As reported in The New England Journal of Medicine by Karim Fizazi, MD, and colleagues, the phase III ARAMIS trial has shown significantly prolonged overall survival with darolutamide vs placebo in men with nonmetastatic castration-resistant prostate cancer.

The previously reported primary analysis in ARAMIS showed that darolutamide significantly prolonged median metastasis-free survival (40.4 months vs 18.4 months, hazard ratio = 0.41; P < .001). The primary analysis of the trial supported the July 2019 U.S. Food and Drug Administration approval of darolutamide for the treatment of patients with nonmetastatic castration-resistant prostate cancer. Overall survival data were not mature at the time of that analysis.

Karim Fizazi, MD

Study Details

In the double-blind trial, 1,509 men were randomly assigned between September 2014 and March 2018 to receive darolutamide at 600 mg twice daily (n = 955) or placebo (n = 554) while they continued to receive androgen-deprivation therapy. Random assignment was stratified according to prostate-specific antigen (PSA) doubling time (≤ 6 months vs > 6 months) and the use of osteoclast-targeted therapy at random assignment.

Patients continued study treatment until disease progression, discontinuation of treatment due to adverse events, start of another anticancer therapy, or withdrawal of consent. After the results of the primary analysis were found to be positive, treatment was unblinded and patients in the placebo group crossed over to receive open-label darolutamide.

Overall Survival

The data cutoff for the primary analysis was in September 2018, and unblinding of treatment assignments occurred in November 2018. At the time of unblinding, all 170 patients still receiving placebo crossed over to receive open-label darolutamide (crossover group). The data cutoff for the final analysis of overall survival was in November 2019.

At data cutoff, 49% of patients in the darolutamide group were still receiving darolutamide, and 86% of the patients in the crossover group were still receiving darolutamide. Median duration of exposure to darolutamide in the darolutamide group was 25.8 months during the combined double-blind and open-label periods. In the placebo group, median duration of exposure to placebo was 11.6 months; median duration of exposure to open-label darolutamide was 11.0 months in the crossover group.

Among the 384 patients in the placebo group who discontinued placebo before unblinding, 55% received a subsequent life-prolonging therapy, including darolutamide; 137 received therapy other than darolutamide, with the most common being docetaxel, abiraterone acetate, and enzalutamide. In the darolutamide group, 141 of the 955 patients (15%) received subsequent life-prolonging therapy other than darolutamide.

Median follow-up at data cutoff was 29.0 months. Overall survival at 3 years was 83% (95% confidence interval [CI] = 80%–86%) in the darolutamide group and 77% (95% CI = 72%–81%) in the placebo group (hazard ratio [HR] = 0.69, 95% CI = 0.53–0.88; P = .003).

Hazard ratios for overall survival favored darolutamide in nearly all prespecified subgroups examined. For the stratification factors, hazard ratios were:

• 0.55 (95% CI = 0.35–0.88) among 469 patients with baseline PSA doubling time > 6 months and 0.73 (95% CI = 0.54–0.99) among 1,040 with PSA doubling time ≤ 6 months
• 0.28 (95% CI = 0.08–0.95) among 64 receiving osteoclast-targeted therapy at baseline
• 0.71 (95% CI = 0.55–0.92) among 1,445 not receiving osteoclast-targeted therapy. 

Other Secondary Endpoints

Median time to pain progression at data cutoff for the primary analysis was 40.3 months in the darolutamide group vs 25.4 months in the placebo group (HR = 0.65, 95% CI = 0.53–0.79; P < .001). At 3 years, 83% of patients in the darolutamide group vs 75% in the placebo group had not received first cytotoxic chemotherapy, with darolutamide being associated with a significantly longer time to first use (HR = 0.58, 95% CI = 0.44–0.76; P< .001). At 3 years, 96% vs 92% of patients had not had a first symptomatic skeletal event, with time to such an event being significantly prolonged in the darolutamide group (HR = 0.48, 95% CI = 0.29–0.82; P = .005). 

Adverse Events

For the darolutamide and placebo groups during the double-blind period and the crossover group receiving open-label darolutamide, adverse events of any grade occurred in 85.7%, 79.2%, and 70.0% of patients, respectively. Grade 3 or 4 adverse events occurred in 26.3%, 21.7%, and 15.9%; serious adverse events occurred in 26.1%, 21.8%, and 15.3%; and discontinuation of treatment occurred in 8.9%, 8.7%, and 4.7%.

With longer exposure to darolutamide since the time of primary analysis, the incidence of all types of adverse events increased slightly. Adverse events in patients receiving darolutamide in the crossover group were consistent with those observed with darolutamide treatment in the darolutamide group. No new safety signals were observed.

The investigators concluded, “Among men with nonmetastatic, castration-resistant prostate cancer, the percentage of patients who were alive at 3 years was significantly higher among those who received darolutamide than among those who received placebo. The incidence of adverse events was similar in the two groups.”

Disclosure: The study was funded by Bayer HealthCare and Orion Pharma. For full disclosures of the study authors, visit nejm.org.