Background: Carriers of germline pathogenic variants or mutations in BRCA2 and BRCA1 (referred to here as gBRCA1/2m) are enriched in metastatic prostate cancer (PrCa), and now have FDA-approved options for PARP inhibitors in late-stage disease. The NCCN guidelines recommends germline genetic testing for PrCa patients with metastatic, node positive and high risk localized prostate cancer. Prior studies have shown that gBRCA1/2m carriers with PrCa are more likely to have high-risk disease (6,7) and to develop lethal disease even after curative intent treatment (8,9). In other gBRCA1/2m-related cancers (breast, ovarian and pancreas), platinum-based regimens are part of neoadjuvant and front-line metastatic therapy options. Carboplatin is a well-tolerated, widely available and inexpensive DNA-damaging alkylating agent that is familiar to oncologists. The study hypothesis is that 4 cycles of neoadjuvant carboplatin, followed by radical prostatectomy for patients with localized high/very high risk PrCa and gBRCA1/2m will result in a meaningful pathologic complete response (pCR) rate. Methods: S2210 is a single-arm, open label study of 12 wks neoadjuvant carboplatin (4 cycles of AUC 5 every 21 days), followed by radical prostatectomy. Key eligibility criteria include people with high/very high-risk disease: cT3a or Grade Group 4-5 PrCa and/or PSA>20 ng/mL, have no evidence of distant metastases by conventional imaging (PSMA-PET-detected mets permitted if conventional imaging is negative and surgeon deems PSMA-detected sites resectable), who are candidates for radical prostatectomy and carboplatin, and have documented evidence of gBRCA1/2m through testing in a CLIA-certified lab. ADT prior to registration is permitted but must be discontinued on study. The study hypothesis is that the study treatment will result in ³30% rate of pathologic complete response (pCR, primary endpoint). A two-stage design will be used such that if ³1 of first 20 eligible patients achieves pCR, 20 further evaluable patients will be enrolled. This design has a significance level of 4.7%, and a power of 99%. Secondary endpoints include biochemical recurrence-free (at 2-, 3-, 5-yrs), metastasis-free and overall survival. Translational/correlative studies include analysis of 2nd allele inactivation in tumor, HRD signature, and ctDNA signature for monitoring of recurrence. S2210 was activated in August 2023. Clinical trial information: NCT05806515.