Efficacy and safety of darolutamide and ADT in patient subgroups by baseline comorbidities and concomitant medications: ARANOTE post hoc analyses.

178 Background: Darolutamide (DARO) + androgen deprivation therapy (ADT) significantly improved radiological progression-free survival (rPFS) vs placebo (PBO) + ADT (HR 0.54, 95% CI 0.41–0.71; P<0.0001) in patients (pts) with metastatic hormone-sensitive prostate cancer (mHSPC) in the phase 3 ARANOTE (NCT04736199) trial, with a favorable safety profile. DARO is also associated with low blood-brain barrier penetration and limited drug-drug interactions. Here, we report outcomes in pts treated with DARO or PBO by comorbidities (comorbid) and use of concomitant medications (conmeds) at baseline (BL). Methods: Pts were randomized 2:1 to DARO 600 mg orally twice daily or PBO, both with ADT. Pts were grouped by median number and type of comorbid or conmeds reported at BL. A post hoc analysis was conducted for rPFS and hazard ratios (HR) were estimated using a Cox regression model. Descriptive statistics summarized BL demographics, disease characteristics, and treatment-emergent adverse events (TEAEs) by treatment group. Results: BL demographics and disease characteristics were generally similar between DARO (n=446) and PBO (n=223) across all subgroups, defined as a median of ≤4 or >4 comorbid or conmeds. An rPFS benefit for DARO vs PBO was seen across all comorbid (≤4, HR 0.46, 95% CI 0.32–0.65; >4, HR 0.58, 95% CI 0.36–0.93) and conmed (≤4, HR 0.48, 95% CI 0.32–0.72; >4, HR 0.61, 95% CI 0.38–0.97) subgroups. When analyzing specific comorbidities reported at BL that are commonly associated with mHSPC and older age, DARO showed a consistent rPFS benefit compared with PBO, including in pts with/without metabolic (n=185/415), cardiovascular (n=372/228), renal or urinary (n=237/363), gastrointestinal (n=113/487), and musculoskeletal (n=190/410) disorders (HR range: 0.35–0.62). With DARO, the rPFS benefit was similar in pts with cardiovascular disorders with or without corresponding conmeds (HR 1.07, 95% CI 0.58–1.94) and in pts with metabolic disorders with or without corresponding conmeds (HR 0.83, 95% CI 0.42–1.64). TEAEs, including those commonly associated with androgen receptor inhibitors and ADT, were generally similar between DARO vs PBO across comorbid (grade 3–5; ≤4, 34.1% vs 32.8%; >4, 38.4% vs 43.4%), and conmed subgroups (grade 3–5; ≤4, 33.5% vs 34.7%; >4, 39.4% vs 48.6%). Discontinuations due to TEAEs in the DARO group were lower vs PBO for all pts in both the comorbid (≤4; 4.7% vs 6.3%; >4, 8.0% vs 15.8%) and conmed (≤4; 3.3% vs 6.9%; >4, 8.8% vs 16.2%) subgroups. Conclusions: Overall, DARO demonstrated rPFS efficacy, regardless of comorbid or conmeds reported at BL, including pts with cardiovascular or metabolic disorders, with or without corresponding conmeds. DARO was well tolerated across all subgroups, with no new safety signals, supporting the use of DARO in mHSPC, even in pts with substantial comorbidities and greater use of concomitant medication. Clinical trial information: NCT04736199 .