Background: In ARASENS (NCT02799602), darolutamide (DARO) + androgen-deprivation therapy (ADT) + docetaxel significantly reduced risk of death by 32.5% (hazard ratio [HR] 0.68, 95% confidence interval [CI[ 0.57–0.80; P< 0.0001) and significantly delayed time to pain progression (HR 0.79, 95% CI 0.66–0.95; P= 0.006) vs placebo (PBO) + ADT + docetaxel in patients with metastatic hormone-sensitive prostate cancer (mHSPC). We report time to pain progression in patients (pts) with high/low disease volume (HV/LV). Methods: Pts with mHSPC were randomized to oral DARO 600 mg twice daily or PBO, both + ADT + docetaxel. Pain was assessed by the Brief Pain Inventory short form “pain at its worst” score (WPS). Pain progression was defined as WPS increase ≥2 points from nadir (and absolute WPS ≥4 if > 0 at baseline) or initiation of opioid therapy for ≥7 consecutive days. A sensitivity analysis assessed pain progression after completion of docetaxel. HV/LV subgroups were defined per CHAARTED. Results: 1305 pts (DARO 651, PBO 654) were analyzed. At baseline, the mean WPS was 1.5 (standard deviation 1.9) vs 1.4 (1.8) in the DARO vs PBO groups; 258 (40%) vs 274 (42%) pts had no pain (WPS 0). DARO + ADT + docetaxel had a robust impact on delaying time to pain progression vs PBO + ADT + docetaxel in the post-docetaxel sensitivity analysis (stratified HR 0.75, 95% CI 0.62–0.90) and in the HV subgroup (unstratified HR 0.75, 95% CI 0.61–0.93) (Table). Overall, median time to pain progression was longer in the LV vs HV subgroup. WPS change from nadir was the main driver of pain progression events. Conclusions: In pts with mHSPC, the addition of DARO to ADT and docetaxel provided clinically meaningful benefit through delayed time to pain progression, notably in pts with HV disease. Increased overall survival, a delay in time to pain progression, and a favorable safety profile set DARO + ADT + docetaxel as a new standard of care for pts with mHSPC. Clinical trial information: NCT02799602.

*Cox regression model. ^†Stratified by randomization stratification factors (metastatic spread according to TNM classification and alkaline phosphatase levels at study entry). ^‡Unstratified. NE, not estimable.