137 Background: Indirect treatment comparisons in metastatic castration-sensitive prostate cancer (mCSPC) have predominantly focused on efficacy endpoints, with limited evaluation of safety outcomes or consideration of baseline imbalances. This analysis is the first matching-adjusted indirect comparison (MAIC) to evaluate the safety profile of darolutamide (DAR)+ADT versus other androgen receptor pathway inhibitors (ARPIs) in mCSPC. Methods: A MAIC was conducted using individual patient data from ARANOTE (DAR+ADT vs ADT) (n=600) and published aggregate data from ARCHES (enzalutamide (ENZ)+ADT), TITAN (apalutamide (APA)+ADT), and LATITUDE (abiraterone acetate + prednisone (ABI)+ADT). Rates of adverse events (AEs) of special interest in ARANOTE were compared between studies after adjusting for baseline differences in age, Eastern Cooperative Oncology Group performance status (0 vs. 1+), Gleason score (<8 vs. 8+), disease volume, timing of metastatic disease and presence of visceral metastases. Overall survival was used as an offset to account for varying study follow-up across trials. Results: DAR+ADT showed significantly lower rates of fatigue versus ENZ+ADT (RR 0.38, 95% CI 0.21–0.68; p=0.0011) and APA+ADT (RR 0.48, 95% CI 0.27–0.85; p=0.012), and significantly lower rash rates versus APA+ADT (RR 0.27, 95% CI 0.11–0.67; p=0.0043). Numerical trends favored DAR+ADT versus ENZ+ADT and ABI+ADT for hypertension and fractures. Falls and vasodilation/hot flush rates were similar, while mental impairment favored DAR+ADT versus ENZ+ADT (RR 0.60, 95% CI 0.10–3.49; p=0.57) (Table 1). Conclusions: In this first safety MAIC in mCSPC, DAR + ADT demonstrated a favorable safety profile compared with other ARPIs. Significant reductions in fatigue and rash, together with numerically lower rates of other adverse events, support the tolerability and differentiated safety profile of DAR + ADT. Clinical trial information: NCT04736199 , NCT02677896 , NCT02489318 , NCT01715285 . Rate ratios of AEs of special interest for DAR + ADT versus other ARPIs in mCSPC. AEs RR vs Enzalutamide + ADT (ESS=458.77) RR vs Apalutamide + ADT (ESS=540.41) RR vs Abiraterone acetate + ADT (ESS=245.25) Fatigue 0.38 (0.21, 0.68) (p: 0.0011) 0.48 (0.27, 0.85) (p: 0.012) 0.78 (0.35, 1.73) (p: 0.55) Fractures 0.52 (0.18, 1.54) (p: 0.24) 0.46 (0.17, 1.27) (p: 0.13) 0.46 (0.13, 1.65) (p: 0.23) Falls 0.47 (0.085, 2.62) (p: 0.39) 1.06 (0.24, 4.65) (p: 0.94) NR Rash 0.56 (0.17, 1.83) (p: 0.34) 0.27 (0.11, 0.67) (p: 0.0043) NR Hypertension 0.54 (0.27, 1.08) (p: 0.083) 0.93 (0.50, 1.73) (p: 0.83) 0.51 (0.24, 1.09) (p: 0.084) Vasodilation/Hot flush 0.89 (0.47, 1.69) (p: 0.73) 0.81 (0.43, 1.51) (p: 0.50) 0.73 (0.28, 1.88) (p: 0.51) Mental impairment 0.60 (0.10, 3.49) (p: 0.57) NR NR RR <1.00 favor darolutamide + ADT. ADT: androgen deprivation therapy. ESS: effective sample size. RR: rate ratio. NR: not reported.
Shore et al. (2026) studied this question.