU that I can’t fully quote, but it was something — I can’t remember if it was expression or amplification, but the amount of HER2 was somewhere between breast and lung in prostate cancer, which was kind of a surprise to me. Anyway, it is there. There is a tumor agnostic approval that is out there, so a patient that is out of options that doesn’t qualify for a clinical trial, it is one of the things that I think we should look for because it does exist.

DR LOVE: I’m not going to ask you about HER2-mutant disease, although we just did a whole program on that in lung cancer where they have 2 new TKIs that are approved that really work.

Here’s some of the data from ifinatamab deruxtecan that we were just talking about.

So Andy, I don’t know if I missed this day in med school in terms of metabolism pathways, but can you kind of — to the uninitiated can you kind of explain what opevesostat is —

DR ARMSTRONG: Sure.

DR LOVE: — how it compares to — to me, it kind of seems like abiraterone in a way, and where you see it heading?

DR ARMSTRONG: So cholesterol is the backbone for the creation of adrenal steroids, both mineralocorticoids, glucocorticoids and androgens, and abiraterone became famous as a CYP17 inhibitor because it blocks the androgenic pathway, at least upregulation of some of the upstream steroids, so that’s one of the side effects, mineralocorticoid excess. But ope is a CYP11A1 inhibitor, and CYP11 is way upstream, and so you basically create adrenal insufficiency with this drug. And the basis for it is that in many prostate cancers they have AR ligand binding domain mutations, and those binding domain mutations create a more promiscuous receptor that combined estrogens, other androgens, glucocorticoids, mineralocorticoids that then stimulate the cancer.

And so blocking all those sources of androgenic ligands has resulted in responses. That was what the Phase I and II studies of ope showed, that it was mostly active in AR LBD-mutated patients.

This trial is particularly focused on CRPC LBD patients but also unselected patients, so I suspect that this trial will probably be positive in the LBD patients, but that’s a pretty small subset, maybe 10% or less of all comers. So whether it’s positive in all comers is to be determined. It seems much less active in that broader nonmutated patient population.

DR LOVE: So Scott, I’m kind of curious whether you’ve had any experience with this. I was kind of shocked when I asked you about actinium. You said you’ve treated a hundred patients. I was going to ask you did you ever treat one. You said you treated a hundred. So I don’t know if you’ve used ope. I like that abbreviation. Where do you see things heading with that, Scott? Where do you think it’s going to fit in?

DR TAGAWA: I think it’s going to fit in. I think it’s very clear that throughout the lifecycle of the vast majority of tumors, in patients with these tumors, despite whatever you want to call it, castration, hormone APM resistance, that the AR pathway remains the driver. So I think targeting that in a more potent manner, I think, has a good chance of working. And in particular, if you select for those that have resistance but are still more driven by the pathway, such as these activating mutations, it makes absolute sense.

This is very akin to — I mean, ketoconazole is lower, but any of these for breast cancer or lung — or prostate cancer we’ve used these — these pathway inhibitors but then had to give back corticosteroids and/or mineralocorticoids. It’s the same kind of a concept. This is just at the very top of the pathway.

DR LOVE: So here’s another one that’s kind of interesting. I noticed they still use the word castrate here. I guess it’s a retro title there or something. But TulmiSTAR, a combination of 2 agents I’m sure everybody’s familiar with, just kidding, tulmimetostat, and EZH2 inhibitor, we remember that from lymphoma with tazemetostat I think it was called, and luxdegalutamide. So can you explain what these are and why we’re using them in combination, Andy, and where you see it heading?

DR ARMSTRONG: Yeah. Thanks, Neil. I think one of the problems is their names are getting just way too long, and so —

DR LOVE: Luxde.

DR ARMSTRONG: Yes, tulmi is an EZH1/2 inhibitor. And why do we care about that? EZH1 and 2 are really important lineage plasticity regulators. These are epigenetic regulators of cell differentiation. The neuroendocrine cell state, which happens in about 20% of patients at the end of life, is regulated by EZH1 and 2, and so preventing resistance along that pathway is critical. Separately, EZH1 and 2 coactivate AR, and so blocking EZH1 and 2 can actually have an anti-AR property.

The second drug, luxdegalutamide, you may have heard of as an AR degrader. It used to be with Arvinas, now Novartis. And so this AR degrader degrades AR. It targets AR to the cellular proteasome or wastebasket. This is the first-in-human study to combine both those drugs, so blocking AR in 2 different ways; blocking lineage plasticity in a second way, so kind of 3 ways to prevent progression. And so it’s a Phase I study finding the optimal dose, and then it expands to a Phase II and randomized Phase II to see if it’s better than physician’s choice standard of care. So it’s an ongoing study. This was our trial in progress poster at the GU symposium.

DR LOVE: So Scott, a question from Addly in the chat room. Relacorilant, I’m not sure if you’ve ever heard of it, but it was just approved in ovarian cancer. It kind of seems like an antiglucocorticoid agent. Has it been looked at in prostate cancer? Do you think it has any potential role in prostate cancer? It’s approved now in ovarian.

DR TAGAWA: I think it has a — I think it could have a role, I’d say particularly in the biomarker selected. I don’t know if that specifically has been studied in prostate cancer —

DR ARMSTRONG: There’s an open study right now at Chicago. It’s a pre-prostatectomy study, but no data.

DR TAGAWA: Okay.

DR ARMSTRONG: Let’s put it that way. Yup. Sorry.

DR TAGAWA: So glucocorticoid receptor is certainly one of the targets that hasn’t been fully validated, but we know it’s a target in prostate cancer of interest.

DR LOVE: So Andy, when I saw that tarlatamab, a CD3 bispecific, was approved in small cell — small cell of the lung I was like wow, we’re going to see CRS in patients with small cell, and actually it looks like it does pretty well. I’m curious what your thoughts are about pasritamig, which is also a CD3 bispecific. What do we know in terms of efficacy and of course tolerability looking for CRS? It doesn’t look like that much, but any thoughts?

DR ARMSTRONG: So yeah. Tarlatamab targets DLL3. That could be effective in small cell prostate cancer, just to throw in a little highlight there for Dr Aggarwal.

DR LOVE: Yeah. That’s a good point. Yeah.

DR ARMSTRONG: The efficacy is very similar in DLL3-positive small cell prostate cancer as you see in small cell lung cancer. With pasritamig, that’s targeting a more AR pathway on the cell surface called hK2. You don’t see CRS, so it’s an outpatient drug. You do see responses. You see great PSA declines. They are now looking at it in various combinations with docetaxel, with ARPis, with PSMA-lutetium, with AR RIPTACs. It’s really an exciting time to — I think probably the next 10 years will be the era of cell surface targeting in this disease because you’re getting that from radioligands, from BiTEs or T-cell engagers, and you’re getting it from ADCs. And so I’m hopeful we’ll have a whole basket of options down the road.

DR LOVE: So final comment from Scott, again in terms of bispecifics. We’re seeing not just CD3 immune bispecifics, Scott, but also, for example, at the GI ASCO Meeting we saw a bispecific already approved in biliary tract cancer for HER2, zanidatamab, that hits 2 parts of HER2. It’s not an immune bispecific. It’s probably going to be first-line gastroesophageal HER2 soon. Any thoughts in general, Scott, about where we’re heading with bispecifics in prostate cancer?

DR TAGAWA: Well, I’ve — as a trialist I have a lot of optimism. I will only open a trial that I think is actually going to benefit patients, and I’m not always right. But I do believe that this is likely to be — I don’t know which drug, but I do believe that this drug or other drugs that are like it against same of different targets will be the immunotherapy that actually works in prostate cancer. We have sipuleucel-T that’s approved and that’s out there. We have not had success in a biomarker unselected patient population with PD-1/PD-L1 or CTLA4, but hopefully these cell surface trials with CD3 or CD28 or the combination will actually work, and the early phase data is quite hopeful.

DR LOVE: So it’s interesting. When I asked you that question somehow I immediately flashed on the ASH Meeting that we just had, and when we were talking about bispecifics in follicular lymphoma some of the investigators were reflecting on the first patients they saw who were treated. That was so shocking to them that they did so well.

Andy and Scott, thank you so much for working with us today. Audience, be safe, stay well and have a great night. Thanks so much, Andy. Thanks so much, Scott.

DR ARMSTRONG: Thank you, Neil.

DR LOVE: Good luck with the game Friday night. Good luck —

DR ARMSTRONG: Thank you.

DR LOVE: — with the Blue Devils.

DR ARMSTRONG: Thank you so much.