5058 Background: PC-BETS registered pts with mCRPC for ctDNA-based genomic screening. A molecular tumor board (MTB) assigned pts to sub-studies (SS) based on prespecified biomarker (BM) criteria: BM-positive (BM+), or by randomization if BM-negative (BM-). IND.234G investigated carboplatin in 2 cohorts (C): C1 included BM+ pts with deleterious DNA damage response (DDR) gene alterations and C2 included BM- pts. Methods: Key inclusion criteria were: mCRPC, ECOG 0-1, evaluable disease, biochemical and/or radiological disease progression, received prior next-generation AR pathway inhibitor; prior chemotherapy allowed (max I regimen for mCRPC). The primary endpoint was clinical benefit rate (CBR: PSA50 response, RECIST CR/PR, or SD ≥12 weeks). Secondary endpoints included time to PSA progression (TTP-PSA), and overall survival (OS). Plasma ctDNA and matched leukocyte DNA underwent deep targeted sequencing with a prostate cancer specific panel that included ATM, BRCA1/2, and 22 other DDR genes. Patients with ctDNA <1% were not eligible unless they carried a germline DDR gene alteration. Pts received IV carboplatin (AUC5) on day 1 of 21-day cycles. Results: From 09/2020 to 02/2024, 36 pts were enrolled: 19 and 17 in C1 and 2, respectively. All pts were evaluable for safety while 1 pt was not evaluable for CBR (biochemical only disease). Median age was 69y (55-83) and 66y (54-77); 67%/82% had prior chemotherapy; 21%/6% had prior PARPi, and 6%/0% had liver metastases in C 1/2, respectively. In C1, qualifying gene alterations were: ATM (n=8 pts), BRCA2 (8), BRCA1 (1) and ATR (1). Median number of cycles was 4 (1-31). The most common adverse events (AEs) were anemia (97%), thrombocytopenia (89%), lymphopenia (69%), nausea (58%), neutropenia (42%), diarrhea (22%), vomiting (22%), and constipation (33%). Grade ≥3 non-hematologic AEs occurred in 28% of patients; 1 pt died from an unrelated myocardial infarction. 22 pts had dose delays and 15 pts had dose reductions for hematologic AEs. A summary of results is shown in Table 1. For C1, CBR was observed in 5/8 pts with BRCA2 alterations (4 pts had PSA response), 2/8 pts with ATM alterations (0 PSA responses), and 0/2 pts with ATR/BRCA1 alterations. CBR (with PSA response) was observed in 1 pt enrolled to C2 who did not have DDR gene alterations. Conclusions: Carboplatin was associated with meaningful clinical benefit in mCRPC pts with DDR alterations detected in ctDNA, but not in pts without DDR alterations. Carboplatin warrants further evaluation in mCRPC pts with DDR gene alterations. Clinical trial information: NCT03385655 . Cohort 1 (BM +) N=18 Cohort 2 (BM -)N=17 Median ctDNA% at baseline 16.5% 20% Clinical Benefit (n, %) 7 (39%) 1 (6%) TTP-PSA (mo; 95% CI) 2.0 (1.4-9.9) 1.7 (0.8-2.6) mOS (mo; 95% CI) 21 (9.3-NR) 9.6 (6.5-NR)