Darolutamide in Nonmetastatic, Castration-Resistant Prostate Cancer

Abstract

BACKGROUNDDarolutamide is a structurally unique androgen-receptor antagonist that is under development for the treatment of prostate cancer. We evaluated the efficacy of darolutamide for delaying metastasis and death in men with nonmetastatic, castrationresistant prostate cancer. METHODSWe conducted a randomized, double-blind, placebo-controlled, phase 3 trial involving men with nonmetastatic, castration-resistant prostate cancer and a prostate-specific antigen doubling time of 10 months or less. Patients were randomly assigned in a 2:1 ratio to receive darolutamide (600 mg [two 300-mg tablets] twice daily) or placebo while continuing androgen-deprivation therapy. The primary end point was metastasis-free survival, with the presence of metastasis determined by independent central review of radiographic imaging every 16 weeks. RESULTSIn total, 1509 patients underwent randomization (955 to the darolutamide group and 554 to the placebo group). In the planned primary analysis, which was performed after 437 primary end-point events had occurred, the median metastasis-free survival was 40.4 months with darolutamide, as compared with 18.4 months with placebo (hazard ratio for metastasis or death in the darolutamide group, 0.41; 95% confidence interval, 0.34 to 0.50; P<0.001). Darolutamide was also associated with benefits with regard to all secondary end points, including overall survival, time to pain progression, time to cytotoxic chemotherapy, and time to a symptomatic skeletal event. The incidence of adverse events that occurred or worsened during the treatment period and had a frequency of 5% or more or were of grade 3 or higher was similar in the two groups; all such events except fatigue occurred in less than 10% of patients in either group. The percentage of patients who discontinued the assigned regimen because of adverse events was 8.9% in the darolutamide group and 8.7% in the placebo group. Darolutamide was not associated with a higher incidence of seizures, falls, fractures, cognitive disorder, or hypertension than placebo. CONCLUSIONSAmong men with nonmetastatic, castration-resistant prostate cancer, metastasis-free survival was significantly longer with darolutamide than with placebo. The incidence of adverse events was similar for darolutamide and placebo. (Funded by Bayer HealthCare and Orion Pharma; ARAMIS ClinicalTrials.gov number, NCT02200614.

Real-world incidence and burden of adverse events among non-metastatic prostate cancer patients treated with secondary hormonal therapies following androgen deprivation therapy

“…Similar rates of CNS AEs were reported in a previous study by Pilon et al 14 using real-world data from patients with advanced PC, including those with metastatic disease. We found that patients initiating 10,11,29 . In addition to providing information about the incidence of AEs in the nmPC patient population, our results showed that prior AEs and a CCI score of 1 (vs 0) in the baseline period increased the likelihood of experiencing an AE after initiating enzalutamide, bicalutamide, or abiraterone therapy, consistent with what has previously been reported among patients with advanced PC 14 .…”

Previous, Current, and Future Pharmacotherapy and Diagnosis of Prostate Cancer—A Comprehensive Review

“…In ARAMIS trial, authors showed that darolutamide prolonged metastasis-free survival status by 22 months in comparison to the placebo group. Metastasis or death risk was reduced by 59% [64].…”

“…Darolutamide is NSAA, which mechanism of action is similar to apalutamide [64]. However, a chemical structure of darolutamide is unique and differs from other AR antagonists by consisting two pharmacologically active diastereomers [84].…”

A Canadian framework for managing prostate cancer during the COVID-19 pandemic: Recommendations from the Canadian Urologic Oncology Group and the Canadian Urological Association

“…In men with a new diagnosis of high risk (PSADT < 10 months) nonmetastatic castrate resistant prostate cancer (nmCRPC) we recommend consideration of apalutamide, enzalutamide or darolutamide per current standard of care [31][32][33] . In nmCRPC patients with a prolonged PSADT we recommend considering a decrease in the frequency of imaging.…”