ARAMIS Trial Reports Darolutamide Improves Outcomes in High-Risk Nonmetastatic Prostate Cancer

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Darolutamide—an investigational androgen receptor inhibitor—significantly improved metastasis-free survival in men with high-risk nonmetastatic castration-resistant prostate cancer vs placebo in the large phase III ARAMIS trial.1 Men treated with darolutamide had a median metastasis-free survival of 40.4 months vs 18 months with placebo (P < .001), representing a 59% improvement for metastasis or death. All secondary endpoints showed a benefit with darolutamide as well.

Darolutamide is a new entry in the androgen receptor inhibitor marketplace, with enzalutamide and apalutamide recently approved by the U.S. Food and Drug Administration for the treatment of nonmetastatic castration-resistant prostate cancer. Darolutamide is distinguished from its “cousins” because it does not cross the blood-brain barrier and therefore has less potential for central nervous system side effects and drug-drug interactions than its predecessors. 

Karim Fizazi, MD, PhD

Karim Fizazi, MD, PhD

“Darolutamide significantly improved metastasis free survival in men with nonmetastatic castration-resistant prostate cancer and a prostate-specific antigen (PSA) doubling time of 10 months or less. Secondary and exploratory endpoints also support the benefit of darolutamide. Patients treated with darolutamide had delayed pain progression and similar quality of life compared with those treated with placebo. No clinically relevant differences in safety were seen between the two groups during the treatment period,” said lead author Karim Fizazi, MD, PhD, of the Institut Gustave Roussy, Université Paris-Sud, Villejuif, France.

“These results suggest that darolutamide should become a new standard of care for men with high-risk nonmetastatic castration-resistant prostate cancer,” he stated. The study results were published in The New England Journal of Medicine 2 to coincide with Dr. Fizazi’s presentation at the 2019 Genitourinary Cancers Symposium.

Study Details

The ARAMIS trial was conducted in 36 countries in 409 centers. A total of 1,509 patients were randomly assigned 2:1 to receive either darolutamide at 600 mg twice daily or placebo while continuing on androgen-deprivation therapy. Treatment was continued until disease progression, unacceptable toxicity, or withdrawal of patient consent.

Androgen Receptor Inhibitor in Prostate Cancer

  • In the phase III ARAMIS trial, the androgen receptor inhibitor darolutamide significantly improved metastasis-free survival vs placebo (40.4 vs 18 months) in men with high-risk nonmetastatic castration-resistant prostate cancer.
  • All secondary endpoints also showed a benefit for darolutamide.
  • Grades 3 and 4 adverse events were rarely observed with darolutamide.
  • For some experts, however, whether this study should change practice is unclear, given the lack of information on the effects of subsequent treatment and cost-effectiveness.
  • For further discussion of the ARAMIS trial of darolutamide in prostate cancer, see an interview with Karim Fizazi, MD, PhD, on The ASCO Post Newsreels at

To be eligible for study entry, patients had to have confirmed castration-resistant prostate cancer, a baseline prostate-specific antigen (PSA) level of 2 ng/mL, a PSA doubling time of 10 months or less, an Eastern Cooperative Oncology Group Performance Status of 0 to 1, and no evidence of bone or visceral metastasis. At baseline, the median PSA doubling time was 4.5 months, which signals high-risk disease.

“Use of bone-targeting agents was rare, in about 5% of men,” Dr. Fizazi noted. “Despite the low use of bone-targeted agents, darolutamide was not associated with a higher incidence of falls or fractures than placebo.”

The median follow-up for this first primary analysis was 17.9 months. The median duration of treatment was 14.8 months with darolutamide vs 11 months with placebo.

Key Outcomes

In a subgroup analysis of metastasis-free survival, darolutamide was superior to placebo in all subgroups, regardless of PSA doubling time, use of bone-targeted therapy, PSA level at baseline, Gleason score, age, and geographic region.

Overall survival also favored darolutamide at this early analysis. At an interim analysis for overall survival, the median overall survival was not reached in either group. The 3-year survival rate was 83% with darolutamide vs 73% with placebo.

Patients who received darolutamide had a significant 35% improvement in the time to pain progression vs placebo (P < .001). The median time to pain progression was 40.3 months with darolutamide vs 25.4 months with placebo.

Darolutamide-treated patients also had a 62% improvement in progression-free survival vs placebo (P < .001). The median progression-free survival was 36.8 months vs 14.8 months, respectively. “Time to cytotoxic chemotherapy and time to first symptomatic skeletal event also favored darolutamide,” Dr. Fizazi said.

Darolutamide treatment did not seem to compromise quality of life, with similar patient-reported results for both treatment arms on on various questionnaires. In addition, “grade 3 and 4 adverse events were rarely observed with darolutamide, which is important for these asymptomatic men,” Dr. Fizazi told the audience. 

DISCLOSURE: The trial was supported by Bayer Health Care and Orion Pharma. Dr. Fizazi is a consultant/advisor for Clovis Oncology, Roche/Genentech, Essa Pharma, AstraZeneca, CureVac, Orion Pharma GmbH, Sanofi, Astellas Pharma, Bayer, and Janssen Oncology; has received honoraria from Janssen, Sanofi, Astellas Pharma, Takeda, Merck, and Amgen; and has received travel/accommodations/expenses from Amgen.


1. Fizazi K, et al: ARAMIS. 2019 Genitourinary Cancers Symposium. Abstract 140. Presented February 14, 2019.

2. Fizazi K, et al: Darolutamide in nonmetastatic, castration-resistant prostate cancer. N Engl J Med. February 14, 2019 (early release online).

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