FDA Approval for Darolutamide in Prostate Cancer

Zosia Chustecka


July 31, 2019

Darolutamide (Nubeqa, Bayer) has been approved by the US Food and Drug Administration (FDA) for use in the treatment of nonmetastatic castration-resistant prostate cancer (nmCRPC).

The approval was granted under the FDA's priority review and came 3 months ahead of the target FDA action date.

It is based on results from the phase 3 ARAMIS trial (n = 1509), which showed a significant improvement in the primary endpoint of metastasis-free survival (MFS).

The ARAMIS trial results were presented in February 2019 at the Genitouirinary Cancers Symposium and were published online in the New England Journal of Medicine, as reported at the time by Medscape Medical News.

New Endpoint, New Clinical Space

MFS is a new endpoint in a new clinical space — until last year, no drugs had been approved for use in nmCRPC.

Now there are three — darlutamide joins two other antiandrogen products that have been approved this indication, also on the basis of improved MFS.

MFS is determined on the basis of independent central review of radiographic imaging every 16 weeks.

It is defined as the time from randomization to the time of first evidence of blinded independent central review–confirmed distant metastasis or death from any cause within 33 weeks after the last evaluable scan, whichever occurs first.

It is a relatively new endpoint in prostate cancer trials, introduced in the past few years. It can be measured more quickly than the ultimate endpoint — overall survival — which can require years of follow-up. However, questions have been raised about the "relevance and applicability" of this surrogate endpoint.

Approached for comment earlier this year, Bobby Liaw, MD, clinical director of genitourinary oncology at Mount Sinai Health System in New York City, said that the ARAMIS trial with darolutamide showcases the activity and efficacy of a new oral androgen receptor antagonist in delaying the development of radiographically evident metastatic disease in men with nmCRPC.

"Prolonging delay in the development of metastatic disease is an endpoint that has more recently been recognized as an objective and clinically meaningful measure," he told Medscape Medical News.

Darolutamide will be competing with two other androgen receptor antagonists in the nmCRPC clinical space, which prior to 2018 had no approved therapeutic agents, he said.

Liaw pointed out that two other agents have recently demonstrated MFS benefit in phase 3 studies: apalutamide (Erleada, Janssen) in the SPARTAN trial and enzalutamide (Xtandi, Astellas/Pfizer) in the PROSPER trial.

The data showing an MFS benefit led to new approvals by the FDA. For apalutamide, approval was granted as a new drug, and for enzalutamide, approval was granted for a new indication, as previously reported by Medscape Medical News.

Commenting on the ARAMIS trial, Liaw said: "Additional follow-up will be able to further define the adverse effect profile of darolutamide, but because it does not cross the blood-brain barrier to any significant degree, it may potentially be associated with less fatigue, falls, and seizure risk, as compared to apalutamide or enzalutamide."

Details of Efficacy

The ARAMIS trial was a double-blind, placebo-controlled phase 3 trial that randomly assigned 1509 men with nmCRPC to receive either darolutamide 600 mg (two 300-mg tablets) twice daily or placebo while continuing to receive androgen deprivation therapy (ADT).

For all patients, the baseline prostate-specific antigen (PSA) level was at least 2 ng/mL, and the PSA doubling time was 10 months or less. The patients were stratified by PSA doubling time (≤6 months or >6 months) and on the basis of use of osteoclast-targeted therapy.

The results showed a significant improvement in MFS when darolutamide was added to ADT.

The median MFS was 40.4 months for the combination, vs 18.4 months for placebo plus ADT (P < .0001).

"The P value was highly significant," commented lead investigator Karim Fizazi, MD, PhD, head of the Department of Cancer Medicine at the Institut Gustave Roussy, Villejuif, France, when he presented the trial results earlier this year.

"When looking at subgroups, all seemed to derive a benefit from darolutamide. There was an improvement in MFS regardless of PSA doubling time, use of targeting agents, Gleason score, or age," he said.

On the basis of these results, "darolutamide should become the new standard of care" in this population in the future, Fizazi concluded at the time.

"Important New Option"

In a company press release, Matthew Smith, MD, PhD, director of the Genitourinary Malignancies Program, Massachusetts General Hospital Cancer Center, Boston, said: "This approval marks an important new option for the prostate cancer community.

"Patients at this stage of prostate cancer typically don't have symptoms of the disease," he explained. "The overarching goals of treatment in this setting are to delay the spread of prostate cancer and limit the burdensome side effects of therapy."

This population of patients with nmCRPC accounts for about 40% of men who develop CRPC but whose disease has not spread to other parts of the body. However, about one third of men with nmCRPC develop metastases within 2 years. PSA monitoring is important for identifying patients and to help offset undertreatment of men before the disease spreads, the company explained.

"We know that men with nmCRPC are still in the prime of their lives and are at a critical point in their disease when action needs to be taken," said Howard R. Soule, PhD, executive vice president and chief science officer, Prostate Cancer Foundation (PCF). "For 26 years, PCF has been focused on research aimed at improving patient outcomes and we welcome the addition of new treatment options that provide men with more choices when working with their doctor to select what's right for them."

"With the approval of Nubeqa, we now have a new therapy that extends MFS and allows physicians greater flexibility to treat men living with nmCRPC," said Robert LaCaze, member of the executive committee of Bayer's Pharmaceuticals Division and head of the Oncology Strategic Business Unit at Bayer.

Adverse Events

In the ARAMIS trial, for both treatment arms, the rate of discontinuation because of adverse reactions was 9%. The most frequent adverse reactions that required discontinuation by patients who received darolutamide were cardiac failure (0.4%) and death (0.4%). Adverse reactions that occurred more frequently in the darolutamide arm (≥2% compared to placebo) were fatigue (16% vs 11%), pain in extremity (6% vs 3%), and rash (3% vs 1%).

Darolutamide is awaiting approval in the European Union, Japan, and other countries. It was developed jointly by Bayer and Orion Corporation.

In the United States, Bayer is launching an innovative patient support program, DUDE (Darolutamide User Drug Experience) Access Services, which offers a 2-month free trial program to eligible patients and a $0 copay for commercially insured patients who qualify.

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