Background: The standard of care for metastatic hormone sensitive prostate cancer (mHSPC) has changed substantially in less than a decade. For patients with suitable functional status, combination therapy is recommended. A diverse molecular landscape of mHSPC exists, however molecular findings have yet to inform treatment in mHSPC. Outcomes for patients vary according to baseline molecular features and patients with mutations of tumor suppressor genes (TSG) have worse survival. We sought to examine the impact of TSG alterations on overall survival (OS) for men with de novo mHSPC. Methods: We identified patients diagnosed with de-novo mHSPC from July 2017-December 2021 within the Veterans Health Affairs. Alterations in TSG including TP53, PTEN, and RB1 were determined from National Precision Oncology Program (NPOP) testing collected at any time and all alterations were included. Only patients who survived 4 months and treated within 4 months of diagnosis were included. Treatments included androgen deprivation therapy (ADT) alone, docetaxel, or androgen receptor pathway inhibitors (ARPI). Kaplan-Meier and Cox proportional hazard models to assess the association between TSG and age, BMI, weight change in the year prior to mHSPC, Charlson comorbidity index, PSA at diagnosis, Black race, treatments for mHSPC, and OS. Results: We identified 2808 veterans with de novo mHSPC and 915 (32.6%) had NPOP data available. Patients with NPOP data were younger (mean age 71.4 vs. 75.2 years, p<0.001) and had longer OS than veterans without testing (43.7 months vs. 31.0, p<0.001). TSG alterations were found in 475 of 915 veterans (51.9%) and included 344 TP53 (37.6%), 206 PTEN (22.5%) and 50 RB1 (5.5%). Veterans with TSG had shorter OS compared to no TSG, median OS 48.5 months without TSG vs 37.7 with 1 or more TSG (p<0.001). Each TSG alteration was associated with mortality, TP53 adjusted Hazard Ratio (aHR) and 95% confidence interval 1.68 (1.35-2.09), PTEN aHR 1.33 (1.02-1.73), RB1 aHR 1.51 (1.01-2.26). ADT alone was given in 354 veterans (38.7%), docetaxel in 139 (15.2%), and ARPI in 422 (46.1%). In veterans with one or more TSG neither docetaxel nor ARPI therapy was associated with OS in unadjusted or adjusted analyses compared to ADT alone (Table). Conclusions: TSG alterations were associated with shorter survival in de novo mHSPC in veterans with molecular testing. In this real-world observational study, treatment intensification with docetaxel or ARPI in veterans with TSG was not associated with improved overall survival.