The FDA has granted a priority review designation to a new drug application for darolutamide for use as a treatment for patients with nonmetastatic castration-resistant prostate cancer.
Scott Z. Fields, MD
The FDA has granted a priority review designation to a new drug application (NDA) for darolutamide for use as a treatment for patients with nonmetastatic castration-resistant prostate cancer (CRPC).1
UPDATE 7/31/2019: FDA Approves Darolutamide for Nonmetastatic CRPC
The NDA is based on data from the phase III ARAMIS trial, in which the investigational nonsteroidal androgen receptor antagonist was associated with a 59% reduction in the risk of metastases or death compared with placebo in this patient population (HR, 0.41; 95% CI, 0.34-0.50; P <.0001).2,3
Bayer, which is manufacturing darolutamide in collaboration with Orion Corporation, stated in a press release that darolutamide has also been granted fast track designation in this setting.
"Bayer is committed to addressing treatment gaps that exist along the continuum of care for men with prostate cancer," Scott Z. Fields, MD, senior vice president and head of Oncology Development, Bayer's Pharmaceutical Division, said in a press release. "With the NDA acceptance and priority review designation, we are an important step closer to bringing darolutamide to patients as quickly as possible."
In March 2019, a marketing authorization application for darolutamide was submitted to the European Medicines Agency and the Ministry of Health, Labor and Welfare in Japan. Bayer is also discussing regulatory submissions with other health authorities.
In the multicenter, double-blind, placebo-controlled, randomized phase III ARAMIS study, investigators evaluated the efficacy and safety of darolutamide in 1509 patients with nonmetastatic CRPC who were currently on standard androgen deprivation therapy (ADT) and at high risk for developing metastatic disease. Patients were randomized 2:1 to receive darolutamide at 600 mg twice daily plus ADT or placebo and ADT.
All patients had an ECOG performance status of 0 to 1. The primary endpoint was metastasis-free survival (MFS), and key secondary endpoints were overall survival (OS), time to pain progression, time to initiation of first cytotoxic chemotherapy, time to first symptomatic skeletal event, and characterization of the safety and tolerability.
At a median follow-up of 17.9 months, the median MFS was 40.4 months with darolutamide compared with 18.4 months in the placebo arm. Additionally, the MFS benefit was observed across patient subgroups, including those for baseline prostate-specific antigen (PSA) doubling time, use of bone-targeting agents, Gleason score, age, and ECOG performance status.
Results also showed that the 3-year rates of OS were 83% in the darolutamide arm versus 73% with placebo, translating to a 29% reduction in the risk of death (HR, 0.71; 95% CI, 0.50-0.99, P = .0452), according to results of an interim analysis for OS. Moreover, the median OS was not yet reached in either arm.
The median time to pain progression, using the Brief Pain Inventory-Short Form or by opioid use, was superior with darolutamide, at a median of 40.3 months versus 25.4 months with placebo, which was consistent with a 35% reduction in risk (HR, 0.65; 95% CI, 0.53-0.79; P <.0001).
Progression-free survival (PFS), which included local relapse, distant metastases, or death, was an exploratory endpoint. Median PFS was 36.8 months in the darolutamide arm versus 14.8 months in the placebo arm, for a 62% risk reduction with darolutamide (HR, 0.38; 95% CI, 0.32-0.45; P <.0001).
Moreover, time to cytotoxic chemotherapy (HR, 0.43; 95% CI, 0.31-0.60; P <.0001) and time to first symptomatic skeletal event (HR, 0.43; 95% CI, 0.22-0.84; P = .0113) also favored the androgen receptor antagonist.
At baseline, the median PSA doubling time was 4.4 months and 4.7 months in the darolutamide and placebo groups, respectively. Only 3% and 6%, respectively, were taking a bone-sparing agent. The median duration of treatment was 14.8 months for darolutamide and 11.0 months for placebo. At the data cutoff of September 3, 2018, 64% of patients on darolutamide and 36% on placebo were still on treatment.
Grade 3/4 adverse events (AEs) were rare; fatigue was the sole AE with an all-grade rate >10% in the darolutamide arm versus placebo, at 12.1% versus 8.7%, respectively. However, the difference in the rate of fatigue between groups disappeared when adjusting for duration of exposure. The incidence of falls and fractures did not differ between arms, at approximately 4% each. The incidence of hypertension was similar as well, at 6.6% with darolutamide versus 5.2% with placebo.