Darolutamide, a Novel Androgen Receptor Inhibitor, Extends Metastasis-Free Survival in Patients with High-Risk Prostate Cancer

May 2019 Vol 10, No 5


Clinical Trials

Darolutamide, an investigational androgen receptor inhibitor, significantly improved metastasis-free survival in men with high-risk nonmetastatic castration-resistant prostate cancer (CRPC) compared with placebo in a large phase 3 clinical trial.

The median metastasis-free survival was 40.4 months with darolutamide versus 18.4 months with placebo (P <.001), for a 59% reduction in metastasis or death with darolutamide. Treatment with darolutamide was superior to placebo in all the secondary end points as well.

“These results suggest that darolutamide should become a new standard of care for men with high-risk nonmetastatic CRPC,” said lead investigator Karim


  • ❯ The investigational androgen receptor inhibitor darolutamide significantly extended metastasis-free survival in men with high-risk nonmetastatic CRPC versus placebo
  • ❯ Although the median overall survival was not yet reached in either group in the phase 3 study, the 3-year survival rate was 83% with darolutamide versus 73% with placebo
  • ❯ The median time to pain progression was 40.3 months with darolutamide versus 25.4 months with placebo
  • ❯ Unlike the 2 currently available androgen receptor inhibitors, darolutamide does not cross the blood-brain barrier and has lower potential for CNS side effects
  • ❯ Overall, darolutamide showed positive efficacy results and a good safety profile in men with high-risk nonmetastatic CRPC

Fizazi, MD, PhD, Chairman, Prostate Cancer, Institut Gustave Roussy, Villejuif, France, who presented the results of the ARAMIS study at the 2019 Genitourinary Cancers Symposium.

The results were simultaneously published in the New England Journal of Medicine.1

In addition to the metastasis-free survival benefit, “Patients treated with darolutamide had delayed pain progression and similar quality of life compared with placebo. No clinically relevant differences in safety were seen between the 2 groups during the treatment period,” Dr Fizazi noted.

The 2 androgen receptor inhibitors enzalutamide and apalutamide are approved by the FDA for the treatment of patients with nonmetastatic CRPC. Unlike these drugs, darolutamide does not cross the blood-brain barrier and has lower potential for central nervous system (CNS) side effects, including seizures, falls, and cognitive impairment. By contrast, enzalutamide and apalutamide are associated with these CNS effects.

The ARAMIS Clinical Trial

The international phase 3 ARAMIS clinical trial included 1509 patients randomized in a 2:1 ratio to darolutamide 600 mg twice daily or placebo. All patients were receiving background androgen-deprivation therapy. Treatment with darolutamide or placebo continued until disease progression, unacceptable toxicity, or withdrawal of patient consent.

At baseline, the median prostate-specific antigen (PSA) doubling time was 4.5 months. The median follow-up for the first primary analysis of the study was 17.9 months. The median duration of treatment was 14.8 months with darolutamide versus 11 months with placebo.

In a subgroup analysis, metastasis-free survival was superior with darolutamide versus placebo in all subgroups regardless of PSA doubling time at less than 6 months or at more than 6 months, use of bone-targeted therapy, PSA level at baseline, Gleason score, age, or geographic region.

An interim analysis showed that the median overall survival was not reached in either group. The 3-year survival rate was 83% with darolutamide compared with 73% with placebo.

Darolutamide was associated with a 35% improvement in time to pain progression versus placebo (P <.001). The median time to pain progression was 40.3 months with darolutamide versus 25.4 months with placebo.

Patients who received darolutamide treatment also had a 62% improvement in progression-free survival (PFS) versus placebo (P <.001). The median PFS was 36.8 months with darolutamide versus 14.8 months with placebo.

Patient-reported quality of life was similar between the 2 arms on the Brief Pain Inventory-Short Form; the Functional Assessment of Cancer Therapy-Prostate for physical and emotional well-being; and the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire for prostate cancer urinary symptom subscale.

Grade 3 or 4 adverse events were rare. The treatment discontinuation rate because of adverse events was similar between the groups—8.9% with darolutamide and 8.7% with placebo. The incidence of adverse events was similar in the 2 arms, except for more fatigue reported with darolutamide.

Darolutamide treatment did increase CNS events compared with placebo, but at a lower rate than seen with currently available androgen receptor inhibitors. The incidence of seizures was 0.2% in both groups.

Commenting on this study, Ian D. Davis, MBBS, PhD, FRACP, FAChPM, Head, Eastern Health Clinical School, Monash University, Victoria, Australia, said, “The question of whether ARAMIS should change practice is open. Toxicity seems acceptable, but we have no information on the effects of subsequent treatment or on cost-effectiveness,” Dr Davis said.


  1. Fizazi K, Shore N, Tammela TL, et al; for the ARAMIS investigators. Darolutamide in nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2019;380:1235-1246.
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Last modified: November 15, 2022

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