Evan Yu: Good morning. We're here at ASCO 2025 again at UroToday. And today we have Dr. Marc Dall'Era who's a professor and chair of urology at UC Davis. So we're going to be talking about your neoadjuvant study that looks-- is looking at patients who have DNA repair gene alterations and using neoadjuvant niraparib.

So I guess one question that I have for you is, is this something-- we know that it happens for metastatic castration resistant prostate cancer. The data shows like 23% or so. Are we seeing this a lot in the earlier stages for high-risk localized disease? I think that's the patient population you studied, right?

Marc Dall’Era: Yeah, it's a great question, I mean. And that was one of the initial challenges when we designed the trial. We really didn't know, so we extrapolated the data in the metastatic setting to design and power our study.

But we did find about 20-- with screening a large group of men with clinically localized yet high risk disease, about 10% to 20%, obviously, depending on your definition of DNA repair, had some gene that was involved in these pathways, that was mutated.

Evan Yu: OK. And how strict were you with your criteria? Did you have a panel of genes that you selected? Did you require that there were biallelic or monoallelic? I mean, how strict was your criteria?

Marc Dall’Era: So not very. We wanted to be more inclusive to see what sort of signals we were able to get. Yes, we wanted to load it with the usual suspects, BRCA2, germline mutations. We did allow other somatic alterations that were involved in different DNA pathways. So essentially, it was up to the principal investigators. We reviewed the genomics and whether we allowed them to be included in the study or not.

Evan Yu: All right. So why don't you just give us a run through. I mean, you treat people with neoadjuvant niraparib. How long did you treat them? Any special characteristics as far as the selection? Just give us a run through.

Marc Dall’Era: So the back story, just in general, the impetus behind this was that many men with high-risk, clinically localized prostate cancer are going to recur after prostatectomy. Most of them still go on. And they can receive salvage therapy.

We wanted to look in the neoadjuvant setting at some of the newer agents that were becoming available. And a lot of the interest in PARP inhibition, as you mentioned, especially in men with-- showing activity in men with castrate-resistant prostate cancer.

There really wasn't data in untreated men. These were men with intact hormonal axes. They had not received androgen deprivation. So we wanted to see what the activity of these PARP inhibitors could be in select men.

We also wanted to do a biomarker-driven trial. So we designed it to include men with defects in genes involved in DNA repair pathways, as you mentioned, and designed and gave them niraparib for essentially three months prior to prostatectomy.

Evan Yu: OK. And so how many patients did you end up with data to analyze?

Marc Dall’Era: Well, so our final was we originally wanted to enroll 30. We built in a futility look at the data after 11 patients. So we enrolled 11. Two of those did not go on to get prostatectomy. They ended up choosing radiation after their niraparib. So we really had nine evaluable men. Small study.

Evan Yu: All right. That's fine. And how many did you test, would you say? Did you track that or?

Marc Dall’Era: We did. That was a great question. And we tested probably-- I mean, less than, like I mentioned, about 10% to 20% of men were offered the trial. And then of those, about 70% enrolled on the trial. So that's the other challenge when we're designing these trials. Even if you power it based on certain gene frequencies you have to realize that, on average, only about 2/3 of people may actually still choose the trial, even if they are candidates.

Evan Yu: But yeah, it sounds like you had to go through about 100, 200 men, is that right?

Marc Dall’Era: Yeah, we screened a lot. The other big challenge was we activated the trial in January of 2020, which is right when the world came to a standstill, so I wouldn't recommend that. But we got through it.

Evan Yu: Good, good. OK, so you treated these 11 patients and nine of them that went on to have surgery. Want to give us their top-line efficacy results?

Marc Dall’Era: Sure. So our primary endpoint was pathologic response. We defined as either complete pathologic response or partial. Using that MRD assay they've used in different neoadjuvant prostatectomy studies of less than 0.5 cc's of residual tumor.

We realized fairly quickly we weren't going to meet that endpoint. There really was not a visible histologic response after 90 days of PARP inhibition with niraparib. We did, however, see some dramatic PSA responses on the drug. So we're still working through the correlative data and presenting some of that in my poster tomorrow, looking at the extreme responder, the genetics of the extreme responder.

And there clearly was some activity with neoadjuvant niraparib. In the most extreme response, we saw nearly an 80% to 90% decline in PSA on drug. There was a visible MRI response. The patient was able to get a bulky tumor but was able to go on and get prostatectomy.

We also did note declining in his circulating tumor DNA-- I mean, circulating tumor DNA in the blood. We saw declined alleles of his somatic alterations that we picked up in his tissue as well, so there was activity. And we were able to pick up much lower allele frequencies in the pre versus the post-tissue as well as in the serum as I mentioned.

Evan Yu: OK great. And that's important because, as you mentioned, traditionally we've used PARP inhibitors in patients that have already had androgen deprivation therapy and are castration-resistant. So this is totally androgen deprivation therapy-naive population, no ADT at all, and showing those level of response.

Marc Dall’Era: Well, that's what we wanted. We were interested in-- there is emerging data on synergy between blocking their hormonal access with PARP inhibitors perhaps. There's only one other study I know of showing activity in men that are testosterone intact. But we really wanted to look at that because the toxicities of ADT, especially when you're taking a very healthy surgical population, is important to consider.

Evan Yu: Right. Now, you segued into the next thing, is a healthy surgical population. Of course, PARP inhibitors, they can be very efficacious. But like everything in life, no free lunch. There can be side effects.

So how did that go? Because sometimes when I use PARP inhibitors, my patients get some subtle GI side effects. They lose their appetite. And then, of course, the thing we're worried about is the myelosuppression issues. Of course, this was only three months of treatment, so maybe it wasn't that bad. But I'd love to hear what your findings were.

Marc Dall’Era: Well, actually, it was extremely well tolerated, so all men completed their three months of niraparib. There was really only one grade 3 toxicity, which was thrombocytopenia in one of our patients with a germline or biallelic loss of BRCA2. We were able to reduce his dose and complete still the three months. But other than that, it was extremely well tolerated.

Evan Yu: Great, great. And I read through your abstract, and this is one thing I just remembered I wanted to ask you is it sounds like you had one patient with a reversion mutation. Is that right?

Marc Dall’Era: So correct. Yeah.

Evan Yu: Was that a patient that responded initially and--

Marc Dall’Era: So that was actually in. And this is in the poster we're showing tomorrow. That was in the patient that also had the most dramatic response, which was unexpected but fascinating, how quickly that-- how we were able to pick that up.

So we were able to pick up a BRCA2 reversion mutation within 60 days of treatment on niraparib. And interestingly, once he stopped the niraparib, it went away. So it was clearly the selective pressure of the drug that led to this and speaks to potentially intermittent therapy with these drugs. We really don't know. But I was surprised at how quickly that reversion showed up.

Evan Yu: Well, that was what I was-- really why I wanted to ask you is, I always thought that it would be after long periods of exposure that you'd develop a reversion mutation. That was like 90 days, while you're telling me it happened within 60.

Marc Dall’Era: Correct.

Evan Yu: Did you have enough PSA assessments to assess whether maybe even their PSA dropped and then started to head up, and it maybe correlated with that.

Marc Dall’Era: Great question. We did have enough PSA. But it didn't look like it. He still had a good PSA response prior to prostatectomy. I think we were picking up very, very early low levels of the DNA in his blood before it really had any clinical effect, I would say.

Evan Yu: But if you followed him out longer, you might have started to see the PSA.

Marc Dall’Era: Well, and that's what we see. In the castrate-resistance setting, we see these mutations arise. And we're currently looking at our other patients on the study, analyzing their genomics. Because we have those data now that nine of them at least underwent prostatectomy and seeing if we've seen any similar effects in the other patients on the study.

Evan Yu: Super interesting work. If you were to take this, your next steps, next level, what would you do next? Would you think about maybe combining with androgen deprivation therapy, seeing if you get more efficacy, or what do you think your next steps might be?

Marc Dall’Era: Well, one of the most important aspects I want to figure out is we need a better biomarker. I think, clearly, we don't know. I mean, I had other-- I had another gentleman on our study with a germline BRCA2 mutation that did not respond at all. So clearly, that's at least in the--

Evan Yu: It was confirmed by allelic also?

Marc Dall’Era: Yes.

Evan Yu: OK.

Marc Dall’Era: Yeah. So it's interesting. And the other extreme responder actually had Lynch syndrome. So he was a gentleman with MSH6 germline, had a coincident BRCA2 somatic mutation as well. I also didn't mention that the gentleman that did have-- that had the germline BRCA with the extreme response also had a somatic ATM alterations.

So it may be that if you knock out multiple pathways involved in DNA repair, that these drugs are more potent in this setting. We just don't know. So clearly, we need a better biomarker to identify who is going to respond, and then how to treat these men.

The 30 days was-- I mean, the 90 days was very arbitrary. We felt that was a good spot between how long men would be willing to wait to have their surgery. There's other neoadjuvant trials out now that extend that even to four to six months of treatment, so we don't know the length of time, nor, like I mentioned, is there a role for intermittent therapy.

Evan Yu: All right. Well, I think provocative things that your studies brought up. So thanks for meeting with me today. I think super cool results. Really appreciate you doing the study and for coming here to UroToday to talk about it.

Marc Dall’Era: Of course. Great, Evan. Thank you for having us.

Evan Yu: All right. Have a good one.