The androgen receptor (AR) inhibitors apalutamide and enzalutamide prolong metastasis-free survival (MFS) and are currently approved for use in men with nonmetastatic castration-resistant prostate cancer (nmCRPC). Now, the results of the phase III ARAMIS trial of darolutamide suggest that this novel AR inhibitor is set to become an alternative option for these men.

ARAMIS involved 1,509 patients with a prostate-specific antigen (PSA) doubling time of ≤10 months. The median MFS of the 955 men assigned to receive darolutamide plus continued androgen-deprivation therapy (ADT) was 40.4 months versus 18.4 months with placebo plus ADT (HR 0.41, 95% CI 0.34–0.50; P < 0.001). In interim analyses of secondary or exploratory end points, darolutamide also improved the times to PSA progression, pain progression, chemotherapy or anti-neoplastic therapy and a symptomatic skeletal event, as well as progression-free and overall survival. In general, the ARAMIS data are consistent with those of the SPARTAN and PROSPER trials of apalutamide and enzalutamide, respectively, in similar patient cohorts.

Darolutamide has a distinct structure and might have a different safety profile compared with apalutamide and enzalutamide. The rate of discontinuation for adverse events (AEs) was 8.9% with darolutamide versus 8.7% with placebo. In SPARTAN and PROSPER, the frequencies were 10.6% versus 7% and 10% versus 6%, respectively. Notably, unlike apalutamide and enzalutamide, darolutamide was not associated with a higher incidence of falls or fractures than placebo. Overall, however, 83.2% of patients in the darolutamide group had AEs, 28.6% of grade ≥3 (versus 76.9% and 22.7% with placebo) — rates not dissimilar to those of the other two trials.

Further studies are needed to clarify the relative efficacy and safety of these agents. Nevertheless, darolutamide seems to be an attractive new treatment for nmCRPC.