Talazoparib Combo Prolongs Survival in Mets Prostate Cancer

Adding talazoparib to enzalutamide led to a statistically significant and clinically meaningful improvement in overall survival in patients with metastatic castration-resistant prostate cancer compared with treatment with enzalutamide alone, according to the final results of the phase 3 TALAPRO-2 study.

This survival benefit occurred in both an unselected “all-comers” population and in those with homologous recombination repair (HRR) gene alterations, Neeraj Agarwal, MD, reported at Genitourinary Cancers Symposium (GCS) 2025.

“We are very encouraged” by the final overall survival results, said Agarwal, director of the Genitourinary Oncology Program at the Huntsman Cancer Institute, University of Utah, Salt Lake City. “We really hope this combination makes a difference in our patients’ lives.”

Enzalutamide, an androgen receptor pathway inhibitor, is currently the standard first-line treatment for metastatic castration-resistant prostate cancer. Talazoparib is a poly (adenosine diphosphate-ribose) polymerase inhibitor.

TALAPRO-2 enrolled two groups of patients with previously untreated metastatic castration-resistant prostate cancer. Cohort 1 included an unselected cohort of 805 patients with and without HRR alterations. Cohort 2 included 399 patients, all with HRR gene alterations.

Patients in both cohorts were randomly assigned 1:1 to receive enzalutamide (160 mg daily) combined with either talazoparib (0.5 mg daily) or placebo.

Earlier data from the trial showed that the talazoparib/enzalutamide combination significantly improved radiographic progression-free survival compared with enzalutamide alone, as reported by Medscape Medical News. This finding led to 2023 FDA approval of the combination to treat HRR gene–mutated metastatic castration-resistant prostate cancer.

Final Analysis

Overall survival data in the unselected cohort showed a median overall survival of 45.8 months with the combination vs 37.0 months with enzalutamide plus placebo, for a 20% reduction in the risk for death (hazard ratio [HR], 0.796), Agarwal said. Median overall survival with the combination was similar in both HRR-deficient and HRR–non-deficient patients.

The unselected subgroup without HRR alterations had a clinically meaningful 22% reduction in the risk for death with the combination (median overall survival, 46.6 months vs 37.4 months; HR, 0.782).

In the HRR-deficient cohort, the talazoparib/enzalutamide combination was associated with a 38% reduction in the risk for death and a 14-month improvement in median overall survival (median overall survival, 45.1 months vs 31.1 months; HR, 0.622).

With the additional 2 years of follow-up, Agarwal also reported the “statistically significant and clinically meaningful” benefit in radiographic progression-free survival with the combination was maintained. In the unselected cohort, median radiographic progression-free survival was 33.1 months with talazoparib/enzalutamide vs 19.5 months with enzalutamide alone (HR, 0.667).

The improvement in overall survival of 14 months in the HRR-deficient patients and 8.8 months in the unselected population is “impressive,” said William K. Kelly, DO, professor of medical oncology and urology, Thomas Jefferson University Hospital at Sidney Kimmel Comprehensive Cancer Center, Philadelphia. 

Overall, the data support talazoparib and enzalutamide as “a standard of care” in metastatic castration-resistant prostate cancer, Kelly said.

Kelly explained that while there were no new safety signals identified with extended follow-up in either cohort, grade 3-4 anemia was observed in 49% of the unselected population and 43% of the HRR-deficient population, highlighting the need for “careful consideration of the risk and benefits” of the combination.

He also noted that “further work is needed to show how this combination of talazoparib and enzalutamide will be integrated into today’s treatment paradigm for patients with advanced prostate cancer.”

This study was sponsored by Pfizer, Inc. Astellas Pharma Inc. provided enzalutamide. Agarwal had disclosed relationships with Pfizer, Janssen, Bayer, Amgen, and others. Kelly had disclosed relationships with Amgen, Bayer, and Janssen Oncology.