Stratification subgroup analysis of overall survival with darolutamide versus placebo in combination with androgen-deprivation therapy and docetaxel in the phase 3 ARASENS trial

Introduction & Objectives: In ARASENS (NCT02799602), darolutamide added to a current standard of care, androgen-deprivation therapy (ADT) + docetaxel, significantly reduced the risk of death by 32.5% (hazard ratio [HR] 0.68; 95% confidence interval [CI] 0.57, 0.80; PMaterials & Methods: Patients were randomized 1:1 to receive darolutamide 600 mg or matching placebo twice daily in combination with standard ADT + docetaxel. Randomization was stratified by metastatic spread according to TNM classification (nonregional lymph node metastases only [M1a]; bone ± lymph node metastases [M1b]; visceral ± lymph node/bone metastases [M1c]) and ALP value (< or ≥ upper limit of normal [ULN] at study entry). OS was the primary endpoint. Time to castration-resistant prostate cancer (CRPC) and safety were key secondary endpoints.
Results: Between November 2016 and June 2018, 1306 patients were randomized to receive darolutamide (n=651) or placebo (n=655), of whom 1305 patients (darolutamide n=651, placebo n=654) were included in the full analysis set. By extent of disease, 3.0% of patients had M1a (not analyzed further), 79.5% had bone metastases (M1b), and 17.5% had visceral metastases (M1c). In the ALP subgroups, 44.5% and 55.5% had ALP < and ≥ ULN, respectively. Baseline characteristics were generally balanced between arms in all stratification subgroups. The primary data cut-off date was October 25, 2021. All subgroups showed consistently favorable OS benefits of darolutamide vs placebo, with stratified HRs (95% CIs) of 0.66 (0.54, 0.80) for M1b and 0.76 (0.53, 1.10) for M1c, and 0.65 (0.47, 0.89) for ALP < ULN and 0.69 (0.56, 0.85) for ALP ≥ ULN. The significant benefit of darolutamide vs placebo in delaying time to CRPC in the overall population (HR 0.36; 95% CI 0.30, 0.42; PConclusions: In patients with mHSPC, addition of darolutamide to ADT + docetaxel significantly increased OS and delayed time to CRPC vs ADT + docetaxel alone. Consistent OS benefits were observed in prespecified stratification subgroup analyses based on extent of disease (bone or visceral metastases) and ALP (< or ≥ ULN). AE rates were similar in both arms.