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Pedro Barata: Hello, everyone. I'm Pedro Barata. I'm a GU oncologist out of University Hospitals in Cleveland, Ohio. We're here at AUA 2025. I'm very, very happy to have the chance to sit down with Dr. Manish Patel, a great trialist, GU oncologist out of Florida Cancer Specialists and Sarah Cannon (Research Institute) in Florida. Welcome.

Manish R. Patel: Thank you very much. Pleased to be here.

Pedro Barata: Absolutely. So I'm really excited about our little chat today because we're going to be talking about a novel therapeutic with a new MOA. Great work, by the way. Great presentation, great work on a phase I. A therapy has been developed now for a couple of years-- or a few years, I should say. And it appears that it might be moving forward.

So let's talk a little bit about that biodegrader. And perhaps for our group, for the people that are listening to us, some might not be as familiar with that. So can you walk me through the mechanism of action of the BMS therapy, oral therapy for metastatic prostate cancer?

Manish R. Patel: Yeah. Absolutely. So one of the biggest challenges we have in the treatment of metastatic, castration-resistant prostate cancer, as you know, is the resistance to our current androgen receptor pathway inhibitors and to also make drugs that bind to the androgen receptor with low agonism.

So what's interesting about BMS-- and we'll call it 365, study drug. What's interesting about BMS 365 is a dual mechanism of action. So it has a cereblon binding moiety that induces ubiquitination through proteasome and that causes AR degradation. At the same time, it also has an AR binding moiety to the ligand-binding domain that causes AR antagonism.

So it's a dual mechanism of action, a degrader as well as an antagonist. And because of this dual mechanism of action, you have AR inhibition to much deeper levels than the current available therapies. And what's neat is when you-- let's say AR were not to be degraded through this mechanism. It's still in an inhibited state through the other mechanism. So activity has been seen pre-clinically and clinically, as we will discuss, in both the AR wild-type population as well as the mutant population.

Pedro Barata: So you touched base-- so very important points that you're making there. We really need therapies beyond the ARPIs. Most patients are exposed to ARPI, whether the hormone-sensitive disease or getting to mCRPC. That's the therapy they get. So exploring a novel therapeutic that's oral, easy to do, and it works after progression ARPI is needed, right?

Manish R. Patel: Absolutely.

Pedro Barata: So the field absolutely welcomes therapies like that. So as far as I know, the setting or where this drug is being developed is being post ARPI, pre and post chemotherapy. Or at least, you have data to look at the signal at the same time that you look at safety. Can you just walk us through the take-home message from your presentation on that particular compound in these two settings? How does that look like?

Manish R. Patel: Yeah. So I can go over to the trial design a little bit. So it was a phase I, first-in-class dose escalation trial. That was a part one, was dose escalation, dose finding. QD and then BID dosing was explored. And in that part of the trial-- these are castration-resistant prostate metastatic patients that have received one at least one prior secondary hormonal therapy.

The patients had to have received docetaxel or were unfit to receive. So there were about 46% of patients-- and I'll talk about the part two-- that had received prior docetaxel. So in the part two, the part B section, that was a dose expansion part of the trial. And in the dose expansion, 68 patients, where BID dosing was explored, mainly. We took out the 600-milligram QD dosing because there was a lack of efficacy. But there was a 400, 600, 900 milligrams BID cohort.

And same criteria, except we added a few others-- no prior platinum, no brain mets, liver mets, PSA of 2. But same situation-- prior docetaxel or unfit for docetaxel and then, of course, secondary hormonal therapy. So that was a trial design. Median follow-up was about 14 months. But the primary endpoint for this particular phase I, of course, is--

Pedro Barata: PSA response?

Manish R. Patel: --MTD, MTD, figure out the recommended phase II. The secondary objectives were further PK utilization as well as more efficacy, including PSA responses.

Pedro Barata: Because you are reporting PSA and PFS, I believe--

Manish R. Patel: Correct, correct.

Pedro Barata: --along with the safety.

Manish R. Patel: Absolutely.

Pedro Barata: So what are the take-home points?

Manish R. Patel: Yeah, so the take home is-- these are heavily pretreated patients and median 4 prior lines of therapy. 27% of patients had AR ligand mutations, which is kind of reflective of this population, anyways. And 46% of patients had prior abiraterone and enzalutamide-- so pretty heavily pretreated population, kind of what we see in this post ARPI population trials.

Pedro Barata: So many of these patients, we explore more than one ARPI.

Manish R. Patel: Absolutely.

Pedro Barata: That's an important aspect.

Manish R. Patel: 46% had both and, of course, the other radioligands and other therapies.

Pedro Barata: Did they receive prior RLTs?

Manish R. Patel: There were some patients who did.

Pedro Barata: OK.

Manish R. Patel: So In terms of efficacy-- and I'm sure we'll talk about safety. But in terms of efficacy, what's interesting is that the PSA responses were increasing, were dose proportional when you go from 400 to 600 to the highest dose of 900 milligrams BID. In fact, the PSA 30 was 70%, PSA 50 was 50% in the 900-milligrams BID cohort.

And we saw some interesting PSA responses, not only in the mutant population-- 55% in the mutant population PSA 50-- but also in the wild-type population, about 27% But the median progression-free survival was 6.3 months. 42% of patients did not have progression or death within six months. But the PFS overall was 6.3. But in the higher dose in the 900-milligrams BID, it was 8.3 months.

But yeah, there was no major difference by age. Now, going back to your question about chemo, there was a significant difference between patients who did not have prior chemo versus had chemo. 

So a pretty significant difference-- and the same wide gap between patients who were on pain meds versus not on opioids.

Pedro Barata: I see. And is that an association if you look into it-- probably not yet-- but does it matter the timing of docetaxel? Because I'm thinking of patients exposed to triple therapy--

Manish R. Patel: Correct.

Pedro Barata: --based on when the study was enrolled, they might have received docetaxel, then ARPI too and then go on trial. Is it different from the patient population that end up getting ARPI and docetaxel for CRPC? Or you don't have those details yet?

Manish R. Patel: That's correct. So small numbers overall when you take the phase I, and then within that, patients who receive docetaxel. And within that, what was the timing? So it's very difficult to differentiate if that made a difference. But the subsequent trials that are being planned, that will be looked at in particular.

Pedro Barata: I want to talk about that.

Manish R. Patel: Yeah, absolutely.

Pedro Barata: Because clearly, it's an active therapy. And I think it is well deserved of an oral presentation, important meeting like AUA. So the question was, where are we going to go from here? It appears the signal is enhanced in the pre-chemo setting, whatever that means. What is the chemo fitting, right? We just heard RLT moving early on. Everything seems to be moving early on.

So can you walk us through a little bit about, based on the data that you see that leverage further investigation, where do you see this being the sweet spot for development of the therapy? And a second question is whether or not-- since you have these dual activity, including antagonism of AR, the next question would be, do we need to see exposed patients to ARPI versus ARPI naive, especially if the efficacy does not to see be dependent on the type of AR alteration that you have?

Manish R. Patel: Exactly, a great point. So yeah, in terms of where we see this drug-- so as you mentioned, the results seem to suggest that the less pretreated, earlier line you give this therapy, the better results could be-- pre-chemo data, non-opioid data. And so I do think that will play a role of where this drug ends up.

In terms of the plan, there is a phase III that's being conducted. The details of that are going to be presented at ASCO in the next couple months here. But it will be a dose-optimization design to begin with and then randomized to investigator choice. But those patients have had to receive prior ARPI, at least one.

Pedro Barata: So CRPC, pre ARPI, we'll see the details of the design later time.

Manish R. Patel: But to your point, there is activity in the wild-type population as well as the ligand-binding domain mutated patients. We know the mechanism of this drug should and has shown activity in the wild-type population. And that makes sense because there's other ways of building resistance rather than just ligand-binding domain mutations-- amplification and so on.

And so, certainly, this could move in different directions. But certainly, if you find a population that could benefit from both because of the mechanism, that's a win, right?

Pedro Barata: Right. So, listen, this is amazing. Again, congratulations. Because when we're building portfolios, you always want to bring the studies that are winners for everyone-- for your patients, for the community, to move the field forward. So it appears that we're dealing with one therapeutic among others, that it's making their way to late stages of development, it's always good news. Because when that happens, it means there seems to be enough there helping enough people to justify the further investigation.

Manish R. Patel: That's what's convenient. It's oral therapy.

Pedro Barata: Exactly.

Manish R. Patel: Patients want to stay home. They don't want more complicated therapies that interrupt their travel and other lifestyle. And so these types of therapies are not too lifestyle altering.

Pedro Barata: Right. No, I agree with you. So congratulations for that and for keep helping the development of these and other therapeutics. So I really appreciate you taking the time to be here with us today.

Manish R. Patel: Yeah, absolutely.

Pedro Barata: Super informative-- I learned a lot. And always a pleasure talking to you. Thank you.

Manish R. Patel: Yeah, appreciate it. Thank you very much. Thanks for the opportunity.