Androgen-receptor therapy, such as apalutamide and enzalutamide, has been used for nonmetastatic, castration-resistant prostate cancer; however, side effects can limit the use of these agents. Darolutamide is also an androgen receptor, but it has a different structure that results in fewer side effects than other agents in its class. Androgen Receptor Antagonizing Agent for Metastasis-free Survival (ARAMIS) is a phase III randomized, double-blind, placebo-controlled, multinational trial that looked at the safety and efficacy of darolutamide. The trial was conducted in 36 countries across 409 centers from September 2014 to March 2018 and included a total of 1,509 patients (955 taking darolutamide vs. 554 taking placebo, assigned in a 2:1 ratio and randomized in a stratified manner according to prostate-specific antigen [PSA] doubling time of less than or greater than 6 months). 

The median age in both groups was 74 years, and most patients were from European countries. Patients were included if they were aged 18 years or older, had adenocarcinoma of the prostate, baseline PSA time of 10 or fewer months, castration-resistant prostate cancer, baseline PSA level of at least 2 ng/mL, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were excluded if they had a history of metastatic disease or detectable metastases, and those with a history of seizures were not excluded. Patients were assigned to either darolutamide 600 mg by mouth twice a day with food or placebo. 

The primary endpoint was metastasis-free survival (time from randomization to confirmed evidence of distant metastasis or death). Median progression-free survival was 36.8 months in the darolutamide group versus 14.8 months in the placebo group. The median time to PSA progression was 33.2 months for darolutamide versus 7.3 months for placebo. In the darolutamide group, 83.2% of patients had side effects, versus 76.9% of those in the placebo group. Most side effects were grade 1 or 2, but grade 3 or 4 side effects occurred in 24.7% of patients in the darolutamide group versus 19.5% in the placebo group. The most common side effects were hypertension, rash, dizziness, and seizures; however, they were common in both groups. Darolutamide prolonged metastasis-free survival to 40.4 months versus 18.4 months in the placebo group. The benefits of darolutamide for overall survival were increased time-to-pain progression, cytotoxic chemotherapy, and first symptomatic skeletal event. 

The trial’s large sample size and detailed quality-of-life assessments were positive attributes of the ARAMIS study. A significant limitation, however, was the underrepresentation of African Americans (only 52 patients), which hindered the application of these results to that population (unfortunate since prostate cancer is most prevalent in African Americans). 

Nonetheless, these results provide more options for nonmetastatic, castration-resistant prostate cancer, especially for patients who experience significant side effects and have to discontinue therapy with other medications. Future directions should include studying the role of darolutamide in different settings and examining its efficacy in treating different types of prostate cancer. 

« Click here to return to Hematology & Oncology Update.