Background: Patients (pts) with nonmetastatic castration-resistant prostate cancer (nmCRPC) are primarily older, have comorbidities, and take concomitant medications. Darolutamide (DARO), a structurally distinct and highly potent androgen receptor inhibitor, significantly reduced the risk of metastasis by ̃2 years and the risk of death by 31% versus placebo (PBO) and demonstrated favorable safety and tolerability in the phase 3 ARAMIS trial. DARO also has low potential for drug−drug interactions. This post hoc analysis of ARAMIS evaluated overall survival (OS) and safety in pts with ongoing comorbidities and concomitant medications. Methods: Pts with nmCRPC were randomized 2:1 to DARO (n=955) or PBO (n=554) while continuing androgen-deprivation therapy. At the final data cutoff (Nov 15, 2019), OS and adverse events (AEs) were evaluated in pts with a median of ≤ and >6 comorbidities or ≤ and >10 concomitant medications in the double-blind period. HRs (95% CIs) were determined from univariate analysis using Cox regression. Results: The majority of pts had ≥6 comorbidities (53%; 795/1509) or received ≥10 concomitant medications (54%; 813/1509). For pts with ≤6 and >6 comorbidities, DARO prolonged OS vs PBO (HR 0.65 and 0.73, respectively). OS benefit of DARO vs PBO was consistent for pts with metabolic, cardiovascular (CV), and other comorbid disorders (HR range: 0.39–0.88). For pts receiving ≤10 and >10 concomitant medications, OS was prolonged with DARO vs PBO (HR 0.76 and 0.66, respectively). Subgroups of pts receiving concomitant medications for gastrointestinal/metabolic disorders, CV disease, urologic disorders, and pain/inflammation achieved similar OS benefit with DARO vs PBO (HR range: 0.45–0.80). Incidence of AEs and AEs leading to treatment discontinuation with DARO was comparable to PBO across subgroups by number of comorbidities and concomitant medications (Table). Conclusions: The OS benefit and safety of DARO remained consistent with that observed in the overall ARAMIS population, even in patients with a high number of comorbidities or concomitant medications. Clinical trial information: NCT02200614.

^aOne pt randomized to DARO did not receive treatment and was excluded from the safety analysis.