ASCO GU 2019: Efficacy and Safety Data of the ARAMIS Study, Darolutamide in Nonmetastatic Castration-Resistant Prostate Cancer Patients

San Francisco, CA ( The treatment landscape for non-metastatic castration-resistant prostate (nmCRPC) cancer is rapidly evolving. In 2018, Enzalutamide (July 2018) and Apalutamide (February 2018) became the first two drugs to obtain FDA approval for the treatment of nmCRPC. SPARTAN was a phase 3 double-blind, randomized study of apalutamide versus placebo in patients nmCRPC. Apalutamide significantly improved median metastasis-free survival by 2 years in men with nmCRPC and also increased the time to metastasis, progression-free survival, symptomatic progression, and second progression-free survival1. PROSPER was a double-blind, phase 3 trial, where patients with nmCRPC were randomly assigned to receive enzalutamide (ata dose of 160 mg) or placebo once daily. The median metastasis-free survival was 36.6 months for patients receiving enzalutamide compared with14.7 months for patients receiving placebo(HRfor metastasis or death, 0.29; 95% confidence interval, 0.24 to 0.35; P<0.001)2.  Both of these studies enrolled men who had a PSA doubling time of 10 months or less. This trial, ARAMIS, aims to study the efficacy of darolutamide in a similar population of patients with nmCRPC.

This is a placebo-controlled, double-blind study which randomized patients with non-metastatic castration-resistant prostate cancer to darolutamide 600 mg twice daily or placebo. Patients were stratified by PSA doubling time of greater than 6 months and less than 6 months, as well as the use of an osteoclast targeting agent. Metastasis-free survival (MFS) was the primary endpoint and radiographic imaging was done every 16 weeks.

ASCO GU 2019 ARAMIS trial design

A total of 1509 patients were recruited and randomized, 955 to darolutamide and 554 to placebo. Baseline characteristics were balanced and median PSA doubling time was 4 months in both arms. The median age was 74 for all patients and the median PSA was 9.0 in the darolutamide arm and 9.7 in the placebo arm.

ASCO GU 2019 ARAMIS baseline pt characteristics

Median metastasis free survival was 40.4 months with darolutamide compared with 18.4 months with placebo (hazard ratio0.41; 95% confidence interval [CI] 0.34–0.50; 2-sided p<0.0001) and overall survival trended towards improvement as well, with a hazard ratio of 0.71 (95% CI 0.50–0.99, 2-sided p=0.045). The MFS benefit was consistent across all pre-specified subgroup analyses (PSA doubling time above and below 6 months, patients on osteoclast targeted therapies, patients with high and low baseline PSA, and patients in all age groups.

ASCO GU 2019 metastasis free survival

In terms of safety, there was essentially no difference in discontinuation of darolutamide vs placebo (8.9% vs 8.7%) due to adverse events. There were no significant differences in grade 3-5 adverse events between placebo and darolutamide, and the only AE which occurred in more than 10% of patients was fatigue.

ASCO GU 2019 TEAEs of interest

Based on the results of ARAMIS, darolutamide appears safe and effective for men with nmCRPC, increasing both metastasis-free survival and overall survival at this interim analysis. Darolutamide will be the third drug to join the nmCRPC space, along with apalutamide and enzalutamide. Darolutamide is structurally unique compared with enzalutamide and apalutamide and does not cross the blood brain barrier –this may help patients avoid the fatigue that is sometimes seen with the other two therapies. The side effect profiles and final analysis of quality of life will be important for future studies to help clinicians decide which of these three drugs should be used for their patients with nmCRPC.

Original Article Reference:   Fizazi, K., Shore, N., Tammela, T., Ulys, A., Vjaters, E., & Polyakov, S. et al. Darolutamide in Nonmetastatic, Castration-Resistant Prostate Cancer (2019).  New England Journal Of Medicine. doi: 10.1056/nejmoa1815671

Presented by: Karim Fizazi, MD, Ph.D., Gustave Roussy, University of Paris Sud, Villejuif, France

Written By: Jason Zhu, MD. Fellow, Division of Hematology and Oncology, Duke UniversityTwitter: @TheRealJasonZhu at the 2019 American Society of Clinical Oncology Genitourinary Cancers Symposium, (ASCO GU) #GU19, February 14-16, 2019 - San Francisco, CA

1. Small EJ, Saad F, Chowdhury S, et al. SPARTAN, a phase 3 double-blind, randomized study of apalutamide (APA) versus placebo (PBO) in patients (pts) with nonmetastatic castration-resistant prostate cancer (nmCRPC). American Society of Clinical Oncology; 2018.
2. Hussain M, Fizazi K, Saad F, et al. PROSPER: A phase 3, randomized, double-blind, placebo (PBO)-controlled study of enzalutamide (ENZA) in men with nonmetastatic castration-resistant prostate cancer (M0 CRPC). American Society of Clinical Oncology; 2018.

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