Standard of care management for metastatic castration sensitive prostate cancer (mCSPC) includes androgen deprivation therapy (ADT) with docetaxel or second-generation anti-androgen therapy. Recently, randomized data has demonstrated radiotherapy to the prostate is associated with an improvement in overall survival among patients with low-volume metastatic disease. Tumor genomics represents an additional dimension to understand the clinical trajectory of patients with mCSPC. Herein we aim to evaluate a high-risk genomic signature for its ability to predict response to prostate directed therapy (PDT). We performed a single institution retrospective review of men with low-volume mCSPC who underwent next-generation sequencing of their tumor. Patients were classified according to the presence of high-risk (HiRi) mutation including pathogenic mutations in either TP53, ATM, BRCA1/2, or Rb1. Our primary endpoint was to determine the effect of PDT on overall survival (OS) in patients with and without a HiRi mutation. Survival analysis was performed with the Kaplan-Meier method compared with log-rank test and multivariable cox regression. Interaction between HiRi mutation and PDT was evaluated. A total of 101 patients with synchronous low-volume CSPC were included in our analysis with a median follow-up of 44 months. Approximately half of patients were found to have a HiRi pathogenic mutation (48.5%) with TP53 mutations accounting for 75.5% of HiRi mutations. On multivariable cox regression PDT was associated with improvement in OS (HR = 0.37, 95% CI 0.16-0.88; p = 0.03). When stratified by presence of HiRi mutation, PDT was not associated with any clinical outcome. Patients with HiRi mutations demonstrated a median OS of 73 vs 66.8 months (p = 0.28) for no PDT and PDT, respectively. Conversely, patients without a HiRi mutation demonstrated a significant improvement in median OS of 60 vs 105.3 months (p<0.01) for no PDT and PDT, respectively. The p-value for interaction for OS between PDT and HiRi mutation was statistically significant (p<0.01). Here we have identified a high-risk genomic biomarker that appears predictive for response to PDT in men with synchronous low-volume mCSPC. Further work validating these results with prospective randomized data is warranted.