Background: Prospective reports suggest metastasis directed therapy (MDT) in oligometastatic castration sensitive prostate cancer (omCSPC) is associated with improved treatment outcomes. Here we present long term outcomes of the phase II STOMP and ORIOLE trials and assess the ability of a high-risk (HiRi) mutational signature to provide prognostic and predictive information regarding MDT response. Methods: Patients with omCSPC (< 3 lesions) enrolled on STOMP (n = 62) and ORIOLE (n = 54) randomized to MDT or observation were pooled. The primary endpoint was progression-free survival (PFS) defined as either PSA or radiographic progression, initiation of androgen deprivation, or death. Secondary endpoint was radiographic PFS (rPFS) defined as radiographic progression or death. Both were calculated using the Kaplan-Meier method and stratified by treatment group. Next generation sequencing (NGS) was performed to identify a HiRi mutational signature defined as pathogenic mutations within ATM, BRCA1/2, Rb1, or TP53. Cox proportional hazards regressions were fit to calculate hazard ratios (HR) and assess the prognostic and predictive values of HiRi mutational status. Results: Median follow-up was 52.5 months. Median PFS was prolonged with MDT (11.9 months) compared to observation (5.9 months) with a pooled HR of 0.44 (95% CI, 0.29 – 0.66, p-value < 0.001). MDT was associated with PSA decrease in a majority of patients (84%) as compared to the observation group (41%). On NGS, the incidence of a pathogenic mutation in a HiRi gene was 24.3%. HiRi mutation was prognostic for PFS -- in those without a HiRi mutation median PFS was 11.9 months compared to 5.9 months in those with a HiRi mutation (HR of 1.74, p = 0.06). HiRi mutation was also prognostic for rPFS -- those without a high-risk mutation experienced median rPFS of 22.6 months compared to 10.0 months in those with a high-risk mutation (HR 2.62, p < 0.01). Tumors without a HiRi mutation treated with MDT experienced the longest PFS (13.4 months) while those with a HiRi randomized to observation experienced the shortest PFS (2.8 months). Stratifying by both treatment arms and HiRi status appeared to show a differential benefit to MDT, with those with HiRi mutations experiencing a larger relative magnitude of benefit to treatment: (HiRi mutation: HR of 0.05, p < 0.01; no HiRi mutation: HR of 0.42, p = 0.01; p interaction, 0.12) suggesting a HiRi mutational status can provide information regarding differential response to treatment. Conclusions: Long-term outcomes from the only two randomized trials in omCSPC suggest a sustained benefit to MDT over observation. A HiRi mutational signature appears prognostic for outcomes in omCSPC and those with HiRi might have a relatively larger magnitude of response to MDT. Future studies are needed to optimize patient selection. Clinical trial information: NCT02680587.