Background: Treatment with novel antiandrogens (NAA) and androgen deprivation therapy prolongs life in men with mCRPC but approximately 40% patients (pts) have radiographic progression within the first year. Inhibition of androgen receptor signaling results in increased double-strand DNA breaks and genomic instability. NAA+PARP inhibitor (PARPi) combinations have shown induction of synthetic lethality by this mechanism in multiple preclinical studies. Homologous recombination repair (HRR) gene aberrations do not appear to be necessary for this synergy and an NAA+PARPi combination has shown improved radiographic progression-free survival (rPFS) in HRR-wild-type pts compared with NAA alone. Methods: CASPAR (A031902) is a randomized phase 3 study in which 984 pts will be randomized on a 1:1 basis to ENZ plus RUCA/PBO. A PK substudy will precede the phase 3 portion and enroll 6-18 pts to various doses of ENZ plus RUCA to establish safety and evaluate any clinically-significant drug-drug interactions (S-DDI). Treatment will be continued until disease progression and cross-over is not allowed. Co-primary endpoints are rPFS and overall survival (OS). The OS analysis will be undertaken as a primary endpoint if the rPFS endpoint is met. For a one-sided logrank test with a type 1 error rate equal to 0.025, the study has 90% power to detect a hazard ratio (HR) of 0.71 in rPFS (median rPFS of 15 and 21 months in control and combination arms, respectively), and 80% power to detect an HR of 0.80 in OS (median OS of 32 and 40 months, respectively). Key secondary endpoints are rPFS and OS in pts with vs without pathogenic BRCA1, BRCA2, or PALB2 mutations; and differences in adverse events and quality of life (QOL) outcomes between the treatment arms. QOL assessments include Functional Assessment of Cancer Therapy–Prostate (FACT-P), Brief Pain Inventory Short Form (BPI-SF), and EQ-5D-5L. A key correlative endpoint is the concordance between tissue and plasma ctDNA-based HRR testing. Key eligibility criteria are age ≥ 18 years, ECOG PS 0-2, biopsy-proven prostate adenocarcinoma, progressive (PSA or radiographic) disease per Prostate Cancer Working Group 3 guidelines, measurable or non-measurable disease per RECIST 1.1, no prior treatment for mCRPC (prior abiraterone, darolutamide, or apalutamide in non-mCRPC setting is allowed), no significant uncontrolled comorbidity, and no medications with S-DDI with ENZ/RUCA. HRR gene aberration is not required for enrollment. All pts will undergo next-generation targeted-exome sequencing from archival tumor tissue (new biopsy only required if no archival tissue available). CASPAR is available for participation to all US-NCTN sites starting in October 2020 with a projected enrollment of 3 years. Support: U10CA180821, U10CA180882; acknowledgments.alliancefound.org. Clinical trial information: NCT04455750