Darolutamide for Treatment of Castration-Resistant Prostate Cancer - Beyond the Abstract

Darolutamide is a novel anti-androgen that is recently approved for men with non-metastatic castration-resistant prostate cancer. Darolutamide is structurally different from the previously discovered androgen receptor (AR) agents enzalutamide, bicalutamide and apalutamide. Early phase trials showed promising results with overall safety profiles that are generally well-tolerated. However, the trial that ultimately led to the approval of darolutamide was the ARAMIS trial which was a Phase III randomized, double-blind, placebo-controlled trial that evaluated the safety and efficacy of darolutamide in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) who are at high risk for developing metastasis.1

This intent-to-treat study enrolled 1,509 men with nmCRPC and a prostate-specific antigen doubling time (PSADT) of 10 months or less, in 36 countries at 409 centers. Patients were enrolled and randomized in a 2:1 ratio with 955 in the darolutamide group and 554 in the placebo group. The primary endpoint was metastasis-free survival (MFS), defined as the time from randomization to distant metastasis or death. The primary endpoint of MFS was met after 437 events occurred, with a median MFS of 40 four months in the darolutamide group, compared with 18 four months in the placebo group, translating into a 59% reduction in the risk of death or metastasis (hazard ratio [HR], 0 41; 95% confidence interval [CI] 0 34-0 50; P < 0 001). Overall, the incidence of adverse events (AE) in both groups was similar, with only grade 1 or 2 fatigue occurring more frequently in the darolutamide arm. Darolutamide was not associated with higher incidences of seizures, falls, fractures, cognitive disorders, or hypertension than placebo. This has led to the role of darolutamide in the armamentarium of treatment for non-metastatic prostate cancer.

There are several challenges and issues with regard to the use of different anti-androgens for non-metastatic CRPC. Given almost equivalent benefit in terms of MFS, the primary endpoint seen with all these trials including that of enzalutamide (PROSPER)2 and apalutamide (SPARTAN),3 attempts to differentiate these varying treatment options to distinguish benefit in specific populations abound. The choice between all different novel antiandrogens is dependent on the different side-effect profiles that best fit the right population of patients. In addition, the ability of darolutamide to inhibit the transcriptional activity of certain AR mutations that typically allow enzalutamide to transform into a partial agonist, including F877L, H875Y/T878A, F877L/T878A, and T878G AR mutations, may result in an improved resistance profile of darolutamide.

There are other trials that are either ongoing or finished accrual that serve to determine the role of darolutamide in other phases of disease in prostate cancer. This manuscript serves to discuss the key trials that are relevant for the use of darolutamide mainly in non-metastatic CRPC.

Written by: Jeanny B. Aragon-Ching, M.D., F.A.C.P., Clinical Program Director of Genitourinary Cancers, Inova Schar Cancer Institute/ Inova Fairfax Hospital, Associate Professor of Medicine, Virginia Commonwealth University, Fairfax, Virginia

Published May 2020

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Written by: Jeanny B. Aragon-Ching, M.D., F.A.C.P.
  1. Fizazi, Karim, Neal Shore, Teuvo L. Tammela, Albertas Ulys, Egils Vjaters, Sergey Polyakov, Mindaugas Jievaltas et al. "Darolutamide in nonmetastatic, castration-resistant prostate cancer." New England Journal of Medicine 380, no. 13 (2019): 1235-1246.
  2. Hussain, Maha, Karim Fizazi, Fred Saad, Per Rathenborg, Neal Shore, Ubirajara Ferreira, Petro Ivashchenko et al. "Enzalutamide in men with nonmetastatic, castration-resistant prostate cancer." New England Journal of Medicine 378, no. 26 (2018): 2465-2474.
  3. Smith, M. R., M. K. Yu, and E. J. Small. "Apalutamide and Metastasis-free Survival in Prostate Cancer." The New England journal of medicine 378, no. 26 (2018): 2542-2542.