Background: Recent updates to genetic testing recommendations and approved treatment options for prostate cancer (PCa) patients (pts) have clarified the need for comprehensive genetic registries. Germline DNA damage repair (DDR) defects are present in over 10% of pts who develop metastatic castration-resistant prostate cancer (mCRPC) while 5-10% of pts with localized PCa have germline pathogenic variants in DDR genes. NCCN guidelines have recently expanded to address genetic testing to include high risk localized, node positive and metastatic disease, in addition to family cancer history criteria. In May 2020, the FDA approved 2 PARP inhibitors for mCRPC treatment. Genetic registries can address the critical need to identify pts for recently approved targeted treatments, understand real-world effects of targeted therapies, and expand clinical trials examining less common mutations. PROMISE is a prospective genetic registry equipped to meet these needs. Methods: 5,000 PCa pts will be screened via the online study portal and at-home germline testing to identify and enroll 500 eligible pts with germline pathogenic variants, likely pathogenic variants, and variants of uncertain significance (VUS) in the genes of interest: ATM, ATR, BRCA1, BRCA2, BRIP1, CHEK2, FAM175A, GEN1, HOXB13, MRE11A, MLH1, MSH2, MSH6, NBN, PALB2, PMS2, PTEN, RAD51C, RAD51D, TP53 and XRCC2. Additional genes may be added as evidence emerges. Eligible pts must be assigned male at birth and have documented PCa through tissue biopsy, and/or PSA >100ng/dL, and/or radiographic evidence of disease. Pts with or without prior genetic testing, including those with known pathogenic variants, are encouraged to enroll. Exclusion criteria are: inability or unwillingness to provide information for eligibility and incomplete inclusion criteria. Following germline testing, all pts will be offered genetic counseling and periodic newsletters with updates on treatments and clinical trials. Every 6 months, eligible pts will complete a patient-reported outcome (PRO) survey (EORTC QLQ-C30) and updated medical records will be obtained for clinical data abstraction. Eligible pts will enter long-term follow-up. The primary endpoint is the creation of a prospective genetic registry of PCa pts. Additional endpoints include: frequency of pathogenic or likely pathogenic germline variants of interest, recruitment of a control group with a VUS in the genes of interest, association between disease characteristics and germline testing results, comparison of PROs between disease subpopulations, longitudinal outcomes, and overall survival. Study duration will be 20 years (active recruitment: 5 years, follow-up: 15 years). PROMISE is recruiting at 10 US sites and has 282 subjects enrolled in the screening phase to date. PROMISE is sponsored and managed by the Prostate Cancer Clinical Trials Consortium. Clinical trial information: NCT04995198.