5056 Background: DARO is a unique AR antagonist, with preclinical studies suggesting activity in mCRPC models resistant to abiraterone or enzalutamide due to AR amplification (amp) or ligand binding domain mutations. In this substudy (SS) of the (PC-BETS) master protocol, we explored DARO in ARPI-resistant mCRPC stratified by ctDNA AR status. Methods: Pts had mCRPC, ECOG PS 0–1, evaluable disease, biochemical or radiographic progression, prior ARPI, and no cytotoxic chemotherapy in mCRPC. Genomic screening tested plasma cell-free DNA and matched leukocyte DNA via targeted sequencing with a prostate cancer panel including the AR exons, introns, and flank. Only patients with evidence of ctDNA ≥1% were eligible. Pts were assigned to SS by molecular tumor board if biomarker (BM)+; otherwise, BM- pts were randomized to BM- SS. SS-C tested DARO 600mg od in three cohorts—AR amp (C1), AR mutation (C2), or BM- (C3) in a 2-stage design. Primary endpoint was clinical benefit rate (CBR), defined by PSA50 response, RECIST CR/PR, or SD ≥12 weeks. Results: PC-BETS Arm C opened in Jan 2018 and closed Feb 2024; 72 pts were enrolled: 27, 26, and 19 in C1, C2, and C3, respectively. Median age was 74 y (53–88), 100% ECOG PS 0-1. Sixteen pts (22%) had docetaxel for hormone-sensitive disease and none for mCRPC. Prior ARPI were abiraterone (31/72, 43%), enzalutamide (37/72, 51%), or apalutamide (4/72, 6%). Pts had bone (67/72, 93%), lung (9/72, 13%), and/or liver (5/72, 7%) metastases. Baseline PSA was 2–20 in 13/72 (18%), 20–100 in 32/72 (44%) or >100 in 27/72 (38%). CBR was more frequent in AR amp or mutated cohorts than BM– (Table 1). DARO median exposure was 4 months (range 1–29). Common related AEs were fatigue (38%), diarrhea (18%), nausea (15%), and anorexia (11%). Median ctDNA fraction of CBR vs no CBR was: C1: 5 vs 16%, p=0.059; C2: 5 vs 19%, p=0.042; C3: 13 vs 13%, p=0.944. C1 CBR was higher with SPOP mutations (3/5, 60%) and all CBR pts had >10 AR copies. C2 CBR was seen with L702H (3/7, 43%) and T878A (4/7, 57%) but not F877L, W724C/L, or V716M. By data cutoff, all had discontinued therapy (radiographic ± biochemical 61%, biochemical only 22%, symptomatic 7%). DARO was well tolerated, with only 6% discontinuing for AEs. Conclusions: DARO demonstrates modest activity for unselected mCRPC following ARPIs. ctDNA analysis enriched for pts more likely to benefit from DARO including SPOP alterations, AR amp, and AR mutations L702H and T878A. Clinical trial information: NCT03385655 . C1: AR-amp C2: AR-mutated C3: BM negative CBR 5/27 (19%) 7/26 (27%) 2/19 (11%) PSA response 3/27 (11%) 4/26 (15%) 1/19 (5%) TTP-PSA (mo) 2.8 (1.8–3.7) 2.8 (1.9–4.0) 1.9 (1.8–2.8) OS (mo) 12.9 (6.6–19.9) 16.4 (12.9–29.0) 15.5 (12.2–NR)