Darolutamide Benefit May Have Been Underestimated Among Patients With Non-Metastatic Castration-Resistant Prostate Cancer

Sensitivity Analyses from Phase 3 ARAMIS Trial

After adjusting for crossover from placebo to darolutamide, results from the phase 3 ARAMIS study found darolutamide reduced the risk of death by up to 41% among patients with non-metastatic castration-resistant prostate cancer.

In the double-blind, phase 3 ARAMIS study, 1509 patients with non-metastatic castration-resistant prostate cancer and a PSA doubling time of ≤10 months were randomized on a 2-to-1 basis to receive either darolutamide (n = 955) or placebo (n = 554), while continuing standard androgen-deprivation therapy. At the time of the primary metastasis-free analysis (MFS), patients still receiving either darolutamide or placebo were permitted to receive open-label treatment with darolutamide. Previously reported results showed darolutamide significantly improved MFS and overall survival (OS).

At the time of the primary analysis, there were 170 patients still receiving placebo who then chose to crossover to receive darolutamide. At the time of the final analysis of OS, median duration of follow-up was 19.0 months, with 11.2 months from unblinding. At the final OS analysis, darolutamide significantly improved OS by 31% vs placebo (hazard ratio, 0.69; 95% confidence interval (CI), 0.53 to 0.88; P = .003).

Neal Shore, MD, Carolina Urologic Research Center, Myrtle Beach, South Carolina, and coauthors wrote, “All four sensitivity analyses [rank-preserving structural failure time, iterative parameter estimation, OS-adjusted censoring, and inverse probability of censoring weighting] showed that crossover from placebo to darolutamide affected the estimate of the treatment effect, with lower [hazard ratios] for OS, ranging from 0.59 to 0.68 (32% to 41% risk reduction).” The original OS analysis may have, therefore, underestimated the benefit of darolutamide.

Dr Shore et al, concluded, “These findings confirm that darolutamide is an effective and well-tolerated androgen receptor inhibitor when used as an early treatment option in patients with [non-metastatic castration-resistant prostate cancer.”

Source:

Shore N, Fizazi K, Tammela TLJ, et al. Effect of crossover from placebo to darolutamide on overall survival in men with non-metastatic prostate cancer: sensitivity analyses from the randomised phase 3 ARAMIS study. Eur J Cancer. Published online September 16, 2023. doi: 10.1016/j.ejca.2023.113342