Background: In 3 published randomized trials, adjuvant radiation therapy (ART) for prostate cancer (PCa) resulted in improved progression free survival. However, the impact on metastases and overall survival is unclear. To date, there have been no published prospective trials examining the impact of salvage radiation therapy (SRT) in this disease state. Hence, we conducted a retrospective, nonrandomized comparative study of ART, SRT, or no radiation following radical prostatectomy (RP) for men with pT3 disease or positive margins (adverse pathologic features, APF). Methods: 422 PCa men treated at 4 institutions with RP and having APF were analyzed with a primary end point of clinical metastasis. ART (n = 111), early SRT (n = 70) and delayed SRT (n = 83) were defined by PSA levels of < 0.2, 0.2 to 0.5, and ≥ 0.5 ng/mL, respectively, prior to RT initiation. Remaining 157 men who did not receive additional therapy prior to metastatic onset formed the no RT arm. Clinical-genomic risk was assessed by CAPRA-S and Decipher. Cox multivariable (MVA) model was used to evaluate the impact of treatment on outcome. Results: During study follow-up, 37 men developed metastasis with a median follow-up of 8 years. Both CAPRA-S and Decipher had independent predictive value on MVA for metastatic outcome (both p < 0.05). On MVA adjusting for clinical-genomic risk, delayed SRT and no RT had an HR of 4.31 (95%CI, 1.20-15.47) and 5.42 (95% CI, 1.59-18.44) for metastasis compared to ART. No significance difference was observed between early SRT and ART (p = 0.28). Men with low to intermediate CAPRA-S and low Decipher have a low rate of metastatic events regardless of treatment selection. In contrast, men with high CAPRA-S and Decipher benefit from ART, however the cumulative incidence of metastasis remains high. Conclusions: The decision as to the timing and need for additional local therapy following RP is nuanced and requires providers and men to balance risks of morbidity with improved oncologic outcomes. This analysis provides the most robust and accurate quantification of risk for these men. Post-RP treatment can be safely avoided for men who are low risk by clinical-genomic risk, whereas those at high risk should favor enrollment in clinical trials.