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.
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.
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.
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.
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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