Background: Genomic characterization of mCRPC has identified commonly occurring alterations but also recurrently mutated genes at much lower frequencies. To efficiently evaluate anti-tumor activity of novel targeted therapies in mCRPC patients (pts) we initiated an umbrella trial using circulating tumour DNA (ctDNA) to enrich accrual for cancers with alterations that may predict response. Methods: mCRPC pts that have progressed after treatment with a next generation AR-pathway inhibitor (ARPI) were enrolled to this multi-center, multi-arm, 2-stage phase II trial. Plasma cell-free DNA was subjected to targeted sequencing and pts allocated to a treatment arm by a Tumor Board (TB) based on a priori criteria (biomarker positive, BM+) or by randomization if biomarker negative (BM-). Primary objective was to determine the clinical benefit rate (CBR: PSA decline ≥50% (PSA50), CR/PR, or stable disease ≥12 weeks). We report on 1st-stage activity of arms evaluating inhibitors of CDK4/6 (palbociclib), WEE1 kinase (adavosertib), cMET (savolitinib) and the AR inhibitor darolutamide. Additional planned arms include inhibitors of AKT (ipatasertib), Polo-like Kinase 4 (CFI-400945), immune checkpoints (durvalumab, tremelimumab) and carboplatin. Results: 250 pts were screened from two sequential trials over 29 months at 11 centers. Median time from blood draw to TB decision was 35 days. 169 pts (68%) had detectable ctDNA (≥1%) with a mean ctDNA fraction of 24% (range 1-95%). Commonly detected genomic alterations involved AR (49% gain, 24% mutation), TP53 (49%), PTEN/PI3K pathway (35%), DNA repair (23%: mismatch repair (5%), BRCA2 (8%), ATM (3%), CDK12 (5%), other (2%)) and CTNNB1/APC (14%). To date, 46 BM+ pts and 37 BM- patients were enrolled: median age 70 years (53-88), 100% had prior ARPI, 45% had prior docetaxel, 17% with visceral metastases. Accrual and CBR are presented in table. Adverse events were as expected. Conclusions: Prospective centralized screening of ctDNA to stratify mCRPC pts into a precision oncology trial is feasible. Activity was seen in 4 of 7 evaluable cohorts with darolutamide and adavosertib, meeting the threshold for expansion of these arms. Clinical trial information: NCT03385655, NCT02905318.