Background: TALAPRO-2 (NCT03395197) is the first phase 3 study to combine the poly(ADP-ribose) polymerase inhibitor TALA with the androgen receptor inhibitor ENZA. Pts unselected for genetic alterations in DNA damage repair pathways, directly or indirectly involved with homologous recombination repair (HRR), received either TALA + ENZA or PBO + ENZA as 1L treatment for mCRPC. Methods: Pts randomized 1:1 to TALA 0.5 mg or PBO (all pts received ENZA 160 mg daily) were stratified by prior abiraterone or docetaxel for castration-sensitive PC and HRR gene alteration status. Key eligibility criteria: mildly or asymptomatic mCRPC with disease progression at study entry, ECOG PS ≤1, ongoing androgen deprivation therapy, no prior life-prolonging therapy for CRPC. Primary endpoint: imaging-based progression-free survival (ibPFS) by BICR per RECIST 1.1 and PCWG3. Results: 402 pts were randomized to receive TALA + ENZA and 403 PBO + ENZA. Of these 805 pts, enrollment was informed by tumor tissue for 804 (99.9%), by tumor tissue and blood for 114 (14.2%), and by blood only for 1 (0.1%). Median ibPFS by BICR was significantly improved in the TALA + ENZA vs PBO + ENZA arm (not reached vs 21.9 months, respectively; HR, 0.63; 95% CI, 0.51–0.78; P< 0.001). ibPFS was significantly improved in HRR-deficient (HR, 0.46; 95% CI, 0.30–0.70; P< 0.001), HRR-non-deficient or unknown (HR, 0.70; 95% CI, 0.54–0.89; P= 0.004), and HRR-non-deficient pts by tumor tissue testing (HR, 0.66; 95% CI, 0.49–0.91; P= 0.009) in the TALA + ENZA vs PBO + ENZA arm. Overall survival data are immature; 30.6% (TALA) and 32.0% (PBO) pts had died; HR (0.89 [95% CI, 0.69–1.14; P= 0.35]) favored the TALA + ENZA arm. Objective response rates, PSA response ≥50%, and time to PSA progression and use of subsequent cytotoxic chemotherapy and antineoplastic therapy significantly favored the TALA + ENZA vs PBO + ENZA arm. In pts, 71.9% (TALA + ENZA) and 40.6% (PBO + ENZA) had grade 3-4 treatment-emergent adverse events (TEAEs). The most common grade ≥3 TEAEs were anemia, low neutrophil, and low platelet counts (TALA + ENZA), and hypertension, anemia, and fatigue (PBO + ENZA). TEAEs led to discontinuation of TALA in 19.1% of pts (vs PBO in 12.2%). Discontinuation rates of ENZA were 10.8% in the TALA + ENZA vs 11.0% in PBO + ENZA arm. Median time to definitive clinically meaningful deterioration in global health status/quality of life (GHS/QoL) was significantly longer with TALA + ENZA vs PBO + ENZA (30.8 vs 25.0 months, respectively; HR, 0.78; 95% CI, 0.62–0.99; P= 0.04). Conclusions: TALA + ENZA demonstrated statistically significant and clinically meaningful improvement in ibPFS over standard of care ENZA as 1L treatment in pts with mCRPC regardless of HRR status, while delaying time to worsening in GHS/QoL. There were no new safety signals; toxicity was generally manageable. Clinical trial information: NCT03395197.