Neeraj Agarwal, MD, Huntsman Cancer Institute, Salt Lake City, Utah, discusses final overall survival (OS) results from the phase 3 TALAPRO-2 trial, as presented at the 2025 American Society for Clinical Oncology (ASCO) Genitourinary Cancers Symposium. Results demonstrated that first-line talazoparib plus enzalutamide improved OS among patients with metastatic castration-resistant prostate cancer.

As Dr Agarwal concluded, “talazoparib plus enzalutamide can be considered as one of the standard-of-care treatment options for our patients with mCRPC.”

Transcript:  

My name is Dr Neeraj Agarwal, I'm a professor of medicine and director of the genitourinary oncology program at the Huntsman Cancer Institute, University of Utah, in Salt Lake City in the United States. At the ASCO GU 2025, I presented the data on overall survival results from the TALAPRO-2 phase 3 trial, which evaluated the combination of talazoparib plus enzalutamide versus enzalutamide plus placebo in patients with metastatic castrate-resistant prostate cancer [mCRPC] who had not been treated with any treatment, or any therapies, for castration-resistant disease.

Before I move forward, there has been pre-clinical evidence to suggest that PARP inhibitor plus enzalutamide, or ARPIs in general, androgen receptor pathway inhibitor combinations, may extend the benefit of PARP inhibitor to those patients with mCRPC who do not have HRR gene alterations. And that was the basis for designing this trial of 805 patients who were unselected for HRR gene alterations. Just as a background, I'd like to mention to our viewers that in the real-world, the median overall survival of patients with metastatic CRPC is less than 3 years and about half of these patients do not receive more than 1 line of systemic therapies. Combination therapy may have an edge over sequencing of therapies just because we lose so many patients when they have disease progression. 

As I said, this was a large phase 3 trial which had 2 cohorts, essentially 2 trials in 1 trial, and I'll be talking about the first one, which was recruited first, which was cohort 1 – all-comer patient population with metastatic CRPC who were unselected for HRR gene alterations. Radiographic progression-free survival was the primary end point and overall survival was the key alpha-protected secondary end point. We previously presented the radiographic progression-free survival data, which we updated during the meeting, and showed that there was a 33% reduction in risk of progression or death when talazoparib was added to enzalutamide. Enzalutamide is an active control here, we saw the median progression-free survival of 19.5 months, which is very similar to what we saw with the PrEvENT trial, reported more than a decade ago. The interesting part was when you combined talazoparib to enzalutamide, the median radiographic progression-free survival was 33.1 months, almost 33 months. This is about a 14-month improvement in radiographic progression-free survival, by adding talazoparib to enzalutamide. 

Now, the overall survival results, which was the focus of the presentation, there was a 20% reduction in risk of death when talazoparib was added to enzalutamide compared to those patients who only received enzalutamide, and it resulted in an 8-month improvement in overall survival. Median overall survival in patients who received enzalutamide only was 37 months and patients who received both enzalutamide and talazoparib it was 46 months about. This is quite striking – one of the highest magnitudes of overall survival benefit we have seen in metastatic CRPC trials in the recent past. In the last 10 years, if you look at multiple mCRPC trials, this trial has one of the highest magnitudes of overall survival benefit. If you look at the forest plots, we see that the overall survival benefit with talazoparib was present across the subgroups whether patients had high Gleason score or they had M1 disease, if they had de novo disease at the time of initial presentation, or if they had prior abiraterone or docetaxel chemotherapy in the past in hormone sensitive setting, although these are a small number of patients, or patients had HRR deficiency, or patients who did not have HRR deficiency, or had unknown status. 

To better define the benefit of the combination of talazoparib plus enzalutamide in patients who did not have any HRR gene alterations as detected by both ctDNA and tumor tissue testing. These patients undergo both tumor tissue testing and ctDNA testing, and they were not detected to have any known HRR gene alterations, which are pre-specified in this study. If you just look at those patients, there was a 9-month improvement in overall survival, with talazoparib plus enzalutamide, The overall survival was 46.6 months in the experiment arm, or the combination arm, and it was 37.4 months in the enzalutamide plus placebo arm, with a 22% reduction in risk of death with this combination. The quality of life data did not show any deterioration in quality of life when talazoparib was added to enzalutamide, so quality of life was maintained in these patients. And other secondary end points such as time to cytotoxic chemotherapy, which is a pretty meaningful end point to many of our patients, was also favored in the talazoparib arm, so no concerns from that perspective. 

If you look at the side effects, we usually think of some side effects of special interest such as leukemia, acute leukemia, or MDS [myelodysplastic syndromes], and we had previously reported 2 cases: 1 of MDS and 1 case of acute myeloid leukemia at the time of initial presentation in 2023. We did not show any new cases at the time of data cut-off at this presentation, which is good news for our patients. If you look at more common side effects like grade 3/4 side effects, the most common was anemia and neutropenia. I would like to bring your attention to the fact that 49% of these patients had grade 1/2 anemia at baseline and when they started receiving treatment with talazoparib plus enzalutamide, 49% of these patients developed grade 3/4 anemia after a median duration of 3.3 months. This is an expected side effect. 

The key point here is once they reduced the dose of talazoparib, which was mandated by the protocol once they developed grade 3/4 toxicity, and the dose was of talazoparib was reduced, patients were able to tolerate talazoparib pretty well as evident by a long treatment duration of talazoparib in these patients. The median duration of treatment of talazoparib was 20 months and only 8.5% patients discontinued talazoparib because of anemia and these 2 pieces of data tell me that talazoparib was well tolerated after that initial dose reduction in those patients who develop grade 3/4 anemia. I suggest my colleagues to not reduce the dose of talazoparib upfront because half of the patients are not going to develop grade 3/4 anemia and in those who develop grade 3/4 anemia, initial dose reduction allow them to receive talazoparib. 

I'd like to conclude that TALAPRO-2 is the first PARP inhibitor plus ARPI combination study to show a statistically significant and a clinically meaningful improvement in overall survival in patients with metastatic castrate-resistant prostate cancer compared to an active control of enzalutamide in patients who are unselected as well as selected for HRR gene alterations. The selected cohort was presented by Dr Karim Fizazi, [Gustave Roussy] and this had 400 patients with 169 patients overlapping between these 2 cohorts, so selected cohort was accrued or recruited after the unselected patients, and we saw very similar benefit in overall survival. The median radiographic progression-free survival was 33 months with the combination and 19.5 months with the enzalutamide, about 14 months longer median PFS which is also quite meaningful, and we did not see any new safety signal. 

I'd like to conclude by saying that talazoparib plus enzalutamide can be considered as one of the standard-of-care treatment options for our patients with mCRPC. Thank you very much.

Source: 

Agarwal N, Azad A, Carles J, et al. Final overall survival (OS) with talazoparib (TALA) + enzalutamide (ENZA) as first-line treatment in unselected patients with metastatic castration-resistant prostate cancer (mCRPC) in the phase 3 TALAPRO-2 trial. Presented at 2025 ASCO Genitourinary Cancers Symposium. February 13-15, 2025; San Francisco, CA. Abstract LBA18