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Alicia Morgans: Hi, I'm so excited to be here at GU ASCO 2025, where I am delighted to be speaking with Alan Bryce of City of Hope about the TRITON3 trial. Congratulations, thanks for the update. So happy to have you here.

Alan Bryce: Thanks, Alicia. A pleasure to be here.

Alicia Morgans: Wonderful. You know, I'd love to hear if you could just recount for us what was the TRITON3 trial? Tell us about the design, and why it's so important. What did you present previously?

Alan Bryce: Yeah, so TRITON3, remember, is our study where rucaparib was randomized against physician's choice therapy for patients with BRCA1/2, or ATM mutations in mCRPC. This was the pre-docetaxel study. So this was data I first presented a couple of years ago at GU ASCO. It's a positive phase III trial, as with all the PARP inhibitor studies powered for RPFS. And we had a very strong signal, unequivocally positive, really, a testament to all the patients and investigators.

And then Clovis went bankrupt, and the data really disappeared, right? I mean, we should have, in the normal scheme of things, been presenting data for the last couple of years, and catching everybody up on the subsequent analyzes, but we haven't seen that. So really, right now, we're kind of reintroducing rucaparib back to the community.

What subsequently happened is, rucaparib the asset has been picked up by Pharma& out of Europe, and then licensed here in the United States to Tolmar. So now, we've reengaged, we're able to analyze the data, we're able to complete the scientific analysis that really should be completed with all these clinical trials. So that's what we were bringing here today at GU ASCO, the first subsequent data set, the final overall survival. And happily, Tolmar and Pharma& are going to continue with the subsequent analysis, so we'll be able to finish the scientific effort that we started.

Alicia Morgans: Wonderful. So one thing I just want to also reiterate is that this was the first time that we really saw the randomization of a PARP inhibitor versus that subgroup of docetaxel treated patients. Can you remind everybody what that showed? Because I think that was really a clinically important thing, of course, that you presented before, but we should remind everybody.

Alan Bryce: Absolutely, yeah. Thank you. So this study was randomized against physician’s choice of systemic therapy. So all the patients would have had at least a prior ARPI. They did not have prior docetaxel.

And so the physician’s choice—the big debate is, should you do an ARPI switch, which really is almost every other study in this space, or should we treat with docetaxel? And, we've had this conversation in so many forums. I think so many of us believe it's important to say that docetaxel is our control arm here. And this was the one study that allowed for that, right?

This is the one data set, even today, to date, that we have where a PARP inhibitor is randomized against a control arm where the physician and patient enrolled in the study would choose either docetaxel or the ARPI switch. I'll go back and say, when we designed this study, when the study started, there was a belief in the field that patients would not accept getting randomized to docetaxel, but it had to be pre-specified prior to enrollment, and prior to randomization, so you couldn't just decide after the fact.

And what happened was, 60% of the patients were randomized, or chose docetaxel as their control arm.

So I think we proved a couple of things. Number one, we proved that you certainly can run a clinical trial of an oral therapy versus IV chemotherapy, and that patients would accept this randomization versus chemotherapy. And then secondly, what we saw in the RPFS, the primary endpoint, rucaparib beat docetaxel. And for those of us in the prostate cancer community, we've been doing this work for decades, we have dozens of trials randomized against docetaxel—this is the first time we've ever seen any agent win.

So I think it was a watershed moment in that sense for the prostate cancer community to say, yes, we can randomize versus docetaxel, an oral drug versus an IV. And yes, we have a drug that's superior. And I think for the entire space of the post-ARPI, I think it's really meaningful for the field to be able to look at that data from the perspective of trial design, and from the perspective of understanding how docetaxel compares to a PARP.

Alicia Morgans: Great. Well, thank you for recapping that, and certainly for the design. Now, can you tell us what were the findings that you presented at GU ASCO this year? This is really the survival data in this selected population.

Alan Bryce: Yes. So we've got the final overall survival data. And the OS here really shows no difference between the control arm or the rucaparib arm. Now, you know what I haven't referenced is the fact that the clinical trial design included a study-provided crossover. So for patients who progressed on the control arm, they were allowed to cross over to rucaparib. And so within the study, 74% of eligible patients crossed over from the control to the rucaparib.

And we're seeing this more and more in prostate cancer, but in other cancers as well, whenever we've got this crossover from the control arm. Generally, what we find is there's no OS signal, right? Because really, what this study ends up testing is the immediate rucaparib versus delayed rucaparib. And in that setting, we just don't see that overall survival difference. So we get equivalent survival after a significant improvement in RPFS.

I think this leads to the whole conversation that we've talked about in previous years when we were talking about previous studies. In my opinion, I think we really have to decide up front if we want to design crossover, we do it because we feel that it's best for the patients. It's the patient-centric way to do a study design, right? If someone agrees to go on to a clinical trial, agrees to randomization, the patient-centric way to design the study is to say, we're going to let you get the drug, because it's something that they might not otherwise have access to in different countries and different regulatory environments.

But when we do that, we have to accept that there will be a secondary impact on the OS signal. And as a community, as a scientific community, and also for the regulators, how are we going to—how are we going to respond to the impact that the crossover has on OS? I think that's a question that we haven't resolved as a field, and we've heard this discussion happening across various clinical trials. And I think it will be very impactful moving forward. How we respond to this probably is going to inform whether we feel that crossover designs can continue.

Alicia Morgans: Absolutely. And especially as we're talking about a pre-chemotherapy design, I think this crossover issue is even more impactful, because if it's at the very end of one's life, after many, many therapies, there may be less of a chance to make up the difference. But in this earlier state, certainly, subsequent therapies come into play, and can affect the way that survival happens. Now, did you collect any information or data? Did you share anything on subsequent therapies in this population?

Alan Bryce: Yeah, so subsequent therapies have been previously reported. We didn't focus on it this year. But you think about the era that this study happened in. It was largely going to be chemotherapy, or further ARPI.

So some patients would go from the rucaparib arm to ARPIs, or docetaxel, were the most common options. At that point, Pluvicto wasn't an option, at least in the US. So we didn't see that kind of crossover, so docetaxel commonly. And then some of the patients eventually end up trying a second PARP. And I'm not sure, I think that is something I would do in practice, but you can understand why people would have gone that direction.

Alicia Morgans: Absolutely. Well, I would love to hear anything new in the safety, tolerability side of things in this updated report?

Alan Bryce: Yeah. So a lot of play right now, a lot of conversations around PARP inhibitor toxicity, and it's something that people really need to think about, because now, PARP inhibitors, the toxicities are largely a class effect, right? The myelosuppression, the fatigue, the GI toxicity, and the myelosuppression is really, I think, the most profound and most important—across the various studies we see a significant transfusion rate. We see a significant anemia rate across the various PARP inhibitor studies, transfusion rates of 15 to almost 50%.

Recall, these drugs are multiple pills, daily, taken orally, and within the context of the study, of course, we have to follow protocol, and be very careful in terms of drug titration, and how things are managed. But I think we found in clinical practice that we can really proactively manage anemia. We don't have to wait till someone gets to a transfusion level before we're making those adjustments when we're not on protocol. And I think those of us who give a lot of PARP inhibitors, we've gotten quite comfortable with the fact that these are very manageable drugs.

So what you see on this study, and on really, all the PARP inhibitor studies, even as we heard from Doctor Agarwal yesterday with regards to TALAPRO, after dose adjustments are made, almost all patients really are able to maintain long-term treatment. And that's absolutely been my clinical experience as well, and what we saw in TRITON. And what that's saying is that there is a right dose for a patient. We just have to actively titrate to find what that is.

Alicia Morgans: Wonderful. So I would love for you to give a summary, the bottom line to the listeners. What should they take away from this presentation?

Alan Bryce: Yeah, so the bottom line is rucaparib is certainly an active drug for BRCA mutant prostate cancer. Remember, in rucaparib, we really just looked at BRCA1/2 and ATM. And as we've learned from many studies now, ATM is not a PARP-susceptible gene. So it's really the BRCA2, BRCA1—rucaparib works very well, superior for RPFS when compared to either an ARPI or docetaxel in this setting.

Very well-tolerated drug, a drug where we can really titrate and find a safe dose for patients. And it is available in the United States right now, in the post-docetaxel setting, and perhaps, based on this data, we'll see an approval in the pre-docetaxel setting.

Alicia Morgans: Wonderful. Well, thank you so much for your time. Thank you for your diligence in ensuring that the data that the patients contributed, the work that was done on this clinical trial continued to be read out, to be analyzed, and reported to the people who need that information. We really appreciate your time.

Alan Bryce: Thank you, Alicia.