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Evan Yu: Good day, it's good to be here again, here at ASCO 2025. We're here at UroToday, and I'm here with Dr. Michael Ong, and he's an associate professor at University of Ottawa in Canada. And it's a real pleasure to have you here today, and we're going to talk a little bit about a biomarker selected study that you've done, and my understanding is there's some darolutamide in there and in metastatic castration resistant prostate cancer. Why don't you set the stage for us?

Michael Ong: Yeah. Great lab in Vancouver Prostate Centre, where essentially screen for a detection of circling tumor DNA and then what alterations those patients had. So we had, together with Kim Chi, Alex Wyatt, the whole Canadian Cancer Trials, group have this platform of potential treatments that might benefit these patients. Essentially, a multi-armed phase-two study, where we looked at different targets of interest. And so one of them in the study that we're going to talk, about was AR alterations, either AR gain or AR mutation, and the opportunity to try darolutamide in that arm.

Evan Yu: Now it's great to have test darolutamide in an arm because as the audience knows, we use darolutamide in a lot of other disease states, M0 castration resistant prostate cancer, metastatic hormone sensitive prostate cancer, in combination with docetaxel. So it's great to see data in metastatic castration resistant prostate cancer, but I think there's some other reasons why, if I remember, so please kind of fill in the blanks for me, there was a very early study, or preclinical study when it was an ODM compound before it became darolutamide where they actually showed preclinical activity in, I think, three different antigen receptor mutant populations. Is that correct?

Michael Ong: Yeah, that's right.

Evan Yu: It kind of makes sense to do this.

Michael Ong: So I think first of all, darolutamide is structurally different than enzalutamide and apalutamide. So because it is structurally different, some of the reasons for acquired resistance to enza and apa have to do with alterations in the ligand binding domain that confer that resistance. And in fact, abiraterone has its own AR mutants as well, that might confer sensitivity to glucocorticoids and again, as a resistance mechanism. So there are reasons to believe why either AR gain or AR mutation might be still sensitive to darolutamide, even though I think in general, we think we see modest activity of a switch from ARPI to ARPI, right, as a general strategy.

Evan Yu: Yeah.

Michael Ong: So I think that really set the stage for the interest to see, okay, we know that if we have unselected patients ARPI to ARPI, that we may not gain that much, but if we're able to really hone in on specific alterations, there's a potential for benefit there.

Evan Yu: Yeah, yeah, that makes sense, because what I always kind of tell patients is that if you've had, let's say enzalutamide before, you want to switch to abiraterone, and it's not a real good, right? I mean, we have the PLATO study, we have the UBC study that was done, where it was somewhere like 2.54% PSA response rates, but when you go from abiraterone to enzalutamide, it might be 20 to 30%. I've always wondered whether it's some sort of mutant population, et cetera, that maybe can respond to enzalutamide. And of course I always wondered about darolutamide with the potential, at least pre-clinically, to take out some of these mutants. So what did you find?

Michael Ong: Yeah, so first of all, we had quite a few patients, 29 patients in the AR gain arm. We had another 28 in the AR mutated arm. Some of the most common AR mutations was the common culprits, like T878A, or L702H. And actually the rates of that differed based on if you had abiraterone treatment, or you had enzalutamide treatment. We also found that within the population there were some with SPOP alterations that we know may confer additional AR antagonist sensitivity. And so overall, we found that there was an enrichment and benefit from darolutamide.

And our primary endpoint in the study was clinical benefit rate, that meant PSA falling or stable disease over 12 weeks, or objective response on resist. But overall, still there are modest rates of response or longevity to response of progression-free survival on darolutamide. So I think it's behaving really similarly to how we would think ARPI to ARPI switches, despite darolutamide being different. I think patients that have metastatic castration resistant prostate cancer, we're looking for other strategies to make a difference. Once you've progressed on one of these very good treatments like enzalutamide and abiraterone.

Evan Yu: Okay. Were the numbers big enough to look at the high AR copy number, essentially AR amplified patients, which I always think of as having not great treatment strategies. We haven't really figured out what to do, versus the T878A and the L702H mutants. I mean, I might think that latter group might respond a little bit better than the amplified group.

Michael Ong: The numbers still overall are small, and so when you look statistically, yes, there was a slightly higher rate of clinical benefit and particularly a copy number over 10. Yeah, there was a little bit of a signal there. I don't think we're still at numbers large enough that we could say for sure, okay, we should start selecting patients on that basis. And no, darolutamide still doesn't have an approval for metastatic CRPC, but it's definitely an interesting area. I think that the fact that we're seeing some activity does mean that there perhaps are some patients that may benefit, but I think unselected or even selected in our patient population, I mean, you're not seeing enough activity that you wouldn't be thinking about some other therapies if the patient is eligible.

Importantly, I told you that the Umbrella study had chosen patients that were receiving docetaxel before, but in this substudy, we excluded patients that had had prior docetaxel chemotherapy just to make sure these weren't, because they were very heavily pretreated, so we're really truly talking about ARPI to ARPI switch strategy.

Evan Yu: Oh, I see.

Michael Ong: So once again, I think there's also lessons learned too about the greater experience of screening almost 600 patients with ctDNA and putting them into a platform study. And if I can may, there are a few learning points there, I think.

Evan Yu: Yeah, yeah.

Michael Ong: So we had many different arms in this Umbrella, right? So we had things that were less experimental, things like carboplatin, durvalumab tremelimumab for hypermutated, and of course the darolutamide. But we had things that if you had an AKT alteration, there's ipatasertib, if you had PTEN loss, we had polo kinase four inhibitor, and there was a CDK4/6 inhibitor in there. So there's so many different arms, and so you're running all these phase two studies, but we know that ctDNA is a real negative prognostic marker. When you have detectable ctDNA, you're doing worse clinically, and you're at a time where scans are getting worse, ctDNA is positive, and that patient is about to become symptomatic or is symptomatic.

Evan Yu: Sure.

Michael Ong: So when you're trying to develop drugs in that space, you want something that works. And so this is a really interesting thinking about the balance of here's a target of interest that we can identify with biomarkers, but do we have a drug that really works, and is powerful enough for us to see the signal when we screen positive? So I think that we learned a lot in conducting that study.

Evan Yu: So what happens to the ctDNA negative patients in your study?

Michael Ong: So they end up being re-screened at a later point.

Evan Yu: Oh, okay.

Michael Ong: So if they're progressing.

Evan Yu: So you got to be positive to get on.

Michael Ong: Yeah, so we had over 600 screens, but there was 500 something patients. So that means that a proportion, maybe a hundred of those patients were re-screened on study just to, sometimes you're just not spilling enough that we have a current biomarker. So the study was all about the ctDNA positivity informing our treatment choices. And so we didn't, even if somebody had an analysis of their primary tumor, we weren't taking that at its word and putting them on study.

Evan Yu: Do you mind me asking what the kind of hit rates are for some sort of alteration, and especially for, let's say the AR mutant population where there's some reports out there, it's been 15, 20, 25% range. Is that kind of what you guys are seeing or?

Michael Ong: Yeah, I'm sorry to say, I don't have all that information right in front of me, but certainly like AR alterations, like AR gain and AR mutations were one of the most common things that we were seeing in the entire cohort. So I think, I don't have the percentages, but that was common. TP53 alterations were common. PTEN loss or alterations were fairly common. I don't think these are commonly reported. So I think the rates were what we expect for a large population, but I just don't have the exact percentages.

Evan Yu: That's fine. I mean, I'm sure we'll see future presentations, so we're going to be in a really, really rich data set, I'm sure. And so probably you and I will be talking about this in a lot of future UroToday interviews to come, some of the other data sets for patients with other alterations as well. So seems like a lot more to come and look forward to chatting with you more about this topic.

Michael Ong: Yeah. Thanks so much, Evan.