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.

Abstract

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 <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 .