Talazoparib Plus Enzalutamide Extends Survival in mCRPC
Talazoparib plus enzalutamide boosts overall survival in metastatic castration-resistant prostate cancer, with HRR-deficient patients seeing a 14-month gain and 38% lower death risk.
New final overall survival (OS) data from the TALAPRO-2 trial (NCT03395197) confirm that the combination of talazoparib (Talzenna) plus enzalutamide (Xtandi) provides a significant survival benefit in patients with metastatic castration-resistant prostate cancer (mCRPC), according to findings presented at the 2025 Genitourinary Cancers Symposium.1,2
The trial demonstrated an 8.8-month improvement in median OS, with the combination therapy extending survival to 45.8 months (95% CI, 39.4-50.8) compared with 37.0 months (95% CI, 34.1-40.4)with enzalutamide alone, representing a 20.4% reduction in the risk of death. The hazard ratio (HR) for OS with the talazoparib combination vs placebo plus enzalutamide was 0.796 (95% CI, 0.661-0.958; 2-sided P =.0155).
Patients with homologous recombination repair (HRR)-deficient tumors had an even greater 38% reduction in the risk of death, translating to a 14-month OS improvement. In this group, the median OS with talazoparib plus enzalutamide was 45.1 months (95% CI, 35.4-not reached) and 31.1 months (95% CI, 27.3-35.4) in the placebo and enzalutamide arm. The HR was 0.622 (95% CI, 0.475-0.814; P =.0005). However, the benefit extended beyond patients who were HRR-deficient, as those without DNA repair mutations also saw an OS gain of approximately 9 months.
“TALAPRO-2 is the first PARP inhibitor plus [androgen receptor pathway inhibitor (ARPI)] combination study to show not only a statistically significant, but also a clinically meaningful improvement in overall survival in patients with metastatic CRPC in unselected and in HRR-deficient [patients],” Neeraj Agarwal, MD, FASCO, professor of medicine, Presidential Endowed Chair of Cancer Research, director, the Genitourinary Oncology Program, the Center of Investigational Therapeutics, the Huntsman Cancer Institute (HCI), University of Utah.
Conceptual image for viral etiology of prostate cancer: © Dr_Microbe - stock.adobe.com
Looking at OS in subgroups of patients with no alterations detected by both circulating tumor DNA and tumor tissue, those with no BRCA alterations detected had a median OS of 48.4 months (95% 37.2-54.1) in the talazoparib and enzalutamide arm and 37.1 months (95% CI, 31.1-40.7) in the placebo and enzalutamide arm (HR, 0.749; 95% CI, 0.582-0.963; P =.0237). For those with no HRR alterations detected, the median OS in the talazoparib plus enzalutamide arm was 46.6 months (95% CI, 33.0-54.1) and 37.4 months for those given placebo and enzalutamide (95% CI, 30.0-40.9). The HR here was 0.782 (95% CI, 0.582-1.050; P =.1008)
In patients with BRCA1/2 alterations, the median OS was not reached in the talazoparib plus enzalutamide arm vs 28.5 months in the placebo plus enzalutamide arm (HR, 0.497; 95% CI, 0.318-0.776; P =.0017). For those with non-BRCA1/2 HRR alterations, the median OS was 42.4 vs 32.6 months (HR, 0.727; 95% CI, 0.516-1.024; P =.0665).
The trial’s primary end point, radiographic progression-free survival (rPFS), also saw a substantial improvement. The HR for rPFS with the talazoparib and enzalutamide combination vs placebo was 0.667 (95% CI, 0.551-0.807; 2-sided P <.0001). Patients receiving talazoparib plus enzalutamide had a median rPFS of 33.1 months (95% CI, 27.4-39.0), compared with 19.5 months with enzalutamide alone (95% CI, 16.6-24.7).
In the HRR-deficient cohort, patients given talazoparib plus enzalutamide had a median rPFS of 30.7 months (95% CI, 24.3-38.5), compared with 12.3 months (95% CI, 11.0-16.5) with enzalutamide alone. The HR in the HRR-deficient population was 0.468 (95% CI, 0.359-0.612; P <.0001).
For safety, there were no new safety signals seen after an additional 2 years of follow-up in either patient population. While grade 3 or 4 anemia was the most common adverse event, occurring in 49% of patients in the unselected population and 43.4% in the HRR-deficient population, it was largely manageable with dose adjustments. Patients also reported that their quality of life was maintained, even with the extended treatment duration.
In the unselected patient population, the rate of discontinuation due to AEs was 21.6%, which was similar to that seen in the primary analysis, and 8.5% of patients discontinued talazoparib treatment due to anemia. In the HRR-deficient population, the rate of discontinuation of talazoparib due to AEs was 13.1% and 4.5% of patients discontinued treatment due to anemia.
Overall, these data support the broad use of this combination in both HRR-deficient and non-deficient populations.
“We are very encouraged, very happy with these results and also there were no safety signals seen. So, we really hope this combination makes a difference in our patients lives,” added Agarwal.
Background and Rationale of TALAPRO-2
The phase 3, double-blind, placebo-controlled TALAPRO-2 trial was designed to test whether combining the PARP inhibitor talazoparib with enzalutamide could provide longer-lasting disease control and improve survival outcomes in patients with HRR gene-mutated mCRPC compared with placebo plus enzalutamide.3,4
Male patients aged 18 and older were eligible to enroll in the study if they had progressive disease at study entry, an ECOG performance status of 1 or lower, and a life expectancy of at least 12 months. Those who had been previously treated with a second-generation ARPI, PARP inhibitor, cyclophosphamide, or mitoxantrone for prostate cancer; clinically significant cardiovascular disease; or significant renal or hepatic dysfunction were ineligible for participation.
A total of 805 patients were randomly assigned in cohort 1 to receive talazoparib 0.5 mg with enzalutamide 160 mg per day (n = 402) or placebo and enzalutamide 160 mg per day (n = 403). Randomization was stratified by HRR gene alteration status. The study’s primary end point was rPFS.3
One-hundred percent of patients underwent prospective tumor tissue testing before enrollment. In this cohort, 20% of patients were found to have HRR alterations. For specific gene alterations, BRCA1, BRCA2, ATM, and CDK12 mutations were evenly distributed between the treatment arms. Notably, BRCA1 and BRCA2 alterations were present in approximately 7% of patients.
In June 2023, the FDA approved the talazoparib/enzalutamide combination for the treatment of HRR gene-mutant mCRPC, supported by data from TALAPRO-2.5 The data the FDA considered at the time showed that the combination led to a 55% reduction in the risk of disease progression or death (HR, 0.45; 95% CI, 0.33-0.61; P <.0001).4 The median rPFS at the time was not reached (NR, 95% CI, 27.5 months-NR) with talazoparib and enzalutamide vs 21.9 months (range, 16.6-25.1) with placebo plus enzalutamide.
