Delaying the development of metastases is a major goal in the management of patients with nonmetastatic castration-resistant prostate cancer (nmCRPC), as these patients typically have poor outcomes and short survival once their disease becomes metastatic. Currently, two androgen receptor (AR) inhibitors apalutamide and enzalutamide are approved for patients with nmCRPC, based on results of the large phase III SPARTAN and PROSPER clinical trials. While these agents are highly successful in delaying the time to metastases when used in conjunction with androgen deprivation therapy (ADT), they are associated with a variety of side effects that may limit their utility. Darolutamide is a novel AR antagonist with structural differences from other AR inhibitors that limit its ability to penetrate the blood-brain barrier, potentially resulting in fewer adverse events (AEs).
The large, randomized, placebo-controlled, phase III ARAMIS trial (N = 1,509) evaluated the efficacy and safety of darolutamide (300 mg twice daily) compared to placebo in men with nmCRPC and a prostate specific antigen (PSA) doubling time of 10 months or less. All patients continued to receive ADT during this study. The study met its primary endpoint of prolonged metastasis-free survival (MFS) with darolutamide compared to placebo (40.4 months vs 18.4 months; HR 0.41, P<.001). The MFS benefit of darolutamide was consistent across all prespecified patient subgroups, including those with a PSA doubling time of <6 months. Darolutamide was associated with a nonsignificant improvement in overall survival (OS) compared to placebo (HR 0.71, P = .045). Other endpoints favored darolutamide over placebo, including median progression-free survival (36.8 months vs 14.8 months; HR 0.38, P<.001), time to PSA progression (33.2 months vs 7.3 months; HR 0.13, P<.001), and time to pain progression (40.3 months vs 25.4 months; HR 0.65, P<.001).
Darolutamide was associated with a manageable AE profile. Grade 3/4 AEs occurred in 24.7% of patients receiving darolutamide and 19.5% of patients receiving placebo. Fatigue was the only grade 3 or higher AE to occur in more than 10% of patients. Importantly, key toxicities associated with apalutamide and enzalutamide , including seizures, falls, fractures, cognitive disorders, and hypertension, were absent in patients receiving darolutamide. Furthermore, patients with history of seizures were not excluded from the ARTEMIS trial.
The investigators concluded that these results support the safety and efficacy of darolutamide in patients with nmCRPC and confirm the clinical activity of this class of agents as a treatment in this setting. The tolerable safety profile of darolutamide, coupled with its clinical activity, support its inclusion as a new treatment option for patients with nmCRPC.