Studies show that about one-quarter of advanced prostate cancers have alterations in DNA damage response genes involved directly or indirectly in homologous recombination repair (HRR) gene alterations, including BRCA1/BRCA2 genes, which can sensitize them to treatment with PARP inhibitors. Final data from cohort 2 of the phase III TALAPRO-2 study show a significant improvement in overall survival in men with HRR-deficient metastatic prostate cancer treated with a combination of the PARP inhibitor talazoparib and the androgen receptor inhibitor enzalutamide compared with enzalutamide alone. The study by Fizazi et al is being presented during the 2025 ASCO Genitourinary (GU) Cancers Symposium, February 13 to 15, in San Francisco (Abstract LBA141).

Study Methodology

The researchers divided the study into two cohorts; cohort 1 evaluated the addition of talazoparib to enzalutamide in patients regardless of their HRR gene alteration status, while cohort 2 specifically looked at patients who had HRR gene alterations.

The primary endpoint of the study was radiographic progression-free survival by blinded independent central review. Overall survival was an alpha-protected key secondary endpoint. To achieve statistical significance at the final overall survival analysis, the stratified log-ranked two-sided P value needed to be less than or equal to .024 using a group sequential design with O’Brien-Fleming spending function.

Results

Overall, 399 patients with HRR gene alterations were randomly assigned to cohort 2: 200 in the talazoparib plus enzalutamide arm; and 199 in the placebo plus enzalutamide arm. At data cutoff on September 3, 2024, 93 patients (46%) in the talazoparib plus enzalutamide arm and 126 patients (63%) in the placebo plus enzalutamide arm had died; median follow-up was 44.2 and 44.4 months, respectively.

The hazard ratio (HR) for overall survival with talazoparib plus enzalutamide vs placebo plus enzalutamide was 0.622 (95% confidence interval [CI] = 0.475–0.814; two-sided P = .0005); median overall survival was 45.1 months (95% CI = 35.4 to not reached) vs 31.1 months (95% CI = 27.3–35.4 months), respectively.

In an exploratory analyses, the researchers found that overall survival favored talazoparib plus enzalutamide vs placebo plus enzalutamide in patients with BRCA1/2 gene alterations (n = 155; HR = 0.497, 95% CI = 0.318–0.776, P = .0017) and patients without BRCA1/2 alterations (n = 244; HR = 0.727, 95% CI = 0.516–1.024, P = .0665).

Updated radiographic progression-free survival data were consistent with the primary analysis, favoring the talazoparib plus enzalutamide arm vs the placebo plus enzalutamide arm (HR = 0.468, 95% CI = 0.359–0.612, P < .0001); median radiographic progression-free survival was 30.7 vs 12.3 months, respectively.

Consistent with the primary results, the most common grade 3 to 4 treatment-emergent adverse events with the talazoparib plus enzalutamide combination were anemia (43%) and neutropenia (20%). Treatment-emergent adverse events were generally manageable; 26 patients (13%) discontinued talazoparib treatment due to treatment-emergent adverse events.

“Talazoparib plus enzalutamide demonstrated a statistically significant and clinically meaningful improvement in overall survival vs enzalutamide [alone]. These data establish talazoparib plus enzalutamide as a standard of care for [first-line] treatment in patients with HRR-deficient metastatic castration-resistant prostate cancer. Radiographic progression-free survival continued to favor talazoparib plus enzalutamide. Safety was consistent with previous reports; no new safety signals were identified,” concluded the study authors.

Clinical Significance

In addition to the improvement in overall survival in patients with HRR gene alterations, patients with HRR-unselected metastatic castration-resistant prostate cancer also saw benefit from the combination regimen, as reported by Agarwal et al in cohort 1 of the TALAPRO-2 study.

“TALAPRO-2 is the first trial to show a clinically meaningful and statistically significant improvement in overall survival in patients with metastatic castration-resistant prostate cancer when the combination of a PARP inhibitor plus an androgen receptor pathway inhibitor was compared with the standard-of-care androgen receptor pathway inhibitor enzalutamide in metastatic castration-resistant prostate cancer regardless of whether or not they had HRR gene alterations,” said Neeraj Agarwal, MD, FASCO, lead author of this study and Professor of Medicine and a Presidential Endowed Chair of Cancer Research at the Huntsman Cancer Institute, University of Utah, in a statement. “These findings represent the longest median overall survival and the largest improvement in median overall survival observed among randomized, controlled phase III trials in metastatic castration-resistant prostate cancer conducted to date.”

ASCO’s Perspective

“The TALAPRO-2 study showed a significant improvement in overall survival in men with metastatic castration-resistant prostate cancer treated with the combination of talazoparib and enzalutamide whether they had HRR gene alterations,” said William Kevin Kelly, DO, Chair, Department of Medical Oncology at Thomas Jefferson University, in a statement. “In this sub-analysis, men without HRR-deficient or cancer with unknown HRR statuses had modest clinical benefit. Careful consideration of the risk(s) and benefits of talazoparib and enzalutamide should be given in the treatment of patients with metastatic castration-resistant prostate cancer that do not have HRR gene alterations or unknown HRR status.”

Disclosure: Funding for this study was provided by Pfizer. For full disclosures of the study authors, visit meetings.asco.org.