Background: Given the technical limitations of obtaining tissue next-generation sequencing, there has been interest in blood ctDNA to assess genomic alterations in mCRPC. We examined the genomic landscape and prognostic significance of ctDNA in mCRPC. Methods: Single center retrospective analysis of mCRPC patients who underwent ctDNA genomic profiling using Guardant360. Overall survival (OS) and time to progression (TTP) were examined and stratified by the presence of tumor suppressor mutations (p53, PTEN, Rb), androgen receptor (AR) amplification or mutation, number of genomic alterations, and highest allelic fraction of detected mutations. Results: At the time of ctDNA collection, all patients (n=46) had mCRPC with bone metastases present in 100% of patients and visceral metastases present in 17.3%. Median age at ctDNA collection was 71 years, median time from CRPC diagnosis to ctDNA was 13 months (range 0-45), and median follow-up time from CRPC diagnosis was 17.5 months (4-40). The most common alterations present were TP53 mutation (41.3%), AR amplification (30.4%), and CDK6 amplification (21.7%). Actionable mutations were detected in BRCA1 (4.3%), BRCA2 (4.3%), ATM (2.2%), and PMS2 (2.2%). The median number of genomic alterations was 2 (0-8) and the median ctDNA allelic fraction was 4.6% (0-86.9%). Median OS of the cohort was 36 months. The presence of a tumor suppressor mutation, > 2 genomic alterations, and >5% mutation allelic fraction was associated with inferior OS (Table). In terms of time to progression on 1st line abiraterone or enzalutamide, the presence of an AR amplification or mutation was associated with significantly worse median TTP of 6.9 vs 13.5 months (p- 0.015). Conclusions: ctDNA is frequently detected in mCRPC; and the type, number and frequency of alterations are potentially prognostic of OS in mCRPC. Ongoing studies are needed to assess concordance of ctDNA with tissue NGS and the predictability of ctDNA.