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Alicia Morgans: Hi, I'm so thrilled to be here with Professor Karim Fizazi who is a GU medical oncologist and professor of oncology at Gustave Roussy in Paris. Thank you so much for being here with me.

Karim Fizazi: Thank you, Alicia.

Alicia Morgans: Wonderful. Karim, you, again, bring some wonderful and highly anticipated work to ASCO 2023. You were here to talk about, and you did talk about, cohort two for TALAPRO-2. Can you tell me a little bit about this unique cohort, how it really synergizes, or is maybe separate, but important, in relation to the initial cohort and how this is informing our understanding of the TALAPRO-2 data?

Karim Fizazi: Sure, happy to. Basically, TALAPRO-2 is not just one phase III trial, it's really two phase III trials in one study. And I'm saying that because when we initially designed the trial, the plan was only to assess with whether adding talazoparib to enzalutamide would help patients with DNA repair. But then during the discussions we decided, finally, to do also an all-comer cohort. Basically, the all-comer cohort was reported at ASCO GU by Neeraj. It's positive by rPFS. But when we completed the vast cohort, this all-comer cohort with 800 men, we carried on by accruing more patients with DNA repair defects, and actually, we included an additional 230 men with those alterations for A total of almost 400. So cohort two, which is the one I presented at ASCO, is really a very specific cohort of men with DNA repair defects. I'm saying that those are two phase III trials just because the alpha risk was split into the two cohorts. So it's really two different questions, if you will.

In that cohort with DNA repair defects, we enrolled patients with BRCA2 alterations, but also ATM, CDK12, PALB2, and some others. What we found was that radiographic progression-free survival is clearly impacted favorably, favoring the combination arm with a 55% reduction in the risk of progression or death. Highly significant, very obviously. I guess this was expected, but it's really good to see. When we dig into details for gene alterations, which I think is really key in this discussion, we saw that, obviously, BRCA2 patients clearly benefit, with an 80% reduction in the risk of progression or death, but also BRCA1 patients. The numbers are small, but the pattern is exactly the same. Hazard ratio less than 0.2. So really, really impressive. Of note, also, patients with CDK12 alterations, and you know, like me, that it's usually bad, an aggressive cancer, tend to benefit from PARP inhibition from talazoparib plus enzalutamide, with a hazard ratio of approximately 0.4. I think this is a new information. Non-expectantly, patients with ATM alterations or other alterations, CHEK2, for example, do not really benefit from the combo. This is about rPFS.

Overall survival, which is a key secondary endpoint, is immature, with approximately less than 25% men who have died. Still, we see a clear trend favoring the combo arm, with 31% reduction in risk of death and p-value is almost significant. So we'll see later on, probably in a year from now, with longer follow up, but I'm quite enthusiastic about OS data. The secondary endpoints are all positive. Time to PSA progression, time to cytotoxic, all these things.

Toxicity is mainly driven by anemia, similar to what we reported for the all-comer population, with approximately 40% grade 3 or 4 rates. So this is the most annoying thing in the story, really, because the rest is really quite okay. Last but not least, and I'm sure you'd like it knowing you, quality of life was analyzed for this cohort. We see a significant improvement into in terms of time to deterioration in quality of life, with also a 41% reduction in the risk, which is really telling us clearly that we are helping these men, and I think it's a good way to look at the balance between efficacy and safety. Obviously we clearly see a favorable impact.

So I think good news for all the patients. Clearly, I think patients with BRCA alteration should get a PARP inhibitor and should get it as soon as possible during their natural history. I didn't say it, but, by the way, we don't see in terms of safety any myelodysplasia or leukemia. So again, reassuring, and this is why I'm confident to say that old men with early CRPC and BRCA alterations should be treated, of course pending approval, but it's also pending the field for some other alterations such as CDK12 and it would be good to have something new for patients with CDK12 alterations, really.

Alicia Morgans: Absolutely, and it's also, I think, very interesting that the BRCA1 patients seem to have a similar benefit because I would say that that data, in certain studies, particularly those that looked at PARP inhibitors as a single agent, were a little bit lukewarm when it comes to BRCA1 and that robust response that we can see with BRCA2.

Karim Fizazi: I agree. I was actually surprised because I actually had good experience, personally, with my few patients with BRCA1 alterations. They tended to benefit tremendously or normally, let's say, for patients with bar alterations from a PARP inhibitor, and sometimes there was durability as well and clinical improvement, all these things. So I was actually surprised to see in other trials that it was not that obvious looking at the entire picture. But, of course, the numbers are small, and this is true also in TALAPRO-2. In all these phase III trials, BRCA1 patients are rare. It simply reflects the reality. It's just probably one person of the total overall population of mCRPC men. But it's really good to see good news for these patients as well, I agree.

Alicia Morgans: Absolutely. One other thing I would like to dig into is the quality of life data that you were talking about and really I think so important that when patients were reporting quality of life, there was a longer time to deterioration. And just to sort of recap, this is patient reported outcomes on instruments that they're completing on their own?

Karim Fizazi: Absolutely.

Alicia Morgans: And when we think about the CTCAE, which is what we have to worry about, the anemia and the possible transfusions or GI effects or whatever it is that we're looking, at blood pressure, these are things we have to worry about and sometimes can result in interventions that may affect patient's quality of life. What I hear is, when patients were completing these surveys, the pros outweighed the cons in that combination arm. I think that's so important as we look at CTCAE data and say, "We need to be cautious." And yes we do, but if the patients actually have a better quality of life with our caution and our interventions, perhaps it's still worth it. What do you think?

Karim Fizazi: I fully agree. rPFS is an important way to look at efficacy. It's also potentially an endpoint that would lead to approval of a drug, but it remains an image and we're not treat treating image, we're treating humans. And the same applies to other ways to assess toxicity. You and me are typically probably anxious when we see a grade 4 neutropenia, but patients don't necessarily care if they don't have fever and quality of life might not be impacted. So I agree with you. I think quality of life, with all the caveats, of course, about the way we can measure them, about how many patients fulfill the questionnaires, all these things, but still, it's measuring direct benefit to the patient, which is key besides duration of life.

Sometimes in the past when I went to VMA and discuss how we could have a drug approved, they simply told me, "Show us your treatment makes your patients live longer or live better." And it's just true. So quality of life is truly important be besides OS. I'm glad we could show that in TALAPRO-2. Again, the benefit is more important as compared to the arming.

Alicia Morgans: I couldn't agree more. As you think about all of this work, and congratulations again to you, to the team, to the patients, of course, how would you put this into context in your clinical practice, recognizing, of course, that there's not an approval right now for talazoparib even alone, let alone in combination?

Karim Fizazi: Correct. Assuming the drug is approved, I think it's a no-brainer to say that we should use it in men with BRCA alterations. The benefit is really enormous. I hope that in the next future we'll be able to report more data, even overall survival specifically for these men, but really even an 80% reduction or even more. 80% reduction in the risk of progression or death is really something meaningful to everybody. And the duration of efficacy for these men is there. All secondary endpoints are supported, quality of life is improved. So for these men, the I'm totally convinced.

Now, for other patients, I think I'm more on the fence, to be honest. This applies to patients with non-BRCA/HRR alterations, but also for the all-comer population, so patients, let's say without any HRD alterations. And here I think we just need a longer follow up of the trial. At this time rPFS is demonstrated, but we don't really know whether we are truly impacting some other things, quality of life as we just spoke about, symptoms, all these things, and on top of that overall survival. So we need to follow these patients longer, at least before I make my opinion, as to whether we should use also talazoparib in patients with non-BRCA alterations.

Alicia Morgans: Yeah, I do think we are so looking forward to continued data cuts and data releases from TALAPRO-2, because I think especially we as a field think about PROpel and we think about MAGNITUDE, really this third example and dataset that helps us understand these combinations is going to be really, really helpful because it is a bit of a mess right now as we try to think as a community without the clear data necessarily pointing us in a direction that's the right way to go.

Karim Fizazi: That's true. I agree. And we are learning every month, basically.

Alicia Morgans: Yes.

Karim Fizazi: Again, in TALAPRO-2, we just saw good data for BRCA1 patients, and I know, as we just said it, some colleagues were wondering whether we should or not treat these patients. CDK12, the same. All of a sudden, we see something happening and it would be really good to have something to propose to these men, of course, assuming this is confirmed. So yes, it's good that we have these trials prior, different PARP inhibitors, different designs, different findings, and at the end of the day, we'll be better able to understand who benefits and who should be treated, and on the other hand, in which population we should just avoid some of these treatment to avoid the cost and the toxicity if they are not useful for these particular men.

Alicia Morgans: Absolutely. And our molecular approaches to understanding all of this continue to evolve, too. Even beyond HRR, I think we have a lot of work to do to understand what else could be influencing the outcomes in these patients. Again, thank you so much for your time, for your expertise. I always appreciate talking to you.

Karim Fizazi: Thank you.