Background: Men with intermediate risk prostate cancer are often recommended external beam radiation therapy (EBRT) with or without 4-6 months of androgen deprivation therapy (ADT). However, ADT can be associated with prolonged erectile dysfunction due to delayed testosterone recovery. Darolutamide is a second-generation androgen receptor with low blood-brain barrier penetration. We hypothesize that men who receive Darolutamide with RT rather than ADT with RT are able to achieve surrogate PSA endpoints indicative of long-term disease control while preserving erectile function. Methods: This is an open label, phase 2B, multi-center, randomized controlled trial. Eligibility criteria include intermediate risk prostate cancer, good erectile quality per the EPIC-26 questionnaire, and archival tissue suitable for submission to Decipher Biosciences (San Diego, CA). Men will be stratified by Decipher score (low/intermediate vs high), RT modality (EBRT vs Brachytherapy/stereotactic body radiation therapy/combination RT), and age (>65 vs <65). Men with a Decipher high score will be strongly encouraged to undergo extreme RT dose-escalation. The primary endpoint is PSA nadir ≤ 0.5 within 6 months from end of treatment (EOT). The hierarchical endpoint is maintenance of good erectile quality at 3 months from EOT. The key secondary endpoint is interval to PSA failure at 3 years from EOT. Endpoints will be analyzed in a fixed-sequence hierarchical method. 220 patients will be accrued over 3 years. Non-inferiority margins for the primary and key secondary endpoints are 9% (90% power) and 4.9% (80% power), respectively. Men will be randomized to 6 months of GnRH agonist plus bicalutamide 50 mg daily with RT or 6 months of darolutamide 600 mg twice daily with RT. Assessments will occur at baseline, during treatment, EOT, and at regularly scheduled intervals up to 36 months from EOT. Correlative endpoints include discovering transcriptomic and radiomic predictors of response. Clinical trial information: NCT04025372