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Alan Bryce: Hello, I'm Alan Bryce, medical oncologist from City of Hope in Arizona. I'm continuing on our series about the consensus recommendations that came out of the US Prostate Consensus Conference in 2024. I'm here today with Dr. Michael Morris from Memorial Sloan Kettering Cancer Center in New York.

Michael Morris: Thanks so much for having me, Alan.

Alan Bryce: Thanks for being here, Michael. We want to talk about the recommendations around mCRPC-- obviously, a complex space, a lot to talk about, and an ever-evolving field. But there were areas where there was clear consensus, despite the lack of level 1 evidence. And we'd like to get your insights on why the experts really felt strongly that these recommendations should carry forward.

Michael Morris: Sure

Alan Bryce: The first one, the committee said that most patients who progressed on ARPI-containing therapy for mCSPC should not receive an ARPI in the first-line setting for mCRPC? So could you explain where is the controversy here? And why does the committee feel so strongly about this?

Michael Morris: So most patients in today's day and age, I think, from a clinical practice standpoint, will get their first exposure to an ARPI in castration-sensitive disease. And the question then comes up, so what should be your next maneuver for first-line metastatic CRPC?

I think that the data that are suggestive of what's the most effective maneuver for that first line of therapy is, first, if you have an actionable mutation, you should take advantage of that. So a PARP inhibitor if you have an HRD mutation. Or if you have MSI-high disease, then your immunotherapy. Of course, that may change with this ASCO that we're recording this in terms of the use of PARP inhibition.

But when the consensus guidelines were formulated, this is the place where PARP inhibitors had the best data. You have good data for going with chemotherapy in this context, but your weakest data is the most commonly deployed maneuver, and that is switching from one ARPI to another ARPI, which, especially if you're going from an amide to abiraterone, is even less effective than the other way around.

But I think that since those guidelines were made, we now have data on radioligand therapy head-to-head against this most commonly used, but least effective maneuver of switching ARPIs. So my hope is that no one now goes from a first to a second-line ARPI, except perhaps for those curiously long responders to a hormone in which you might entertain a switch. But those are uniquely AR-sensitive patients. But I think for the majority of patients in today's day and age, there's really no reason to do that maneuver of switching from one to the other.

Alan Bryce: Yeah, yeah. Oh, fair enough. And yet, like you say, it's the most common treatment.

Michael Morris: It's a pity. Yeah, but hopefully that will change since in March, lutetium was approved specifically for this indication.

Alan Bryce: Yeah, absolutely. Now at the time that the committee met, of course, lutetium wasn't approved. So the field has shifted some. But there is a very, I think, relevant question that people are somewhat uncomfortable with which is we have lutetium. We also have an older radioisotope in radium 223. The question comes up is, can these drugs be sequenced-- radium and lutetium? And the committee said, yes, depending on clinical context, radium is appropriate both before or after lutetium PSMA treatment. So could you speak to perhaps the issues surrounding that?

Michael Morris: I would avoid that dilemma by having the following treatment pathway. So for patients who have not received an ARPI for castration-sensitive disease and who are now in castration-resistant disease and don't have an actionable mutation, my definite first-line maneuver would be enza (enzalutamide) and radium, because we have a beautiful phase III study showing that enza and radium has a substantial survival advantage over enza alone as your first maneuver for metastatic CRPC involving an ARPI.

So if I have to think about any radiopharmaceutical that should be applied as a standard of care in that granted diminishing patient population-- but still we see those patients-- I think that that's a perfect place for radium. And it is early. It's really effective. That trial had the double the usual overall survival advantage than any other study that we have approval on. So there's a real role for early radium in that context.

Otherwise, for a second-line setting where you've progressed through an ARPI, I personally do choose lutetium in today's day and age because I do like a tumor-directed therapy, and it has clear-cut quality of life benefits in that context that really are compelling to me that you're a happier human being if you get lutetium as opposed to a second-line ARPI in that context.

So I like lutetium for its target, its treatment effects, its exertion of really good tumor control, and all of the quality of life benefits-- that is, delaying pain progression, delay in erosion of quality of life. It's a better-tolerated treatment than a second-line ARPI, is fewer dose reductions. I don't have necessarily that complete package of data for radium as monotherapy in that. I don't have the nice secondary endpoints in terms of PSA declines, our PFS benefits. That wasn't part of the ALSYMPCA study.

And so I use radium early in the context of PEACE-3. I use lutetium in the context of PSMAfore. It depends on which of those patients, which scenario the patient is in. That's how I choose-- how I sequence my radiopharmaceuticals.

Alan Bryce: Fantastic! All right. Then another recommendation from the committee. And you touched on this already. But for the MSI-high patient, committee said-- and this is almost unequivocal-- that anti-PD-1 or PD-L1 therapy should be offered for patients with MSI-high mCRPC. So what do you want the listeners to know about this?

Michael Morris: It isn't a large patient population. It does require that you get somatic DNA. I usually do somatic and germline for all my metastatic CRPC patients because it's informing me not just about the MSI-high patients, but as well the HRD patients. For equivocal findings, you can do protein staining and confirm that the patient is indeed protein-deficient for Lynch proteins. But when you have that mutation, it's like hitting pay dirt for the patient because now they have a therapy that they can have a good durable response to.

You never want to miss that opportunity as rare as it is. So it again affirms get some form of genetic sequencing. For many, it might be ctDNA. For those who are tissue-focused, it could be biopsy. You need a fresh biopsy of the tumor since the tumor does evolve in terms of somatic DNA. And your diagnostic biopsy from the prostatectomy specimen or prostate biopsy from a decade ago probably isn't reflective of what's going on now. So it requires a fresh assessment of the patient's DNA. But this is why we do the testing because there are these golden opportunities that you don't want to be overlooking.

Alan Bryce: Yeah, yeah, absolutely. And then a follow on question where there was not consensus. But if you're treating a patient with a checkpoint inhibitor, the appropriate patient with a checkpoint inhibitor, and they have a complete response, would you discontinue therapy? And the committee, a third of the committee, said yes for stable deep response. A third said only for complete radiographic and PSA response. But almost 30% of the committee said, no, I wouldn't discontinue the checkpoint inhibitor. So how do you look at this issue?

Michael Morris: I think a lot of it is how well the patient is tolerating the checkpoint inhibitor and your dosing schedule every three versus every six and how deep and profound that response is. Every so often, you have that patient who comes off therapy and does not recur. I had a patient that I treated 4 and 1/2 years ago with one dose of pembro. I really hurt him in this respect that he had severe myositis and had myocarditis, from which he recovered completely, and I haven't given him any anticancer therapy except for ADT since. So that is an exceptional responder-- no doubt. But I think that the lesson is that immunotherapy is the treatment where there is the possibility that you could really alleviate the treatment burden of the patient for the patient who is a complete responder or has a deep and durable response.

I personally like to give the patient a chance at seeing what happens if we do give the patient a break. And that shouldn't be that controversial. I mean, we give patients chemotherapy breaks. We give patients PARP inhibitor breaks. Why would we not give them immunotherapy breaks? So I approach it the same as with any of these therapies. These patients are chronically ill. But prostate cancer is a disease where you can have periods of disease stability even though you're not on active treatment at the time. And I don't see any reason not to.

Alan Bryce: Now, I think you said there in that patient of yours you still have them on ADT.

Michael Morris: I do. Yeah.

Alan Bryce: Would you ever consider the ADT break?

Michael Morris: I'm not that bold because in the end, I don't think that prostate-- I have no evidence that prostate cancer loses androgen addiction. So once you start firing up that androgen receptor, I almost feel like it would be somewhat paradoxical if you're pouring water on the fire of the cancer with immunotherapy and then gasoline at the same time with androgens. So I'm not that bold.

And I'm not sure the biology makes sense either. Once you stimulate the androgen receptor, that cancer is going to grow. You could say, well, perhaps the immune system will keep up with it. I just don't feel like setting the patient up for that competition.

Alan Bryce: Yeah, fair enough. Understood.

Michael Morris: Let sleeping bears lie.

Alan Bryce: Yeah. Solid advice. Absolutely. All right. Let's guess, this is a different practical question. When patients get docetaxel as part of triplet therapy for CSPC, for mCRPC, and now they've progressed, what is your preferred chemotherapeutic at whatever time you're talking about using chemo? Do you use doce again or is cabazitaxel preferred? And there was no consensus on the panel for this. So how do you think through this?

Michael Morris: There's no consensus because we don't what to do. I'm going to speak on behalf of the people who switch. Many people consider six cycles to be a course of chemotherapy. And when they relapse, then they're going to switch drugs. For me, I approach this, let's say, as one would approach other solid tumors where you assess the response to the first chemotherapy, you assess the duration of remission, so to speak, afterwards.

And then I switch if I feel like there's been a short duration or an incomplete response. But I'll consider them to still be docetaxel-sensitive if years pass, then they relapse, again they tolerate a doce very well. They really responded well. I don't think that you can afford to just waste a drug. And once you switch to cabazitaxel and develop cabazi-refractory disease, going back to docetaxel generally doesn't work. Whereas cabazitaxel was approved based on docetaxel refractory disease.

Alan Bryce: Yeah.

Michael Morris: So my concern about a premature switch is you actually eliminate a later option that maybe you wanted to retain. And in the right patient, I would consider it to be just a rechallenge of a therapy that the patient did really well on. But conversely, if they didn't really respond very well to dosage, just repeating that again would seem to be a lesser approach than switching to what's probably a more potent drug.

Alan Bryce: Well, Dr. Morris, thank you very much. Always a pleasure to learn from you.

Michael Morris: Thank you, Alan.

Alan Bryce: I'm learning from you for 14 years now, I think, since--

Michael Morris: It's been a pleasure being your colleague. And thank you so much for the leadership on the USPCC because it's a really valuable set of criteria and guidance. I think it's very useful for the community. And thanks for all the time and effort you put into it. It's really good.

Alan Bryce: Thank you, Mike.

Michael Morris: Thanks.

Alan Bryce: All right.