Darolutamide, a new androgen-receptor antagonist, prolongs survival without metastases in men with nonmetastatic castration-resistant prostate cancer (CRPC) and a PSA doubling time of 10 months or less. Karim Fizazi, MD, of the Universite Paris-Sud in France, and colleagues reported the new findings in the New England Journal of Medicine.

In the phase 3 ARAMIS (Androgen Receptor Antagonizing Agent for Metastasis-free Survival) trial, investigators randomly assigned 1509 CRPC patients without metastases from 36 countries 2:1 to darolutamide (600 mg twice daily with food) or placebo. Meanwhile, patients continued taking androgen deprivation therapy (luteinizing hormone-releasing hormone agonist or antagonist).

Darolutamide recipients had longer median metastasis-free survival by 22 months compared with placebo recipients: 40.4 vs 18.4 months. Risk for metastasis or death significantly declined by 59% in the intervention group, including for patients with lower-risk PCa. Patients taking darolutamide also experienced significant delays to pain progression, cytotoxic chemotherapy, and symptomatic skeletal events by 35%, 57%, and 57%, respectively. With respect to secondary endpoints, overall survival improved by 29%, whereas progression-free survival, and times to PSA progression, invasive procedure, or antineoplastic therapy significantly improved by 62%, 87%, 61%, and 67%, respectively.

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Darolutamide, a nonsteroidal androgen-receptor antagonist with 2 pharmacologically active diastereomers, is structurally distinct from other androgen-receptor inhibitors, Dr Fizazi and the team explained. By comparison, median metastasis-free survival was 36.6 months with enzalutamide in the PROSPER trial and 40.4 months with apalutamide in the SPARTAN trial.

Darolutamide showed good safety. Unlike the enzalutamide and apalutamide trials, fatigue and asthenia were less common. Hypertension, adverse effects related to central nervous system, falls, and fracture also were no more common with the drug than with placebo. The investigators believe darolutamide has low penetration of the blood-brain barrier. Overall, 24.8% of the darolutamide group and 20% of the placebo group experienced a serious adverse event, and 3.9% vs 3.2% experienced a Grade 5 event. Quality of life was similar for both groups. Similar proportions of the darolutamide and placebo groups discontinued their regimens: 8.9% vs 8.7%.

“These results confirm the benefits of early and potent inhibition of androgen-receptor signaling in patients with nonmetastatic, castration-resistant prostate cancer…” Dr Fizazi and the team stated. “In the current trial, darolutamide treatment did not adversely affect quality of life, and it resulted in delayed occurrence of metastases with a favorable safety profile.”

Men of African ancestry were underrepresented in the trial, so no conclusions can be made for this population. In addition, use of life-prolonging therapy in placebo patients who developed metastases potentially affected secondary results.

The ARAMIS study was funded by Bayer HealthCare and Orion Pharma, developers of darolutamide.

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Fizazi K, et al. Darolutamide in Nonmetastatic, Castration-Resistant Prostate Cancer (ARAMIS). N Engl J Med. DOI:10.1056/NEJMoa1815671