Background: Patients with high-risk scores by Decipher molecular testing after prostatectomy have a 5-year metastasis rate of 28% (Decipher 0.6-0.7) and 38% (Decipher > 0.7), likely due to micrometastatic disease. Clinical trials with intensified systemic treatment are warranted to increase cure rates and address this unmet need. Previous studies of adjuvant androgen deprivation therapy (ADT) in clinically identified high-risk disease have not demonstrated substantial benefit other than in men with lymph node positive disease. Darolutamide is a novel androgen receptor antagonist with demonstrated efficacy in improving metastasis-free survival (MFS) and overall survival (OS) in patients with non-metastatic castration-resistant prostate cancer, and OS in patients with metastatic hormone-sensitive prostate cancer (mHSPC). Whether treatment with ADT and darolutamide can increase MFS versus ADT plus placebo in the adjuvant setting for men with molecularly identified high-risk prostate cancer is unknown. Methods: Patients with CAPRA-S scores ≥3 and a PSA < 0.2 after radical prostatectomy undergo Decipher testing provided by the trial. Eligible patients with high-risk Decipher scores (> 0.6) will be randomized to treatment with ADT with darolutamide or placebo for 12 months. Patients are stratified by intent to deliver adjuvant radiation and by baseline PSA (undetectable vs detectable but < 0.2 ng/mL). The primary endpoint is MFS defined by novel PET or conventional imaging. With a sample size of 810 patients, the trial has 80% power with one-sided alpha = 0.025 to detect a HR of 0.60 for the experimental arm vs control arm for the primary endpoint. Secondary endpoints include recurrence-free survival, event-free survival, and quality of life (FACT-P, FACT-Cog, and FACIT-Fatigue), overall survival, and other disease-related outcomes. Trial was activated on December 9, 2020, and is currently enrolling patients. Clinical trial information: NCT04484818.