As presented at the 2022 ASCO Genitourinary Cancers Symposium and reported in The New England Journal of Medicine by Smith et al, the phase III ARASENS trial has shown significantly improved overall survival with the addition of darolutamide to androgen-deprivation therapy and docetaxel in men with metastatic hormone-sensitive prostate cancer.

Study Details

In the double-blind trial, 1,306 patients from sites in 23 countries were randomly assigned between November 2016 and June 2018 to receive darolutamide at 600 mg twice daily (n = 651) or placebo (n = 655). All patients received androgen-deprivation therapy or underwent orchiectomy within 12 weeks before randomization and received docetaxel at 75 mg/m² on day 1 of 21-day cycles for six cycles.

Patients received darolutamide or placebo until disease progression, change in therapy, or unacceptable toxicity. Patients were excluded if they had received androgen-deprivation therapy more than 12 weeks before randomization; second-generation androgen-receptor pathway inhibitors, chemotherapy, or immunotherapy for prostate cancer; or radiotherapy within 2 weeks before randomization.

Among all patients enrolled, 86% had disease that was metastatic at the time of initial diagnosis. The primary endpoint was overall survival.

Overall Survival and Other Endpoints

At the time of data cutoff for the primary analysis (October 2021), median follow-up for overall survival was 43.7 months in the darolutamide group and 42.4 months in the control group. Death had occurred in 229 patients in the darolutamide group vs 304 patients in the control group (hazard ratio [HR] = 0.68, 95% confidence interval [CI] = 0.57–0.80, P < .001).

Median overall survival was not estimable vs 48.9 months (95% CI = 44.4 months to not estimable). Rates at 4 years were 62.7% (95% CI = 58.7%–66.7%) vs 50.4% (95% CI = 46.3%–54.6%). The benefit of the addition of darolutamide was observed despite receipt of subsequent life-prolonging systemic therapies (primarily different androgen-receptor pathway inhibitors) by 75.6% of patients in the control group.

With regard to secondary endpoints, the darolutamide group showed significant improvements in the time to development of castration-resistant disease (HR = 0.36, 95% CI = 0.30–0.42, P < .001), time to pain progression (HR = 0.79, 95% CI = 0.66–0.95, P = .01), symptomatic skeletal event–free survival (HR = 0.61, 95% CI = 0.52–0.72, P < .001), time to first symptomatic skeletal event (HR = 0.71, 95% CI = 0.54–0.94, P = .02), and time to subsequent systemic antineoplastic therapy (HR = 0.39,  95% CI = 0.33–0.46, P < .001). 

Adverse Events

Grade 3 or 4 adverse events occurred in 66.1% of the darolutamide group vs 63.5% of the placebo group. The most common adverse events included neutropenia (33.7% vs 34.2%) and febrile neutropenia (7.8% vs 7.4%) in both groups, as well as hypertension (6.4% vs 3.2%) in the darolutamide group and anemia (4.8% vs 5.1%) in the control group.

Serious adverse events occurred in 44.8% vs 42.3% of patients. Adverse events led to discontinuation of darolutamide vs placebo in 13.5% vs 10.6% of patients and to discontinuation of docetaxel in 8.0% vs 10.3%. Adverse events led to death in 4.1% of patients in the darolutamide group and 4.0% of patients in the control group.

The investigators concluded: “In this trial involving patients with metastatic, hormone-sensitive prostate cancer, overall survival was significantly longer with the combination of darolutamide, androgen-deprivation therapy, and docetaxel than with placebo plus androgen-deprivation therapy and docetaxel, and the addition of darolutamide led to improvement in key secondary endpoints. The frequency of adverse events was similar in the two groups.”

Matthew R. Smith, MD, PhD, of the Genitourinary Malignancies Program, Massachusetts General Hospital Cancer Center and Harvard Medical School, is the corresponding author of The New England Journal of Medicine article.

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