Background: TALAPRO-2 is the first phase 3 study to combine the poly(ADP-ribose) polymerase inhibitor TALA with the androgen receptor inhibitor ENZA in pts with 1L mCRPC unselected (Cohort 1—previously reported) or selected (Cohort 2) for HRR gene alterations. Here, we report results of the prespecified, independently powered analysis of pts with mCRPC with HRR gene alterations from Cohorts 1 and 2. Methods: From February 2019 to January 2022, 399 pts (169 from Cohort 1) were randomized 1:1 to receive TALA 0.5 mg or PBO (all received ENZA 160 mg) once daily. Randomization was stratified by prior abiraterone or docetaxel for castration-sensitive PC (yes vs no). Key eligibility criteria: mildly or asymptomatic mCRPC with disease progression at study entry, HRR-deficient status prospectively confirmed by tumor tissue and/or ctDNA testing (genes tested: ATM, ATR, BRCA1, BRCA2, CDK12, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, RAD51C), ECOG PS ≤1, ongoing androgen deprivation therapy, no prior life-prolonging therapy for CRPC. Primary endpoint: radiographic progression-free survival (rPFS) by BICR per RECIST 1.1 and PCWG3. Results: 200 pts received TALA + ENZA and 199 PBO + ENZA. TALA + ENZA significantly improved rPFS by BICR (HR 0.45; 95% CI, 0.33–0.61; 2-sided P< 0.001; median PFS not reached vs 13.8 months). The HR for rPFS by BICR was 0.20 (95% CI, 0.11–0.36; P< 0.001) for the BRCA1/2 subgroup (n=155) and 0.68 (95% CI, 0.46–1.02; P = 0.06) in those without a BRCA1/2 alteration (n=240). The first interim analysis of OS was immature: 21.5% (TALA + ENZA) and 26.6% (PBO + ENZA) pts had died; HR 0.69 (95% CI, 0.46–1.03; P = 0.07). TALA + ENZA delayed time to PSA progression, cytotoxic chemotherapy, and antineoplastic therapy, and improved ORR, PSA response, and investigator-assessed PFS2. Grade (G) 3–4 treatment-emergent adverse events (TEAEs) were reported for 66.2% (TALA + ENZA) vs 37.2% (PBO + ENZA). There were more G≥3 hematologic TEAEs (anemia, neutropenia, thrombocytopenia, and leukopenia) with TALA + ENZA vs PBO + ENZA. TEAEs led to discontinuation of TALA in 10.1% vs PBO in 7.0%; discontinuation rates of ENZA were 7.6% (TALA + ENZA) vs 7.0% (PBO + ENZA). Time to definitive clinically meaningful deterioration in global health status/quality of life (GHS/QoL) was significantly longer with TALA + ENZA vs PBO + ENZA (HR 0.69; 95% CI, 0.49–0.97; P = 0.03; median 27.1 vs 19.3 months). Conclusions: TALA + ENZA demonstrated a statistically significant and clinically meaningful improvement in rPFS over standard of care ENZA as 1L treatment for pts with mCRPC and HRR gene alterations, while delaying time to definitive clinically meaningful deterioration in GHS/QoL. Toxicity was generally manageable and consistent with known safety profiles of TALA and ENZA. Clinical trial information: NCT03395197.