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Alicia Morgans: Hi, my name is Alicia Morgans and I'm a GU Medical Oncologist at Dana Farber Cancer Institute. I am so excited to have here with me today a great friend and colleague, Dr. Neeraj Agarwal, who is a Professor of Medicine and the Presidential Endowed Chair of Cancer Research at the Huntsman Cancer Institute at the University of Utah. Thank you so much for being here with me today, Dr. Agarwal.

Neeraj Agarwal: Thank you very much for having me here. It is always a pleasure and an honor to be on this program.

Alicia Morgans: It is always a pleasure and an honor for us to talk to you, too. And today I want to talk with you a little bit about a trial in progress, TALAPRO-3, which I know you've been working on for some time, but I'd love to hear what is this trial? Who is it targeting and how can we as a community best support enrollments that we can understand the answers? I think this is a metastatic hormone-sensitive trial. We need to know the answers in terms of the DDR or HRR mutation population and how we can best support them.

Neeraj Agarwal: Thank you. And thank you for highlighting this very important trial or giving me the opportunity to highlight this trial. So, first of all, this trial is for patients with metastatic castration sensitive or hormone-sensitive prostate cancer as to newly diagnosed hormone nieve, but patients are allowed to have three or four months of androgen deprivation therapy. They are allowed to have prior chemotherapy with docetaxel. They are allowed to be started on novel hormonal therapy with abiraterone, enzalutamide, or apalutamide, but if they are eligible, they will have to switch to the combination of enzalutamide plus talazoparib versus enzalutamide plus placebo. So a very pragmatically designed trial. So, anyone who is a newly diagnosed metastatic prostate cancer patient, who is diagnosed or detected to have these mutations in homologous recombination repair genes, whether they are somatic tumor mutations, or they are germline mutations, they are eligible for the trial.

Alicia Morgans: That is fantastic. And I actually want to commend you and the team for really allowing patients to have had docetaxel and then combining it with an AR-targeted agent. I think that is a phenomenal way to go and really to be quite timely as we have some of the data from PEACE-1, for example. So how would you say that this trial fits into the landscape, given the PEACE-1 data that we just heard at ESMO 2021?

Neeraj Agarwal: Yes. So, wonderful questions. So, first of all, we know in patients who have DNA repair mutations, DNA repair gene mutations, they may not have as good of sensitivity or responsiveness to androgen access inhibitors or androgen deprivation therapy. In fact, we know that regardless of DNA repair gene mutations, just treatment with androgen receptor blockers may up-regulate or down-regulate the DDR genes, which may lead to up-regulation of PARP.

So regardless of the DNA repair gene-related mutations being present, just the presence of drugs, like enzalutamide may sensitize the tumors to action with PARP inhibitors because they are over-reliant on PARP, to begin with. Now they have DNA repair gene mutations, and we already know that these patients who have DNA repair gene-related mutations or HRR mutations, respond to PARP inhibitors. And this has already been validated by approval of olaparib and rucaparib in patients with metastatic castrate-resistant prostate cancer, and three Phase III trials are going on now in metastatic castrate-resistant prostate cancer, combining PARP inhibitors with androgen access inhibitors. So what we are doing is to move the combination and the concept of dual blockade with androgen access inhibition, plus PARP inhibition, just moving it to the hormone-sensitive setting and hope we are able to show a meaningful difference in radiographic progression-free survival, and overall survival and responses down the line.

Alicia Morgans: I think that's fantastic. I am curious though, too, are you and the team collecting patient-reported outcomes and really investigating them in combination with adverse events to understand the patient experience on the trial?

Neeraj Agarwal: Yes. Before I answer that, I think I probably did not address your question on PEACE-1. So wonderful results presented by Dr. Karim Fizazi showing that triplet therapy with docetaxel plus abiraterone plus androgen deprivation therapy was superior to the combination of ADT plus docetaxel, as far as the primary endpoint was concerned, which was overall survival. And it was improved especially in patients with de novo high volume metastatic prostate cancer, not so with low volume disease. I think these results are practice-changing, practice impacting, practice influencing, however way we want to describe that. We also know that in the real world, the use of ADT only for metastatic castration-sensitive prostate cancer remains the most commonly utilized regimen, which is unfortunate. We just showed at ASCO this year, I happen to remember the abstract numbers, abstract 5072 - 5074, there were three abstracts showing exactly very similar findings in different patient populations that ADT alone remains the standard of care for ... remains the most preferred regimen being used by practitioners across the United States.

And we also have similar studies from England, and from other parts of the world. So I think there are two or three things we are talking about here, on one side, we have triplet therapy with docetaxel with abiraterone, and with ADT showing improved survival. On the other side, the majority of the patients still continued to be treated with single-agent ADT. So I think there is no doubt we need to bridge the gap and we need to introduce these combination therapy regiments, but we all agree that if we cannot get to triplet therapy for all patients, at least we have to make sure that dual therapy with the ADT plus androgen access inhibitors can be applied to the majority of patients. So this trial is going to do that for sure. Enzalutamide plus androgen deprivation therapy is going to be offered to all patients as a backbone and talazoparib are being added to that.

Now the good thing we did, I think retrospectively speaking, is that we allowed docetaxel treatment in the hormone-sensitive setting. So I think the way we are going to incorporate this practice is any patient who is eligible is [inaudible 00:07:12] partially eligible for docetaxel will be allowed to go on their trial after they have finished treatment with docetaxel chemotherapy. Obviously, if they have started docetaxel with abiraterone and want to continue abiraterone, they may not be eligible for the trial, but for patients who are treated with docetaxel and then want to switch over to enzalutamide plus-minus talazoparib, I think we will not miss those patients on this trial.

Alicia Morgans: Well, I think that's completely fair because that is what was done in ENZAMET and I think from a theoretical perspective, at least, it's a very similar combination, very similar sequence. So, and actually, ENZAMET as we've discussed before on this program, we did see a progression-free survival advantage, we just haven't seen the mature overall survival results. And at some point, we will see them and we will understand if that combination of the three, ADT, docetaxel, and enzalutamide is going to be as effective as what we saw very recently with PEACE1, but I think that's a completely reasonable approach. And I do think that we will see information from ENZAMET at some point in the very near future that will also help us understand if this is the right approach or if there is something to consider amending with TALAPRO-3, but for now, this seems completely reasonable to me, and very consistent with the standard of care, given what you've discussed in terms of real-world data. So--

Neeraj Agarwal: I would like to highlight the quality of life and patient-reported outcomes, as you said--

Alicia Morgans: Yes.

Neeraj Agarwal: As you asked, and this is... we are convinced that not only improving survival is the goal here, but not at the cost of quality of life. So this trial has very stringent, validated questionnaires, which are being used to assess patient-reported outcomes and quality of life. And I'm really hoping that one day, the combination of enzalutamide with talazoparib will show superior outcomes over enzalutamide in patients who have newly diagnosed metastatic castration-sensitive prostate cancer, who are undergoing treatment with androgen deprivation therapy and have received prior docetaxel if they wanted to, and they will also have an improved quality of life. That is a hope that we will see those endpoints being met in this clinical trial.

Alicia Morgans: I would agree with you. And I would say that sometimes we have to trade quality of life to get survival benefits. And sometimes we are able to maximize both and either way, as long as you and the investigators show the patients, show the clinicians, what they are sacrificing to gain, or what they are maximizing on both levels, I think that information is incredibly powerful. So the fact that you are measuring it alone will give the patients what they need in terms of making that choice. Even if the quality of life is somewhat sacrificed in order to get better disease control, at least you will have the information and at least patients will know what they are getting into when they make that choice.

But we have seen that in most cases when there is better disease control, there is a better quality of life. So I'm hopeful, as you said, that everything will be maximized if this is a successful combination, as we expect. So as you think about this trial, which is extremely exciting and something that I'm glad we were able to highlight today, what would your final thoughts be as clinicians are thinking about how to best help their patients with metastatic castration-sensitive prostate cancer?

Neeraj Agarwal: My final message regarding the TALAPRO-3 trial is; finally, we are seeing hormone-sensitive trials or castration-sensitive trials happening, which are recruiting patients based on underlying biomarkers. It is very critical that we test our patients for homologous recombination repair gene mutations, through tumor tissue profiling, or ctDNA profiling, both are allowed for the trial. And I really hope that all patients who are diagnosed to have metastatic hormone-sensitive prostate cancer have the opportunity to have this testing done. And if they have these mutations, that they are given the opportunity to enroll in this clinical trial.

Alicia Morgans: I think that's a great message. And I really encourage all the clinicians who are watching to look out for these patients. Of course, we know that it is now a recommended test to assess patients for germline genetic alterations, particularly as they relate to DNA repair defects or HRR mutations, as soon as they are metastatic. So all of this population should have that testing done if we find those patients, and they're not everywhere, so when we find them and they are somewhat few and far between, it is helpful if we can at least talk about this trial, I think, and try to enroll those patients. This may be a new standard of care that allows them even better disease control than they might have otherwise. So please consider it. And thank you, Dr. Agarwal, for talking with us about this really innovative trial that as you said, is the first metastatic hormone-sensitive prostate cancer trial that is really relying on a backbone of these, of identifying patients who have these DNA repair defect alterations. Thank you so much for your time and good luck with your trial.

Neeraj Agarwal: Thank you again for the opportunity and for having me here.