Background: Germline alterations are found in approximately 12-17% of CRPC patients. Similarly, evaluating tumoral changes with circulating tumor DNA (ctDNA) has become an increasingly useful tool for understanding mechanisms underpinning disease progression. In this study, we evaluated both germline and somatic genetic changes in patients with mCRPC. Methods: Patients included had germline screening and ctDNA analyzed with the Guardant 360 assay. All patients were CRPC at the time of Guardant testing. Germline alterations were classified as pathogenic/likely-pathogenic or not pathogenic. Only ctDNA alterations with an alleleic fraction greater than 0.5% were included in analyses. Additional evaluation of CRPC status, treatment history, family history and other clinical covariates are ongoing. Chi-square and Fischer’s Exact tests were used for comparison of cohorts. Results: A total of 168 Caucasian CRPC patients had Guardant 360 testing at time of progression and germline testing between 2015-2021. 61% (n = 102/168) of patients have previously had treatment with abiraterone, 49% (n = 82/168) have had Enzalutamide and 40% (n = 68/168) have had treatment with taxanes. 12% (n = 20/168) of CRPC patients had a pathogenic/likely-pathogenic (P/LPv) germline alteration, 46% (n = 77/168) had a germline variant of unknown significance (VUS), 42% (n = 71/168) were germline negative. CRPC patients with pathogenic germline mutations were significantly more likely to have subsequent somatic alterations in BRCA2 (OR = 5.05, 95% C.I. (1.11, 23.01), p = 0.055), NF1 (OR = 7.89, 95% C.I. (2.15, 28.10), p = 0.004), and TP53 (OR = 3.52, 95% C.I. (1.28, 9.68), p = 0.015). In TP53, among germline positive patients, 45% (n = 9/20) had TP53 alterations compared to 30% (n = 45/148) of germline negative patients. Conclusions: Germline positive (P/LPv) CRPC patients were significantly more likely to have somatic alterations in BRCA2, NF1, and TP53. Understanding the totality of genetic changes, both germline and acquired somatic alterations is essential as the arsenal of targeted treatment for CRPC continues to expand. Additional studies including longitudinal assessment genetic changes and clinical correlates will be necessary to evaluate these findings in the context of treatment outcomes and disease progression.