HRR Mutation Testing in mPC
Transcript: TALAPRO-2 at ASCO GU 2025
Dr Karim Fizazi
Interview recorded February 2025. All transcripts are created from interview footage and directly reflect the content of the interview at the time. The content is that of the speaker and is not adjusted by Medthority.
So for TALAPRO-2, the primary endpoint radiographic progression for survival was met, and we know that for basically three years or so. And this was true for the HRR population and cohort, and also for the all-comer population. Of course, much bigger benefit for the HRR population. With this updated analysis, what we see for the HRR population is that the RPFS benefit still clearly remains, the hazard ratio is almost the same, the medians are not reached, and this is approximately a year for the control arm, enzalutamide alone, versus 31 month for the combination. So big gap, big difference. And the more the time, the greater the difference in the Kaplan-Meier curves. So that's important to see.
Second, overall survival is significantly improved in the HRR population, ranging from 31 months in the control arm to 45 months in the experimental arm. So again, quite a big difference with a hazard ratio of approximately 0.6, approximately, let's say 40% reduction in the risk of death. So that's quite, you know, clinically significant, of course. Now digging into more details, of course, because not the... I mean these alterations are not made equal with regards to the efficacy of a PARP inhibitor. First, starting with BRCA alterations, we see really an enormous benefit with a hazard ratio of approximately 0.5, favouring the combination and the median overall survival is not even reached in the experimental arm with quite significant follow-up. While it is reached in the control arm. So, really, really big, big, big benefit in overall survival with talazoparib plus enzalutamide for these patients. There's no debate. For HRR gene alterations non-BRCA, actually you see a clear trend and the p-value is 0.06, which is telling us that these alterations are really not made equal. It's a heterogeneous bag of different cancers basically. And if you dig into the details, you will see that patients with CDK12 alterations, which is associated with aggressivity typically, tend to benefit, for example, while CHEK2 do not.
So, we need the testing probably to tell us whether we should treat with a combo or just with one drug. And that I think is an important message. Now for patients without HRR alterations, there is a trend as we were expecting it for overall survival, but it's not significant. So again, we need probably more science to better understand why do we see this trend and of course, clinically speaking, whether the combination is worth it in this population or not, given the safety profile of this combination.
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