Final overall survival (OS) with talazoparib (TALA) + enzalutamide (ENZA) as first-line (1L) treatment in patients (pts) with homologous recombination repair (HRR)-deficient metastatic castration-resistant prostate cancer (mCRPC) in the phase 3 TALAPRO-2 trial.
Authors: Karim Fizazi, Arun Azad, Nobuaki Matsubara, Joan Carles, Andre P. Fay, Ugo De Giorgi, Jae Young Joung, Peter C.C. Fong, Eric Voog, Robert Jones Jones, Neal D. Shore, Curtis Dunshee, Stefanie Zschaebitz, Jan Oldenburg, Dingwei Ye, Xun Lin, Matko Kalac, Douglas Laird, Dana A. Kennedy, Neeraj Agarwal
Journal: Journal of Clinical Oncology (2025)

LBA141 Background: Approximately one-quarter of advanced prostate cancers have alterations in DNA damage response genes directly or indirectly involved with HRR that can sensitize them to treatment with poly(ADP-ribose) polymerase inhibitors. The Phase 3 TALAPRO-2 trial met its primary endpoint, showing improved radiographic progression-free survival (rPFS) for TALA + ENZA vs placebo (PBO) + ENZA as 1L treatment in pts with mCRPC in the HRR-deficient cohort (cohort 2). At the first interim analysis, immature OS data favored TALA + ENZA vs PBO + ENZA. Here we report final OS data, a descriptive update of rPFS, and extended safety follow-up in cohort 2. Methods: Pts with HRR-deficient tumors were randomized 1:1 to ENZA 160 mg + either TALA 0.5 mg (0.35 mg if moderate renal impairment) or PBO once daily and stratified by prior abiraterone or docetaxel (yes/no) for castration-sensitive PC. Key eligibility criteria included asymptomatic or mildly symptomatic mCRPC, ECOG PS ≤1, ongoing androgen deprivation therapy, and no prior life-prolonging therapy for CRPC. The primary endpoint was rPFS by blinded independent central review. OS was an alpha-protected key secondary endpoint. To achieve statistical significance at the final OS analysis, the stratified log-rank 2-sided P value needed to be ≤0.024 using a group sequential design with O’Brien-Fleming spending function. Results: Overall, 399 pts were randomized (N=200, TALA + ENZA; N=199, PBO + ENZA). At data cutoff (Sept 3, 2024), 93 pts (46%) in the TALA + ENZA arm and 126 pts (63%) in the PBO + ENZA arm had died; median follow-up was 44.2 and 44.4 months, respectively. Hazard ratio (HR) for OS with TALA + ENZA vs PBO + ENZA was 0.622 (95% CI, 0.475–0.814; 2-sided P =0.0005); median OS (95% CI), 45.1 months (35.4–not reached) vs 31.1 months (27.3–35.4 months), respectively. In exploratory analyses, OS favored TALA + ENZA vs PBO + ENZA in pts with BRCA1/2 alterations (n=155; HR, 0.497; 95% CI, 0.318–0.776; P =0.0017) and pts without BRCA1/2 alterations (n=244; HR, 0.727; 95% CI, 0.516–1.024; P =0.0665). Updated rPFS data were consistent with the primary analysis, favoring the TALA + ENZA vs PBO + ENZA arm (HR, 0.468; 95% CI, 0.359–0.612; P &lt;0.0001); median rPFS, 30.7 vs 12.3 months, respectively. Consistent with primary results, the most common grade 3–4 TEAEs with TALA + ENZA were anemia (43%) and neutropenia (20%). TEAEs were generally manageable; 26 pts (13%) discontinued TALA due to TEAEs. Conclusions: TALA + ENZA demonstrated a statistically significant and clinically meaningful improvement in OS vs ENZA. These data establish TALA + ENZA as a standard of care for 1L treatment in pts with HRR-deficient mCRPC. rPFS continued to favor TALA + ENZA. Safety was consistent with previous reports; no new safety signals were identified. Clinical trial information: NCT03395197 .