Background: TALA is a poly(ADP-ribose) polymerase inhibitor (PARPi) that has shown efficacy in metastatic castration-resistant prostate cancers with alterations in DNA damage response (DDR) genes involved directly or indirectly in homologous recombination repair (HRR). ENZA is an androgen receptor (AR) inhibitor and established therapy for mCSPC. Since PARP activity has been shown to support AR function, PARP inhibition may increase sensitivity to AR-directed therapies. In addition, AR blockade downregulates HRR gene regulation, which has been hypothesized to induce a “BRCAness” phenotype. These studies suggest that TALA in combination with ENZA may significantly improve clinical outcomes for men with mCSPC and DDR-HRR alterations. The phase 3, double-blind, randomized trial TALAPRO-3 (NCT04821622) herein presented will compare the combination of TALA plus ENZA vs placebo plus ENZA in this setting. Methods: Approximately 550 patients with mCSPC harboring DDR-HRR alterations will be randomized to TALA (0.5 mg once daily [QD]) plus ENZA (160 mg QD) or placebo (once daily) plus ENZA (160 mg QD). Patients will be stratified according to de novo mCSPC vs relapsed mCSPC, high-volume disease vs low-volume disease, where high-volume disease is defined as the presence of visceral metastases or ≥4 bone lesions with ≥1 beyond the vertebral bodies and pelvis, and BRCA vs non-BRCA mutational status. Key eligibility criteria include age ≥18 years; histological diagnosis of prostate cancer; alterations in at least one of 12 DDR/HRR genes known to sensitize patients to PARPi (ATM, ATR, BRCA1, BRCA2, CDK12, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, RAD51C); and metastatic disease (no brain metastases). Primary endpoint is radiographic progression-free survival (defined as time to radiographic progression in soft tissue per Response Evaluation Criteria in Solid Tumors version 1.1 or in bone per Prostate Cancer Working Group 3 criteria by investigator, or death). Secondary endpoints include overall survival, safety, and patient-reported outcomes. Patient recruitment is planned/ongoing at approximately 285 sites in 27 countries, including the US and Europe, South America, South Africa, and Asia-Pacific. As of 30 September 2022, a total of 319 patients have been randomized in the study. This study was approved by an Institutional Review Board. Clinical trial information: NCT04821622.