FDA Approves Darolutamide for Non-Metastatic Castration Resistant Prostate Cancer Under Fast Track Designation

Aug 3, 2019 | Leading Pharma, nmCRPC, NSAAs, Pharma Watch, Prostate Cancer

FDA Approves Darolutamide for Non-Metastatic Castration Resistant Prostate Cancer Under Fast Track Designation

The FDA approved Bayer and Orion’s Nubeqa (darolutamide) for men experiencing an advanced stage non-metastatic castration-resistant prostate cancer (nmCRPC).

The Problem

An estimated 174,650 new cases of prostate cancer are diagnosed annually and nearly 32,000 men will die from the disease, reports the American Cancer Society. In fact, prostate cancer is the second-leading cause of death from cancer in U.S. men, reports Healthline.

The Study

The approval was ultimately based on the ARAMIS trial. A randomized, phase III, multi-center, double-blind, placebo-controlled trial to evaluate the safety and efficacy of oral Nubeqa in men with nmCRPC also being treated with androgen deprivation therapy (ADT) who face high risk for developing metastatic disease. The study started in 2014.

The sponsors included 1,509 randomized participants to receive 600 milligrams (mg) of the oral drug twice a day, or alternatively, a placebo along with ADT.

The Results

Patients were randomized (2:1) to receive either 600 mg darolutamide orally twice daily (n=955) or matching placebo (n=554). All patients received a gonadotropin-releasing hormone (GnRH) analog concurrently or had a previous bilateral orchiectomy. Twelve patients with previous seizure histories were treated on the darolutamide arm.

The primary endpoint was metastasis free survival (MFS), defined as the time from randomization to first evidence of distant metastasis or death from any cause within 33 weeks after the last evaluable scan, whichever occurred first. The median MFS was 40.4 months (95% CI: 34.3, not reached) for patients treated with darolutamide compared with 18.4 months (95% CI: 15.5, 22.3) for those receiving placebo (hazard ratio 0.41; 95% CI: 0.34, 0.50; p<0.0001). OS data were not mature.

The Approval

The FDA approved Nubeqa under the Agency’s Priority Review Trusted Source designation, which is reserved for drugs that can potentially offer significant improvements in safety or effectiveness of treatment in rare or aggressive diseases.

Adverse Events

The most common adverse reactions (≥2%) in patients who received darolutamide were fatigue, pain in extremity, and rash. Ischemic heart disease (4.3%) and heart failure (2.1%) were more common on the darolutamide arm. The seizure incidence was similar on the two arms (0.2%).

Fast Track

The FDA granted darolutamide fast track designation. FDA granted this application priority review.

The Sponsors

Bayer is a German based, multinational biopharmaceutical company. Orion is a mid-market biopharmaceutical venture based in Finland.


Also known as ODM-201 and BAY-1841788, it is a nonsteroidal antiandrogen (NSAA)—specifically, a selective antagonist of the androgen receptor (AR)—which has been under development by Orion and Bayer Healthcare fort the treatment of advanced, castration-resistant prostate cancer (CRPC).


Darolutamide has shown some advantages as compared to other recent NSAAs (e.g. enzalutamide/Xtandi or apalutamide/Erleada) in that it appears to negligibly cross the blood-brain barrier. This represents a potential benefit due to the reduced risk of seizures and other central side effects from off-target GABAa receptor inhibition that tends to occur in NSAAs that are structurally similar to enzalutamide.

Additionally, with its lack of central penetration, it doesn’t seem to increase testosterone levels in mice or humans, unlike other NSAAs. Moreover, it appears to block the activity of all tested/well-known mutant Ars in prostate cancer, including the recently identified clinically-relevant F876L mutation that produces resistance in enzalutamide and apalutamide.  Darolutamide also evidences higher affinity and inhibitory efficacy at the AR (Ki = 11 nM relative to 86 nM for enzalutamide and 93 nM for apalutamide; IC50 = 26 nM relative to 219 nM for enzalutamide and 200 nM for apalutamide) and greater potency/efficaciousness in non-clinical models of prostate cancer.