TALAPRO-2: Talazoparib/enzalutamide confers significant OS benefit in mCRPC

Treatment of unselected patients with metastatic castration-resistant prostate cancer (mCRPC) with the PARP inhibitor talazoparib (Talzenna) in combination with enzalutamide (Xtandi) was associated with a statistically significant and clinically meaningful improvement in overall survival (OS) vs placebo plus enzalutamide.^1,2

Neeraj Agarwal, MD, FASCO

Results from the phase 3 TALAPRO-2 study (NCT03395197) were presented by Neeraj Agarwal, MD, FASCO, a professor of medicine and a Presidential Endowed Chair of Cancer Research at the Huntsman Cancer Institute, University of Utah, Salt Lake City during the 2025 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium in San Francisco, California.

TALAPRO-2 is a multicenter, randomized, double-blind, placebo-controlled study. It enrolled a total of 1035 patients with mCRPC and was divided into 2 cohorts: cohort 1, consisting of unselected patients (n = 805, of whom 169 had homologous recombination repair (HRR) gene mutations) and cohort 2, which comprised patients with HRR gene mutations (n = 399, including 169 patients from cohort 1 along with 230 patients who were subsequently enrolled). The primary end point was radiographic progression-free survival (rPFS), “defined as the time from the date of randomization to first objective evidence of radiographic progression by blinded independent central review (BICR), or death, whichever occurred first,” according to the news release. Secondary end points included OS, objective response rate, duration of response, prostate-specific antigen response, time to cytotoxic chemotherapy and PFS2.²

At ASCO GU, Agarwal and colleagues reported final OS data along with “a descriptive update of rPFS, and extended safety follow-up in cohort 1,” according to their abstract.

The 805 patients in cohort 1 were randomly assigned 1:1 to enzalutamide 160 mg plus talazoparib 0.5 mg (n = 402) or enzalutamide 160 mg plus placebo once daily (n = 403). Patients were stratified by prior abiraterone acetate (Zytiga) or docetaxel for castration-sensitive prostate cancer HRR gene alteration status. Patients were eligible for the study if they had asymptomatic or mildly symptomatic mCRPC, ECOG Performance Status of 1 or lower, were receiving ongoing androgen deprivation therapy, and had not received prior life-prolonging therapy for CRPC.

At the data cut-off, 211 (52%) patients in the talazoparib/enzalutamide group and 243 (60%) patients in the enzalutamide/placebo group had died. Median follow-up was 52.5 months for the talazoparib/enzalutamide group and 53.0 months for the enzalutamide/placebo group.

The investigators reported an HR for OS of 0.796 (95% CI, 0.661-0.958; 2-sided P = .0155) for talazoparib/enzalutamide vs enzalutamide/placebo. The median OS was 45.8 months (95% CI, 39.4-50.8) in the talazoparib/enzalutamide vs 37.0 months (95% CI, 34.1-40.4). OS was also found to favor the combination of talazoparib/enzalutamide in patients who were HRR-deficient (n = 169; HR, 0.549; 95% CI, 0.364-0.826; P = .0035) or HRR–non-deficient/unknown (n = 636; HR, 0.878; 95% CI, 0.713-1.080; P = .218).

As part of the study, the investigators conducted exploratory analyses of patients who had results available for both circulating tumor DNA and tumor tissue. OS benefit was seen with talazoparib/enzalutamide in patients without BRCA1/BRCA2 alterations (n = 439; HR, 0.749; 95% CI, 0.582-0.963; P= .024) as well as patients without HRR alterations (n = 314; HR, 0.782; 95% CI, 0.582–1.050; P = .101).

Median rPFS was 33.1 months in the talazoparib/enzalutamide group vs 19.5 months in the enzalutamide/placebo group.

Regarding safety, the most common grade 3 or higher treatment-emergent adverse events observed in the talazoparib/enzalutamide group included anemia (49%) and neutropenia (19%).

“TEAEs were generally manageable; 86 pts (22%) discontinued [talazoparib] due to TEAEs,” the authors wrote in their abstract.

“TALAPRO-2 is the first study demonstrating a significant and clinically meaningful survival benefit using a combination of PARP and androgen receptor inhibitors in mCRPC. Survival rates in metastatic castration-resistant prostate cancer are poor due to the advanced and aggressive stage of the disease. Today’s results demonstrate the potential for Talzenna in combination with Xtandi to be a practice-changing treatment to help improve patient survival in mCRPC,” Agarwal said in a news release from Pfizer.²

REFERENCES

1. 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. J Clin Oncol 43, 2025 (suppl 5; abstr LBA18). doi:10.1200/JCO.2025.43.5_suppl.LBA18

2. Pfizer’s TALZENNA in combination with XTANDI improves survival outcomes in metastatic castration resistant prostate cancer. News release. Pfizer. February 13, 2025. Accessed February 15, 2025. https://www.pfizer.com/news/press-release/press-release-detail/pfizers-talzennar-combination-xtandir-improves-survival