SAN FRANCISCO—Darolutamide, a structurally unique androgen receptor antagonist, prolongs metastasis-free survival (MFS) and decreases the risk of pain progression in men with nonmetastatic castration-resistant prostate cancer (nmCRPC), without adversely affecting quality of life, according to study findings presented at the 2019 Genitourinary Cancers Symposium and published concurrently in The New England Journal of Medicine.

“This is really a very safe drug as far as we can tell,” said lead investigator Karim Fizazi, MD, PhD, of Institut Gustave Roussy, Université Paris-Sud, Villejuif, France.

The findings are from the ARAMIS (Androgen Receptor Antagonizing Agent for Metastasis-free Survival) trial, a double-blind, placebo-controlled phase 3 trial in which investigators randomly assigned 955 men with nmCPRC to receive darolutamide (two 300 mg tablets twice daily) and 554 to receive placebo. All patients continued on androgen deprivation therapy. The primary endpoint was MFS.

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The median MFS was 40.4 months in the darolutamide arm compared with 18.4 months in the placebo arm, Dr Fizazi reported. The darolutamide-treated patients had a significant 59% decreased risk of metastasis compared with placebo recipients. With regard to secondary endpoints, darolutamide decreased the risk of death by 29%. It decreased the risk of pain progression by 35%, which Dr Fizazi called clinically meaningful.

The incidences of treatment-emergent adverse events with 5% or greater frequency or grade 3–5 severity were comparable between the study arms. Discontinuation rates due to adverse events were 8.9% in the darolutamide arm and 8.7% with placebo.

The results of the ARAMIS trial confirm the benefits of early and potent inhibition of androgen-receptor signaling in men with nmCPRC, according to Dr Fizazi and his collaborators.

The median MFS found with darolutamide in the ARAMIS trial is similar to that observed with enzalutamide in the phase 3 PROSPER trial (36 months for enzalutamide vs 14.7 months for placebo) and apalutamide in the phase 3 SPARTAN (Selective Prostate Androgen Receptor Targeting with ARN-509) trial (40.4 months for apalutamide vs 16.2 months with placebo.

Dr Fizazi emphasized that darolutamide has a much better safety profile compared with apalutamide and enzalutamide. “This is very important because we’re talking about an asymptomatic population of men. … We can maintain their quality of life,” Dr Fizazi told Renal & Urology News.

Darolutamide, he noted, does not penetrate the blood-brain barrier, which probably explains why he and his team did not observe some of the side effects seen with apalutamide and enzalutamide, such as cognitive impairment and fatigue. Unlike enzalutamide and apalutamide, darolutamide was not associated with a higher risk of falls and fractures, which is probably due to central nervous system toxicity.

Fatigue or other asthenic conditions occurred in 16% of darolutamide-treated patients and 11% of placebo recipients, a nonsignificant difference.

The ARAMIS trial was sponsored by Bayer HealthCare and Orion Pharma.