Exploring the TALAPRO-2 Study of Talazoparib and Enzalutamide in Prostate Cancer: Stephen Freedland, MD, and Neeraj Agarwal, MD

In this interview, Oncology Data Advisor Editorial Board member Dr. Stephen Freedland, Professor of Urology at Cedars-Sinai Medical Center, speaks with Dr. Neeraj Agarwal, Director of the Genitourinary (GU) Medical Oncology Group at Huntsman Cancer Institute, about his recent publication of the TALAPRO-2 study. Dr. Agarwal delves into the results of the trial, which investigated the efficacy of talazoparib plus enzalutamide for first-line metastatic castration-resistant prostate cancer (mCRPC), and their practice-changing significance.

Stephen Freedland, MD: Hi, I’m Steve Freedland, Professor of Urology at Cedars-Sinai Medical Center in Los Angeles, as well as at the Durham Veterans Affairs (VA) Hospital in Durham, North Carolina. It’s my great privilege and honor here today to be with a dear friend, a phenomenal investigator, Professor Neeraj Agrawal, who is a Professor of Medicine and the Director of the GU Medical Oncology Group at Huntsman Cancer Institute of the University of Utah. Welcome to the program, Neeraj.

Neeraj Agarwal, MD: Thank you for having me. It’s such an honor.

Dr. Freedland: We’re going to be talking today about your practice-changing TALAPRO-2 study. It’s a really interesting combination of enzalutamide, to block androgen receptor, and talazoparib, a poly-ADP ribose polymerase (PARP) inhibitor. First, give me a little bit of background. What’s the rationale for combining these two mechanisms of action?

Dr. Agarwal: Great question, Steve. First of all, let me take a step back and talk about mCRPC as a disease, the path towards progression to mCRPC, and then the need to block mutated prostate cancers with the more intensified therapy upfront. I’ll take a moment here, because most people, in my experience, have not really delved into this area before talking about the data.

In the United States, the vast majority of patients are diagnosed with localized prostate cancer. Metastatic hormone-sensitive prostate cancer, or de novo metastasis, is only happening in 5% to 10% of patients. If you look at those localized prostate cancers—you have done similar work in this area—after definitive radiation therapy or surgery, unfortunately, 20% to 50% patients have recurrence. Then they are traditionally treated with androgen deprivation therapy (ADT), either intermittent ADT or continuous ADT.

Based on the data from your trial, the EMBARK trial, many of them will be treated with enzalutamide. But for the next many years, we will have the vast majority of mCRPC patients actually progressing to mCRPC through that localized prostate cancer route and not the de novo metastatic hormone-sensitive prostate cancer route. Metastatic CRPC is actually a much bigger burden of cancer, if you will, than metastatic castration-sensitive prostate cancer. That’s number one.

Number two, if you look at the prevalence of homologous recombination repair (HRR) mutations, these are present in 25% of patients with mCRPC. That’s a huge proportion of the patient population. Then the third point I wanted to make, laying the ground for this discussion, is that the aggressiveness of mCRPC is much higher in patients who have HRR mutations, as evidenced by the control arm’s progression-free survival (PFS) with enzalutamide alone in the mCRPC first-line setting, as we’ll be discussing. It was only an 11-month PFS with prostate-specific antigen (PSA) progression compared to 20 months in the PROPEL trial in the all-comer population.

So, we have three things so far. Number one, mCRPC is a large patient population. Number two, 25% of patients have homologous recombination repair mutations. Number three, they poorly respond to standard therapies. And number four, half of the patients do not receive subsequent lines of therapies. In your work and Dan George’s work that you’ve published in this area, that intensification works in all stages, all cancers, all metastatic disease settings, because we lose half of the patients with subsequent lines of therapy. If we combine all of that together, yes, we have PARP inhibitors available in later lines of therapies, but we felt the need to combine PARP inhibitor with androgen receptor pathway inhibition (ARPI) in the first-line mCRPC setting, based on the preclinical rationale, based on the encouraging results from the study—an 850-patient trial of abiraterone plus olaparib versus abiraterone—and all these facts which compelled us to do the trial in this setting.

Dr. Freedland: This is great. So, tell us about the study.

Dr. Agarwal: The TALAPRO-2 trial, in fact, were two trials in one trial. There was the all-comer population, 800 patients, who were all prospectively tested for presence or absence of homologous recombination repair mutations. They were randomized to enzalutamide plus talazoparib versus enzalutamide alone. Then we prospectively tested another 230 patients and determined them to be HRR-positive. We additionally enrolled them on the trial as Cohort 2, and we included 169 patients from this all-comer cohort to make this HRR-positive cohort. To make it simple, there are 800 patients in the all-comer patient population, and the majority of them, 169 patients, were HRR-negative. About 25% were HRR-positive. We reported the results in the all-comer patient population first, and then we reported the results of the HRR-mutated patient population at ASCO 2023. This was the design of the trial.

Dr. Freedland: And what did you find?

Dr. Agarwal: If we look at the primary end point, radiographic progression-free survival (RPFS)and if you only look at HRR mutation patients first, there was a 55% reduction in risk of disease progression or death, with a hazard ratio of 0.45. This is a very compelling reduction in risk of progression or death, especially in that patient population which already has been established to not respond very well to standard therapies. Now, if you look at overall survival, it’s trending quite well. The maturity level is quite low. Around 25% patient events so far have been met for overall survival. Obviously, the overall survival data are not mature, but still, the hazard ratio is 0.61. I have no doubt that we will show overall survival benefit in addition to having shown RPFS benefit in this patient population.

I would also like to bring your attention to some clinically relevant end points which are relevant to our patients. Time to PSA progression in the control arm was 11 months. If you look at the experimental rm with talazoparib, it was 28.6 month, a 17-month delay in PSA progression. Very similar was the theme with chemotherapy—time to delay for chemotherapy and time to progression on subsequent therapies. Interestingly, if you look at the quality of life, one of the major secondary end points was time to deterioration in quality of life. What we found was quite intriguing. While these patients were being treated with two agents versus one agent, enzalutamide plus talazoparib, there was a significant delay in time to clinically meaningful deterioration in quality of life in the HRR mutation–positive cohort. These data have led to the FDA approval of the enzalutamide plus talazoparib combination in the US for our patients with mCRPC with HRR mutations.

Dr. Freedland:Congratulations, it’s a great study. I know our audience is predominantly US-based, but we do have some people outside the US. We’re not sure what other countries are necessarily going to say in terms of approval, but there are possibilities that it may be broader or different. Can you give us a little idea of Cohort 1, the all-comers, and what you saw in that cohort?

Dr. Agarwal:Thank you very much for the opportunity to talk about the all-comer cohort, because those data are important in my view. First of all, the approval has not been ruled out yet. Even in the US, we are waiting for more maturity on the overall survival data to see how the trends are. The approval has not been ruled out. We just got the approval from the FDA in the HRR mutation cohort. But as you said, Steve, we got approval for this combination in the European Union just two weeks ago, and it was quite discussed for all-comer patient population, so let me discuss the data in the all-comer patient population. Again, among prospectively tested patients, if you look at all patients, the hazard issue was 0.63, with a 37% reduction in risk of progression or death. Again, every single clinically meaningful end point or other end points were met and favored the combination—time to deterioration of quality of life, time to PSA progression, time to cytotoxic chemotherapy, time to progression on subsequent therapy—all favored the combination of enzalutamide plus talazoparib.

The overall survival data are immature right now—the trends are there, but in the absence of overall survival, I would not delve into that very much. But overall, if you look at the patients who are HRR-negative, meaning they did not have an HRR mutation even by prospective tumor tissue testing, which is considered the gold standard, there was a significant delay in radiographic progression with a hazard ratio of 0.66. There was a 34% reduction in risk of progression or death, even in those patients who were HRR mutation–negative by prospective tumor tissue testing. Now, it doesn’t mean every patient who is negative for mutations should be offered this drug while we are waiting for the more data from the overall survival perspective. But I think next steps are to find out who these patients are who are responding.

Dr. Freedland: This is great. I would love to hear more about who you think is the best candidate, but before we do that, the delays in deterioration of quality of life are extremely important. It’s great that you guys track that. Tell me a little bit about the side effects. What would patients expect to see on this combination?

Dr. Agarwal: Yes, no discussion about the efficacy data can be complete without the discussion of side effects. I’m glad you brought up that question. PARP inhibitors, as a class, have three major side effects in general—hematologic toxicities, gastrointestinal toxicities, and fatigue. Now, each PARP inhibitor is separate, with different compounds, different molecules, and different targets, so side effects can vary. For example, in the case of talazoparib, the side effects are predominantly hematologic. In the case of olaparib, you may see a little more domination of gastrointestinal side effects such as nausea or vomiting. In the case of niraparib, you have some unique side effects such as hypertension and cardiovascular side effects.

The bottom line is, all these side effects are very manageable. Most side effects happen within three to four months of starting PARP inhibitors. We can easily recognize them, as long as we follow these patients more often, early on, in first three to four months. We can easily recognize patients who are going to develop severe side effects, and we can preempt those side effects. In the case of anemia, for example, by timely reduction in the dose of talazoparib or in case of nausea and vomiting, my practice is to actually write anti-nausea medication prescriptions. When I write the prescription for olaparib or niraparib for the first time, I tell my patients to regularly monitor their blood pressure.

If you look at the TALAPRO-2 trial, which is the focus of the discussion today, if you look at how many patients had grade 1-2 anemia at baseline, 49% of patients had grade 1 and 2 anemia at baseline in the all-comer cohort, and 56% of patients had grade 1 or 2 anemia at baseline in the HRR mutation–positive cohort. What this tells me is that mCRPC is associated with a symptomatic state of prostate cancer or impending symptoms, if you will. If you don’t have symptoms now, you will have symptoms very soon. Anemia is present in a very large number of patients to begin with.

Now, we treat them with PARP inhibitors which are known to cause anemia. What we see is worsening of anemia in many patients. Surprisingly, if you look at how many patients actually discontinued talazoparib in the all-comer cohort, it was 8.5% of patients. If you look at the median dose intensity of talazoparib, that was more than 80%. The lesson for me, from these data, is that most of these patients require only one dose level reduction, and they do fine after that, as evidenced by most patients not having to discontinue talazoparib because of anemia. If you look at the median dose intensity of talazoparib, 80%, we actually have all those patients at our clinic who are on PARP inhibitors for years now­—not only months, but years.

I’d like to also add one more point. The median time to onset of anemia was 3.4 month. As long as we follow these patients in the first three to four months and do monthly local lab local lab testing, I don’t even have to have them come into my clinic. Patients who are actually dropping their hemoglobin fast, I know they’re heading to grade 3-4 anemia. I don’t let most of my patients develop severe anemia. I actually reduce the dose of talazoparib by the time they’re getting to hemoglobin of 9 g/dL, for example, and I preempt. I think this side effect monitoring early on is quite important. A timely dose reduction allows the vast majority of patients to get talazoparib, or from that perspective, PARP inhibitors, for really long periods of time.

Dr. Freedland: That’s great to know. I guess one last question here, which you kind of hinted at, is do all patients get equal benefits? Are there subsets of patients for whom this really is a home run, and other subsets where it’s maybe a little bit harder of a decision?

Dr. Agarwal: Great question. Everybody does not get a similar magnitude of benefit, but so is the case with every single approved drug we have in the clinic, whether it is chemotherapy with docetaxel, whether it is lutetium-177, or so on. The key is to identify who is going to benefit the most. We know patients with HRR mutations benefit more than patients who do not have HRR mutations. With an HRR mutation category, patients with BRCA2/BRCA1 mutations seem to derive a higher magnitude of benefit than patients who have CDK1/2, PALB2, RAD51, and many other mutations. The bottom line is that when I start patients on PARP inhibitor combination therapies, I follow them, and as long as they respond, I treat them. But I don’t rule out anyone for being treated with a combination just because of my own preconceptions or biases. I want everyone to have the opportunity to have this combination available, and then I follow them and I treat them for as long as they respond.

Dr. Freedland: It makes sense; you want to give them the benefit of the doubt that they’re going to be a responder. Any final thoughts?

Dr. Agarwal: Comprehensive genomic profiling is a must for all prostate cancer patients. Unfortunately, still a small number of patients are undergoing comprehensive genomic profiling. We know from our experience when we were doing the PROFOUND trial, which led to approval of olaparib as a first targeted therapy for prostate cancer, that 30% patients did not have adequate quality or quantity of tissue in the mCRPC setting to allow them to undergo testing. I urge each of my colleagues out there to send out the tumor tissue for comprehensive genomic profiling for every single patient when we see them for the first time with advanced prostate cancer—which includes metastatic prostate cancer, locally advanced prostate cancer, and based on emerging therapies, even high-risk localized prostate cancer—if their insurance allows and if there is no financial constraint.

Dr. Freedland: It’s a great message. We’re definitely not testing enough, and it creates challenges as to what to do when they get to late stage. I know you’re still following the patients for overall survival, so we’ve got our fingers crossed that it’s going to show benefits for the patients. We will certainly have you back when we have those data and talk about the next round of things. It’s been so great, Neeraj, to have you on the call. I really appreciate your time today. This is great work—it’s practice-changing, really important stuff, so congratulations.

Dr. Agarwal: Thank you very much, and congratulations to you, Steve, again, for publishing the EMBARK trial results in the New England Journal of Medicine. We march together, so thank you for the opportunity here.

Dr. Freedland: It was great to have you.

About Dr. Freedland and Dr. Agarwal

Stephen Freedland, MD, is Director of the Center for Integrated Research in Cancer and Lifestyle and Associate Director for Education and Training at the Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute. He also is the Warschaw Robertson Law Families Chair in Prostate Cancer and a Professor in the Department of Urology at Cedars-Sinai in Los Angeles. Dr. Freedland also holds a Staff Physician appointment at the Durham VA Medical Center in Durham, North Carolina. Dr. Freedland has published over 700 articles and served on numerous American Urological Association and American Society of Clinical Oncology guideline panels for prostate cancer. His research interests include the role of diet, lifestyle, and obesity in cancer, cancer health disparities, and cancer risk stratification.

Neeraj Agarwal, MD, is a Professor of Medicine and the Presidential Endowed Chair of Cancer Research at the University of Utah, Huntsman Cancer Institute. He is also the Director of the Genitourinary Oncology Program and the Center of Investigational Therapeutics at Huntsman. Dr. Agarwal is an internationally recognized physician scientist in genitourinary cancers, including prostate, bladder, and kidney cancers. He has authored more than 400 peer-reviewed articles and book chapters and serves on several advisory panels and guideline committees, including for the National Comprehensive Cancer Network (NCCN) and the FDA.

For More Information

Agarwal N, Azad AA, Carles J, et al (2023). Talazoparib plus enzalutamide in men with first-line metastatic castration-resistant prostate cancer (TALAPRO-2): a randomised, placebo-controlled, phase 3 trial. Lancet, 402(10398):291-303. DOI:10.1016/S0140-6736(23)01055-3

Freedland SJ, de Almeida Luz M, De Giorgi U, et al (2023). Improved outcomes with enzalutamide in biochemically recurrent prostate cancer. N Engl J Med, 389:1453-1465. DOI:10.1056/NEJMoa2303974

Transcript edited for clarity. Any views expressed above are the speakers’ own and do not necessarily reflect those of Oncology Data Advisor. 

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