Editor’s note: PARP inhibitors (PARPi) have become key agents in the treatment of metastatic castration-resistant prostate cancer (mCRPC), marking the beginning of precision oncology in this field. At the 2025 ASCO Annual Meeting, Professor Xiaojie Bian from Fudan University Shanghai Cancer Center presented data from the Chinese cohort of the global phase III TALAPRO-2 trial. In an unselected mCRPC population, first-line therapy with talazoparib plus enzalutamide demonstrated significant improvements in both rPFS and OS. Oncology Frontier – Urology Insight invited Prof. Bian to comment on the study and share key highlights.Study Overview
In the Chinese subgroup of TALAPRO-2, patients with unselected mCRPC who received talazoparib plus enzalutamide showed improved radiographic progression-free survival (rPFS) based on BICR assessment (HR = 0.30; 95% CI, 0.17–0.56; P < 0.0001; data cutoff: November 15, 2023). These results align with those observed in the global population (HR = 0.63; 95% CI, 0.51–0.78; P < 0.0001; data cutoff: August 16, 2022). In the pre-specified final analysis, the combination also significantly improved overall survival (OS) globally. This year’s ASCO meeting included updated data on final OS and rPFS, along with extended follow-up of key secondary endpoints in the Chinese subgroup.
The Chinese cohort (n = 125) consisted of 54 patients from the main unselected TALAPRO-2 population and 71 additional patients from a Chinese expansion cohort (regardless of HRR gene mutation status). All participants had asymptomatic or mildly symptomatic mCRPC, were on continuous androgen deprivation therapy (ADT), and had tumors with homologous recombination repair (HRR) alterations. Patients were randomized 1:1 to receive either talazoparib (0.5 mg daily, or 0.35 mg for moderate renal impairment) or placebo, with all patients receiving enzalutamide (160 mg daily). The primary endpoint was BICR-assessed rPFS, with OS as a key secondary endpoint. Additional secondary endpoints included BICR-assessed objective response rate (ORR), time to PSA progression, safety, and patient-reported outcomes.
Updated rPFS results based on BICR continued to support the superiority of the talazoparib plus enzalutamide combination over placebo plus enzalutamide (HR = 0.312; 95% CI, 0.173–0.561; P < 0.0001). Median rPFS was 33.3 months (95% CI, 22.1–not reached) versus 10.5 months (95% CI, 5.7–14.5).
In the final analysis, 35 patients (56%) in the talazoparib plus enzalutamide arm had died, compared with 41 patients (66%) in the placebo plus enzalutamide group. The combination therapy demonstrated an OS advantage over placebo (HR = 0.591; 95% CI, 0.369–0.944; P = 0.0262), with median OS of 36.9 months (95% CI, 21.7–42.4) versus 24.1 months (95% CI, 16.8–30.5).
The talazoparib plus enzalutamide group also had a higher BICR-assessed ORR than the placebo group (50% [7/14] vs. 32% [6/19]; P = 0.2845) and a longer duration of response in patients with measurable disease. Time to PSA progression was also significantly prolonged with the combination (HR = 0.540; 95% CI, 0.298–0.976; P = 0.0411), with median times of 21.2 months (95% CI, 11.2–not reached) versus 11.2 months (95% CI, 7.4–28.6).
Among patients treated with the combination, the most common grade ≥3 treatment-related adverse events (TEAEs) were anemia (59% [37/63]) and neutropenia (25% [16/63]). These adverse events were generally manageable, although 14 patients (22%) discontinued talazoparib due to toxicity.
Quality of life analysis using the EORTC QLQ-C30 showed a clinically meaningful improvement in role functioning in the talazoparib plus enzalutamide group compared to placebo (mean estimated score: 85.4 vs 75.0; mean difference = 10.4; 95% CI, 1.4–19.4; P = 0.0234). No clinically meaningful differences were observed between the two groups in terms of global health status/quality of life, overall functioning, or symptom burden. For disease-related urinary symptoms, the median time to deterioration (TTDD) had not been reached in the combination group, compared to 35.9 months in the placebo arm (HR = 0.474; 95% CI, 0.185–1.213; P = 0.1188).
Investigator’s Perspective
Metastatic castration-resistant prostate cancer (mCRPC) represents a critical stage in advanced prostate cancer, driven by mechanisms such as sustained androgen receptor (AR) dependency, gene mutations, and copy number alterations. Among evolving treatment strategies, therapies targeting defects in DNA repair pathways are gaining prominence—particularly in patients harboring mutations in BRCA1/2 and other homologous recombination repair (HRR) genes.
The TALAPRO-2 study highlights that talazoparib combined with enzalutamide can offer survival benefits in mCRPC patients with DNA repair deficiencies. By focusing on specific gene alterations involved in DNA repair, the study leverages the sensitivity of these defects to PARP inhibition, offering a more personalized approach to treatment. It also underscores the molecular heterogeneity of prostate cancer and the therapeutic potential of targeting DNA repair pathways.
Other pivotal PARP inhibitor trials—such as PROfound and MAGNITUDE—have validated the efficacy of these agents in patients with HRR gene mutations, especially BRCA1/2. The PROpel trial demonstrated that olaparib combined with abiraterone significantly prolonged both PFS and OS in patients with BRCA1/2 mutations. MAGNITUDE further explored this combination, emphasizing the promise of dual-agent strategies in this subgroup.
Collectively, these findings establish DNA repair defects as a key therapeutic target in mCRPC and support the growing momentum toward individualized treatment strategies. The TALAPRO-2 study reinforces the importance of molecular profiling and provides a solid foundation for precision medicine tailored to prostate cancer’s genetic complexity and repair vulnerabilities.
