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Alicia Morgans: Hi! I'm so excited to be here at GU ASCO 2025 speaking with Karim Fizazi of Gustave Roussy. Thank you so much for being here with me today.

Karim Fizazi: My pleasure, Alicia. Thank you for inviting me.

Alicia Morgans: Well, always. You were able to talk about and present the TALAPRO-2 overall survival, focusing on the HRR cohort. I would love to hear more. And, also, can you remind us about these different cohorts or groups that were included in TALAPRO-2.

Karim Fizazi: Absolutely. So you're very right, TALAPRO-2 is not just one phase 3 trial. We should probably look at this trial as being two different phase 3 trials because the alpha was split between two cohorts. One was an all-comers mCRPC cohort. This was reported by Dr. Agarwal as well during the congress. But the second cohort was an HRR pure cohort that actually we completed after the first cohort was completed. Because, of course, these patients are rarer, so it took a longer time to complete the accrual of approximately 400 men in this cohort.

So in both cohorts, we randomize the same question. Should we add talazoparib to enzalutamide versus enzalutamide alone in patients with metastatic castration-resistant disease?

In the HRR cohort, the primary endpoint was radiographic progression-free survival. And we already know that this was met very clearly with approximately a 55% reduction in the risk. We reported that already two years ago. With an updated follow-up, the data remains very robust; hazard ratio remains the same.

And now the medians are reached—approximately a year only on enzalutamide in the control arm for this HRR cohort, which is confirming to us that this is a poor prognosis subgroup of men. And it's 41 months in the experimental arm, so big difference in terms of radiographic progression-free survival. So, by its own, I think this is quite meaningful, of course, clinically.

But, of course, the most important finding from this updated analysis is the overall survival. This was the key secondary endpoint. It's clearly and very significantly improved with a hazard ratio of approximately 0.6 favoring the talazoparib plus enzalutamide arm.The medians have been reached—also 31 months in the control arm versus 45 months in the experimental arm. So more than a year of additional survival for these patients receiving the combination versus enzalutamide alone, which I think is, of course, very important.

We also have a split between BRCA patients versus non-BRCA HR patients. As you would expect, patients with BRCA alterations benefit most. The median overall survival is not even reached for these men in the experimental arm with talazoparib. And it is met in the control arm; hazard ratio is more 0.5 or so, while for patients with HR non-BRCA alterations, we have a borderline significant—let's call it like that—OS data with a p-value of 0.06 favoring also talazoparib.

And I think it really reflects the heterogeneity of this population. Some patients having alterations that benefit or that are associated with benefit, while some others—actually, say ATM or even CHEK2 alterations—really do not benefit from this combo.

Alicia Morgans: That's so interesting. And I know you reported before on some of the clusters that may have had more or less alteration. Do you have any information on those clusters in terms of survival?

Karim Fizazi: We're planning to report all the detail at the next meeting, so I'm not going to speak too much about it right now, but let's put it in simple words. Basically, what we found in terms of rPFS appears to be translated into OS benefit. So BRCA1, BRCA2—clear benefit; probably CDK12 also benefit; while, again, CHEK2 patients really don't benefit from a PARP inhibitor in general.

Alicia Morgans: It's so interesting, especially as we try to think about the benefits versus the side effect profile. And a lot of people have talked about that combination and exposure to PARP inhibitor and/or pathway inhibitor. What did you find in terms of safety? And please put it in context in your practice, given the efficacy benefits, how do you sort through that?

Karim Fizazi: Sure. So most of what we reported basically in terms of safety is confirmed. So no new signal, no long-term side effects, and no bad things. Especially regarding myelodysplasia or leukemia. I think we had two cases overall in the trial and they were previously reported—no more events with this longer follow-up. So that's reassuring. The main side effect is obviously anemia—approximately 40% of grade 3 or 4. So that's not nothing, of course, but this was really, again, reported at the beginning. No more events were reported with this long-term assessment.

Basically, this anemia appears very rapidly while starting the treatment, within three months typically. And it needs to be treated, of course. Transfusion is the main treatment, and dose reduction is also key. And it appears to work, so you probably need to speak with your patient, tell them that almost half of them will need treatment for anemia. But then when you start, you typically don't need to re-transfuse your patient if you dose reduce your patient. And then you can carry on with a lower pathology—with a lower dose basically of talazo.

Alicia Morgans: I think that's such a good strategy, and one that makes sense in our clinics, and allows those patients to stay on a PARP and have that ongoing benefit.

Karim Fizazi: Absolutely.

Alicia Morgans: So when you think about this updated data and certainly think about being in practice, where do we stand? Where do we go? How do you make decisions about patients who have HRR mutations when you're in clinic?

Karim Fizazi: I think if you want a simple message, I think a patient with BRCA alterations needs a PARP inhibitor and probably as soon as possible. This is crystal clear to me now for metastatic castration-resistant disease based on TALAPRO-2 data, but also looking overall to all the phase III trials we have. I think we really need this intervention as soon as possible. I think one limitation from TALAPRO-2, and similar to PROpel or MAGNITUDE, for example, is that nowadays we are using AR pathway inhibitors typically much earlier in the course of a disease, in castration-sensitive disease typically.

And we don't really have data as to whether, say, a patient on abiraterone or darolutamide for metastatic castration-sensitive disease who is now progressing to mCRPC with BRCA alterations, say, or another alteration, should go on enzalutamide plus talazoparib. That is something I think we should really focus on in terms of research. I'd love to know the answer.

I think there's a very reasonable rationale to combine, knowing that enzalutamide remains partially active post-abi in 20%, 30% of patients. And talazoparib is clearly very active in patients with BRCA alterations. So that would be, I think, a very reasonable scenario. But, again, I'd love to see data to feel, of course, more comfortable using this combination in this scenario.

Alicia Morgans: Well, it wasn't a plant, but it could have been. We're launching the TALENT study, which is patients with mCRPC who have had progression on ADT and abi in some earlier state and randomizing them to talazoparib alone or tala-enza. So hopefully we'll get some data to understand that synergy versus potential not need for synergy if it's just a sequencing issue.But, in any event, thank you for keying that up. That should hopefully open within the next few weeks to a month or so. And either way, thank you so much for talking with me about this updated data. It's always a pleasure to talk to you.

Karim Fizazi: Thank you so much.