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Alicia Morgans: Hi, I'm so excited to be here with Professor Neeraj Agarwal who is talking with me today about TALAPRO-2, a really exciting study that was recently released and that you presented at GU ASCO 2023 leading to a lot of discussion and lots of controversy I think, about how to think about the use of PARP inhibitors and androgen receptor signaling inhibitors in the first line mCRPC space. Can you tell us a little bit about the study, Neeraj, and then maybe we can go through some of the results?

Neeraj Agarwal: Of course. TALAPRO-2 phase three trial, let me just talk about the design first. This is a large randomized phase three trial, which compared the combination of enzalutamide plus talazoparib, a PARP inhibitor, versus enzalutamide plus placebo. In patients who were in first line metastatic CRPC setting, who were enrolled on the trial regardless of homologous recombination repair gene-mutations. So these patients for all-comer population. And I would like to remind the audience here, the TALAPRO-2 trial also has a selected cohort which was recruited after this cohort one of unselected patients were recruited. So we are not talking about the cohort two, which will be reported in a future meeting. So coming back to the population of TALAPRO-2 trial, all-comer metastatic CRPC patient population. And radiographic progression-free survival by independent review was the primary endpoint.

Trial was stratified by the presence or absence of HRR status. To be more precise, it was stratified by presence of HRR alterations versus absence of HRR alterations or those patients who had unknown status. They were put together as far as stratification is concerned. And trial was also stratified by the receipt of prior abiratone and docetaxel chemotherapy. So when you look at the radiographic progression-free survival endpoint, it was met in a clinically meaningful, as well as statistically significant fashion. The radiographic PFS was actually 22 months in the enzalutamide arm, which suggest a strong work by the control arm. And in the combination arm of talazoparib per plus enzalutamide, the radiographic progression-free survival was not reached, but it was 37% better. So there was a 37% reduced risk of progression or death, with the hazard ratio of 0.63. Interestingly, if you look at the investigator assessment of HRR, that was 0.64. So 36% reduction in risk of radiographic progression by investigators. So independent radiology and investigator assessment were pretty much overlapping.

If you look at the other secondary endpoints, such as time to PSA progression, time to chemotherapy, time to progression or death on first antineoplastic therapy after the protocol treatment and time to deterioration in quality of life and global health status, all favored the combination arm of talazoparib plus enzalutamide. Almost pretty much all these arms showed statistically significant benefit. Overall survival, which was another secondary endpoint, one of the important secondary endpoints, was immature at 31% maturity right now. The hazard ratio currently stands at 0.89, favoring enzalutamide plus talazoparib. I would also like to bring your attention to the efficacy of the combination of talazoparib plus enzalutamide in the subsets of homologous recombination repair gene-mutations. So if you look at patients who are HRR mutation-positive, and again I would like to point out that 99.9% patients in the study were tested prospectively by tissue testing.

We know there have been some discussions about CT DNA testing not being the gold standard, so we made sure that all patients, except one actually, got under the trial based on tissue testing. If we look at those approximately 20% patients of total patient population who were HRR positive, there was a 54% reduction in risk of progression or death, hazard ratio of 0.46, favoring the talazoparib. If you look at the patients who were HRR negative or unknown status, there was a 30% reduction reduction in risk of progression or death. Because the unknown status patients were together with the HR negative patients, we wanted to, and this was was a stratification factor after discussion with the original regulatory body based discussion so on. So we decided to give a more clean picture for those who are practicing on oncologists.

So we decided to actually do a exploratory analysis of patients who were HRR negative by prospective tumor tissue testing and there were like 400 patients and in this patient population there was a 34% reduction in risk of progression or death with enzalutamide plus talazoparib. So overall it's a pretty strong data as far as efficacy of the combination of talazoparib plus enzalutamide is concerned, in the overall all-comer patient population. With the caveat that the magnitude of benefit is much higher in the HRR positive patients, but it is present still in the HRR negative patient population.

Alicia Morgans: Thank you so much for walking us through that, and what I think is so interesting is that when we talk about the HRR negative population in many conversations I hear people saying, "Well, all of the benefit that we see in an all-comers analysis is really driven by the biomarker selected patients." But you specifically pulled out the biomarker negative patients. To be clear, these are patients where these were negative in terms of their tissue testing. And what we saw was that in a setting where talazoparib should have no impact whatsoever, if there's no biomarker, there was seemingly a synergistic activity between this talazoparib and the enzalutamide that allowed that talazoparib enzalutamide combination to be superior to enzalutamide. And I think it's so important that you pulled that group out by itself as a group that you wanted to understand outside of the all-comers population.

Neeraj Agarwal: Yes, and we thought it was necessary because of the discussions we had last year based on the other trial data where CT DNA testing was utilized in many patients. And at least those were the results presented. And I never had any doubt that definitely there was a signal, but I think it was good for us to learn firsthand, in tumor tissue based HRR negative patient population, to see if there is signal or not, and to show a real signal statistically significant improvement in radiographic progression-free survival compared to a very active control. Enzalutamide is performing better than what we did with PREVAIL trial, despite 27%, although still a small number of patients, having received docetaxel and or abiraterone in castration sensitive setting. So I think this, to me, these are pretty compelling results.

Alicia Morgans: I agree and I think the audience agreed too. Very excited to hear these results. One thing that I do think we should check in on and discuss though too is the safety profile. Was there anything unexpected? I know your group not only reported all adverse events by grade of course, but also some adverse events of special interest, just to ensure that the clinicians and the room really had the information they needed to understand the complications.

Neeraj Agarwal: Of course. No discussion about the results of a clinical trial is complete without discussion of safety results, so I'm so glad you brought this up. If you look at the safety aspect of the trial, the most common cause of dose reduction and discontinuation were cytopenia. So anemia, neutropenia, thrombocytopenia, were the most common grade three, four toxicities as well. If you look at how many patients developed grade three, four anemia, there is 46.5% patients. But then if you look at how many patients had grade one to two anemia at baseline, there were 49% patients had grade one or two anemia at baseline. One good thing about this protocol was the hemoglobin eligibility criteria was nine gram percent hemoglobin, which is one point away from grade three, four anemia. So we wanted a real world population to be recruited in this trial, which is representative of metastatic CRPC population.

Anemia is quite prevalent in this population and as expected, anemia happened, the grade three, four anemia happened within a median of 3.3 months actually. So it happened pretty early during the course of treatment, following which all these patients underwent protocol mandated dose reduction. After that, the talazoparib was actually quite well tolerated as evident by only 8.3% patients on talazoparib actually discontinuing talazoparib par due to anemia. And if you look at interestingly, the median dose intensity of talazoparib par in the talazoparib arm, that was like 84%. So despite frequent dose reductions, dose discontinuation were very uncommon. And even those dose reductions which happened, they mostly happen within first two or three months. And after that, patients seem to be tolerating ta well.

Now let's go beyond cytopenias. Let's look at some other side effects which we know are quite impactful from quality of life perspective, which really can be devastating for patients such as grade three, four fatigue, nausea, vomiting, anorexia. So we just look at the grade three, four aspects of these side effects. They were presenting one to 4% patients in the talazoparib, and that was also reflected in the quality of life and global health status aspects of the treatment where we saw that the combination actually delayed time to deterioration of global health status and quality of life. So if you put all this together, I'm really hoping that we will have this combination available for all our patients with metastatic CRPC and we'll see hopefully regulatory approval of this combination in the near future.

Alicia Morgans: Very, very interesting and important. So thank you for talking that through. I just wonder what are your thoughts if there is an all commerce label, what are your thoughts on genetic testing?

Neeraj Agarwal: Fantastic question, as usual, as expected of you. We want to do genetic testing, germline testing and somatic testing for all patients. "Why?," people may say, and that was a question actually from one of the friends actually who is a good friend. The genetic testing is necessary because when I'm counseling the patient about the benefit versus side effect, this combination may be more compelling to a patient who has a HRR mutation because the reduction of risk of progression or death is 54% with a combination, versus a patient who doesn't have this alteration, where the magnitude of benefit is lower compared to those patients who have HRR alteration positivity. In negative patients, degree of benefit is lower.

So there are two or three options available. In the clinic, a patient may be more likely to choose a combination which is going to give them more benefit over other combination. So I think we have to know who are positive, who are negative, and again, these patients may have other options down the line. New therapies continue to be developed for these patients. We also talk about the other implications of testing, such as on family members, on siblings, on children. If somebody is germline positive for these mutations, I will refer the entire family to a genetic counselor. So I think there are so many implications and testing continues to be very important for all our patients.

Alicia Morgans: And I think you make such a great point that when we're making these decisions with patients, we're making a decision with one patient who either has the biomarker or does not have the biomarker. So understanding the risk in that individual patient, but having the opportunity to use what might be an effective or more effective strategy for that individual, if that is disease control efficacy is worth it despite the side effect profile that would be for the patient to really decide.

Neeraj Agarwal: Absolutely. It also came up like, "Should I wait for overall survival benefit?," "Why shouldn't I wait for the overall survival benefit?," especially when we were talking about side effect. And to be fair to the discussion, there were one case of MDS during the active follow period and there was one case of acute myeloid leukemia both in talazoparib arm after follow-up period. So yes, there were two cases, but there were two cases of MDS or AML, and these are called as you know, adverse event of special interest. There were 2.5% patients in the talazoparib arm, who had pulmonary embolism. There was 0.7% patients in the control arm who had pulmonary embolism. We know that the experimental arm or talazoparib arm, the duration of treatment was longer. They had more CT scans, so they were more likely to be picked up for more pulmonary embolism. Most of them are incidental pulmonary embolism.

But I think all of these can be meaningful to one patient versus other. And when my patient in the clinic is deliberating over the benefit and the side effects, I think all these data are important. And I think, regarding the overall survival question, I will leave it to my patient, whether they are happy with delaying chemotherapy, delaying PSA progression by nine months, by significantly delaying the time to deterioration and quality of life. If those data are meaningful to my patients and they are convinced by the efficacy of the combination and they want to go for it, why not? I don't want to be the one who is making the decision for them. I want to be the one who is making the decision with them.

Alicia Morgans: I think that's a great message and certainly one that resonates here as we think about how to really put the patient at the center of the decision rather than having that paternalism approach of deciding, "Well, this is generally not worth it, I don't want to move in that direction." So very, very appreciated that you frame it that way. And as you think about this study and really some of the big and long-lasting implications that it will have, what would your message be to listeners?

Neeraj Agarwal: TALAPRO-2 phase three trial showed us that the combination of enzalutamide plus talazoparib was superior to enzalutamide alone. A very active control by the way, in terms of radiographic progression-free survival, and several other clinically relevant endpoints. And we expect regulatory approval in the near future, assuming regulatory approval happens for all comers, I think this will be a combination which will be available for our patients, and the patients should be deciding if they want to be treated with this combination or not, with all the information being given by us to them.

Alicia Morgans: Wonderful. I'm sure that they will be happy to share their preferences and questions with you when you are able to offer them that data in return. So thank you so much for your time and your expertise today.

Neeraj Agarwal: Thank you very much for having me here.