- This multinational, randomized, double-blind phase 3 trial compared darolutamide with placebo in 1,509 patients with nonmetastatic, castration-resistant prostate cancer, prostate-specific antigen ≥2 ng/mL and PSA doubling time ≤10 months
- Median metastasis-free survival, the primary outcome, was 40 months with darolutamide and 18 months with placebo (HR, 0.41; 95% CI, 0.34–0.50; P<.001), and darolutamide was favorable across all prespecified subgroups
- The three-year overall survival rate was 83% with darolutamide group vs. 77% with placebo (HR, 0.69; P=.003), even though more than half of the placebo group later received darolutamide or other life-prolonging treatment
- Darolutamide was also significantly superior to placebo on all other prespecified secondary endpoints: time to pain progression, time to cytotoxic chemotherapy and time to a symptomatic skeletal event
- The incidence of specific adverse events, including those associated with apalutamide and enzalutamide (fracture, falls, seizures, cognitive disorders, hypertension), was generally similar in the two arms
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Many patients with nonmetastatic, castration-resistant prostate cancer who receive androgen-deprivation therapy are now also treated with apalutamide or enzalutamide, which increases the risk of adverse effects, often neurologic. Darolutamide, the latest FDA-approved anti-androgen, was shown in preclinical studies to be less likely than apalutamide or enzalutamide to penetrate the blood–brain barrier.
Matthew R. Smith, MD, PhD, director of the Genitourinary Malignancies Program at the Massachusetts General Hospital Cancer Center, served as senior author of two reports on ARAMIS, the multinational phase 3 trial that prompted FDA approval of darolutamide for nonmetastatic, castration-resistant prostate cancer. The findings appear in The New England Journal of Medicine.
Between September 2014 and March 2018, 1,509 patients with nonmetastatic, castration-resistant prostate cancer were randomly assigned 2:1 in double-blind fashion to receive darolutamide (n=955) or placebo (n=554). Eligible patients had baseline prostate-specific antigen ≥2 ng/mL, PSA doubling time ≤10 months and ECOG performance score 0–1.
The median follow-up for the primary analysis was 17.9 months.
- The primary outcome, median metastasis-free survival, was 40 months with darolutamide and 18 months with placebo (HR, 0.41; 95% CI, 0.34–0.50; P<.001)
- Darolutamide was favorable across all prespecified subgroups (e.g., age, Gleason score, number of previous lines of therapy and baseline PSA doubling time)
Safety and Quality of Life
- Most adverse events (AEs) were grade 1/2; grade 3/4 AEs occurred in 25% of the darolutamide group and 20% of the placebo group
- Serious AEs occurred in 25% and 20%
- The discontinuation rates due to AEs were 8.9% and 8.7%
- The incidence of specific AEs, including those associated with apalutamide and enzalutamide (fracture, falls, seizures, cognitive disorders, hypertension) was generally similar in the two arms
- Of the five deaths, one in the darolutamide group and two in the placebo group were considered treatment-related
- Quality of life, measured throughout the study on both prostate-specific and generic scales, was similar in the two arms
Unblinding and Data Cutoff
After the results of the primary analysis were found to be positive, treatment assignments were unblinded on November 30, 2018. All 170 patients who were still receiving placebo crossed over to receive open-label darolutamide ("crossover group"). All told, 307 of the 554 patients in the placebo group (55%) received darolutamide or other life-prolonging pharmacotherapies. 141 patients in the darolutamide group (15%) received other life-prolonging therapies.
The researchers prespecified that the final analysis would be performed after about 240 deaths in the darolutamide group. The data cutoff was November 15, 2019; the median follow-up time was 29.0 months for the overall trial population.
Final Analysis: Efficacy at 3 Years
- Alive—83% in the darolutamide group vs. 77% in the placebo group (HR, 0.69; P=.003); again, darolutamide was favorable across all prespecified subgroups
- Without pain—53% vs. 32% (HR, 0.65; P<.001)
- Not using cytotoxic chemotherapy—83% vs. 75% (HR, 0.58; P<.001)
- No symptomatic skeletal event—96% vs. 92% (HR, 0.48; P=.005)
- No prostate cancer–related invasive procedure—94% vs. 87% (RR, 0.42)
- No subsequent antineoplastic therapy—88% vs. 70% (RR, 0.36)
Final Analysis: Safety
The final safety analysis of the double-blind treatment period confirmed the primary analysis. The types of AEs reported in the crossover group were in line with those observed in the darolutamide group.
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