Background: This study evaluated the ability of the combined clinical cell-cycle risk score (CCR) to prognosticate the risk of prostate cancer metastasis in men receiving dose-escalated radiation therapy (RT) with or without androgen deprivation therapy (ADT). Methods: The CCR score is a validated model that combines the cell cycle progression score (CCP) with the UCSF Cancer of the Prostate Risk Assessment score (CAPRA). The CCR score and a CCR-based multimodality threshold score (2.112) were evaluated in a retrospective, multi-institutional cohort of men with National Comprehensive Cancer Center (NCCN) intermediate- or high-risk localized disease (N = 741) who received single (RT) or multimodality therapy (ADT with RT). Effects of prognostic variables were analyzed using Kaplan-Meier and Cox regression methods. Results: Median follow-up was 5.9 years. CCR predicted metastasis [hazard ratio (HR) 2.21, 95% Confidence Interval (CI) 1.70-2.87, p < 0.001]. The CCR score was a better prognosticator of metastasis (C-index 0.78) than either NCCN-risk group (C-index 0.70), CAPRA score (C-index 0.71), or CCP score (C-index 0.69) alone. In bivariate analyses, the CCR score remained highly prognostic for metastasis when comparing any ADT vs none (HR 2.19, 95% CI 1.62 to 2.97, p < 0.001), ADT duration as a continuous variable (HR 2.05, 95% CI 1.54-2.72, p < 0.001), or ADT use given as less than or at the recommended duration for each NCCN risk group (HR 2.22, 95% CI 1.71-2.88, p < 0.001). Men with CCR scores either below or above the threshold (2.112) had a 10-year risk of metastasis of 4.2% and 25.3%, respectively. For men below the threshold receiving RT alone versus RT+ADT, the 10-year risk of metastasis was 4.2% and 3.9%, respectively. Conclusions: CCR is a highly precise and accurate predictor of metastasis in men undergoing dose-escalated RT, with or without ADT. CCR adds clinically actionable information relative to guideline recommended therapies that are based on NCCN risk groups or CAPRA alone. Men with scores below the multimodality threshold may not significantly reduce their 10-year risk of metastasis with the addition of ADT.