Phase III Study of AR Antagonist in Nonmetastatic Castration-Resistant Prostate Cancer

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In the phase III ARAMIS trial reported in The New England Journal of Medicine,1 Karim Fizazi, MD, PhD, of the Institut Gustave Roussy, Universite Paris-Sud, Villejuif, France, and colleagues found that the androgen-receptor (AR) antagonist darolutamide significantly prolonged metastasis-free survival vs placebo among men with nonmetastatic castration-resistant prostate cancer. As noted by the investigators, darolutamide has a distinct structure that may result in fewer and less severe toxic effects compared with apalutamide and enzalutamide, as a result of low penetration of the blood-brain barrier and low binding affinity for gamma-aminobutyric acid type A receptors.

Study Details

In the double-blind trial, 1,509 patients with nonmetastatic castration-resistant prostate cancer and a prostate-specific antigen (PSA) doubling time of up to 10 months from 409 sites in 36 countries were randomly assigned 2:1 between September 2014 and March 2018 to receive darolutamide at 600 mg twice daily (n = 955) or placebo (n = 554) while continuing androgen-deprivation therapy. Treatment was continued until disease progression, discontinuation due to adverse events, or withdrawal of consent. Randomization was stratified according to PSA doubling time (≤ or > 6 months) and use of osteoclast-targeted therapy at randomization. The primary endpoint was metastasis-free survival in the intention-to-treat population, with the presence of metastasis identified by independent central review of radiographic imaging every 16 weeks.

For the darolutamide vs placebo groups, the median age was 74 years in both, most patients were from European countries, PSA doubling time was up to 6 months in 70% vs 67%, the Eastern Cooperative Oncology Group performance status was 0 or 1 in 100% in both, 97% vs 94% were not using a bone-sparing agent at baseline, and 76% of both groups had received at least two previous hormonal therapies.


  • Darolutamide was associated with significantly prolonged metastasis-free survival in patients with nonmetastatic, castration-resistant prostate cancer.
  • The benefits of darolutamide were observed in overall survival and in the times to pain progression, cytotoxic chemotherapy, and first symptomatic skeletal event.

Metastasis-Free Survival

On independent central review, metastasis was found at baseline in 5.2% of the darolutamide group and 7.0% of the placebo group. The median metastasis-free survival was 40.4 months in the darolutamide group vs 18.4 months in the placebo group (hazard ratio [HR] = 0.41, P < .001). Hazard ratios favored darolutamide in all subgroups examined, including stratification subgroups of PSA doubling time up to 6 months (0.41, 95% confidence interval [CI] = 0.33–0.52) or more than 6 months (HR = 0.38, 95% CI = 0.26–0.55) and use (0.22, 95% CI = 0.08–0.57) or no use of osteoclast-targeted therapy at baseline (0.43, 95% CI = 0.36–0.53).

Among patients who discontinued the study regimen, 29.5% in the darolutamide group and 36.7% in the placebo group received approved therapy for metastatic castration-resistant prostate cancer.

With regard to secondary endpoints, on interim analysis of overall survival, the median survival was not reached in the darolutamide or placebo group (number of events = 78 vs 58, HR = 0.71, P = .045). The median time to pain progression was 40.3 vs 25.4 months (HR = 0.65, P < .001). The median time to cytotoxic therapy was not reached vs 38.2 months (HR = 0.43, P < .001). The median time to first symptomatic skeletal-related event was not reached in either group (16 vs 18 events, HR = 0.43, P = .01). With regard to exploratory endpoints, darolutamide was associated with a benefit in median progression-free survival (36.8 vs 14.8 months, HR = 0.38, P < .001) and median time to PSA progression (33.2 vs 7.3 months, HR = 0.13, P < .001). PSA response of at least 50% was observed in 84% vs 8% of patients.

Adverse Events

Grade 3 or 4 adverse events occurred in 24.7% of the darolutamide group vs 19.5% of the placebo group, with the most common being hypertension (3.1% vs 2.2%). The most common adverse events of any grade in the darolutamide group were fatigue (12.1% vs 8.7% in the placebo group), back pain (8.8% vs 9.0%), and arthralgia (8.1% vs 9.2%). Serious adverse events occurred in 24.8% vs 20.0% of patients. Adverse events led to discontinuation of study treatment in 8.9% vs 8.7%. Adverse events led to death in 3.9% vs 3.2% of patients, with one death in the darolutamide group and two deaths in the placebo group considered related to study treatment.

Darolutamide was not associated with a higher incidence of adverse events of special interest, such as seizures (0.2% in both groups), falls, fractures, cognitive disorder, or hypertension (any grade = 6.6% vs 5.2%) vs placebo.

“[M]etastasis-free survival was significantly longer with darolutamide than with placebo for men with nonmetastatic, castration-resistant prostate cancer and a PSA doubling time of 10 months or less.”
— Karim Fizazi, MD, PhD, and colleagues

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As noted by the investigators, a limitation of the trial is the underrepresentation of patients of African descent (n = 52), with the small number of such patients preventing any conclusions regarding efficacy in this group.

The investigators concluded: “[M]etastasis-free survival was significantly longer with darolutamide than with placebo for men with nonmetastatic, castration-resistant prostate cancer and a PSA doubling time of 10 months or less. The results for the secondary and exploratory endpoints supported the benefits of darolutamide in this clinical context. The safety data indicated no clinically relevant difference between darolutamide and placebo in the incidence of adverse events that occurred during the treatment period, including falls, fractures, seizures, cognitive disorders, and hypertension.” 

DISCLOSURE: The study was funded by Bayer HealthCare and Orion Pharma. Dr. Fizazi has received honoraria from Astellas Pharma, Janssen, Merck, and Sanofi; has served as a consultant or advisor to Astellas Pharma, AstraZeneca, Bayer, Clovis Oncology, CureVac, ESSA Pharma, Janssen Oncology, Orion Pharma GmbH, Roche/Genentech, and Sanofi; and has received travel and accommodation expenses from Amgen and Janssen.


1. Fizazi K, Shore N, Tammela TL, et al: Darolutamide in nonmetastatic, castration-resistant prostate cancer. N Engl J Med 380:1235-1246, 2019.

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