Darolutamide: New Standard of Care in Nonmetastatic CRPC?

Roxanne Nelson, RN, BSN

February 15, 2019

SAN FRANCISCO — Treatment with the investigational agent darolutamide (Bayer/Orion) significantly extended metastasis-free survival in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC), results from the phase 3 ARAMIS trial show.

Darolutamide prolonged metastasis-free survival to 40.4 months, which was 22 months longer than observed with placebo, and the risk of metastasis or death from any cause was reduced by 59%. This was seen across all patient subgroups, including those with lower-risk disease.

Based on these findings, lead author Karim Fizazi, MD, PhD, head of the Department of Cancer Medicine at the Institut Gustave Roussy, Villejuif, France, believes that "darolutamide should become the new standard of care," in this population in the future.

Fizazi presented the results here at the Genitourinary Cancers Symposium (GUCS) 2019; the study was published online February 14 in the New England Journal of Medicine.

Darolutamide is a unique nonsteroidal androgen-receptor antagonist that is structurally distinct from other androgen-receptor inhibitors, and consists of two pharmacologically active diastereomers. Data from preclinical studies suggested that it may have fewer and less severe toxicities than other agents due to its low penetration of the blood–brain barrier, and low binding affinity for γ-aminobutyric acid type A receptors.

Fizazi explained that previous phase 1 and II trials in men with nmCRPC demonstrated significant antitumor activity and a satisfactory side-effect profile, and those findings led to the current study.

Met Primary Endpoint

The ARAMIS trial is a double-blind, placebo-controlled phase III trial that randomized 1509 men with nmCRPC to receive darolutamide 600 mg (two 300 mg tablets) twice daily or placebo, while continuing on androgen deprivation therapy.

All patients had a baseline prostate-specific antigen (PSA) level of at least 2 ng/mL and a PSA doubling time of 10 months or less, and were stratified by PSA doubling time (≤6 months or >6 months) and use of osteoclast-targeted therapy.

The primary endpoint was metastasis-free survival (MFS), with independent central review of radiographic imaging every 16 weeks. MFS is a relatively new endpoint in prostate cancer trials, introduced in the last few years because it can be measured more quickly than the ultimate endpoint — overall survival — which can require years of follow-up; it has already been used for new drug approvals, but there have also been questions raised about this surrogate endpoint.

In the ARAMIS trial, the median MFS was 40.4 months in the darolutamide group as compared with 18.4 months for placebo group (hazard ratio [HR] for metastasis or death in the darolutamide group, 0.41; 95% confidence interval [CI], 0.34 - 0.50; P < .001). The benefit remained consistent across all subgroups, including the subgroup of patients with lower-risk disease.

"The p value was highly significant," said Fizazi. "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."

Secondary and Exploratory Endpoints

Darolutamide treatment also surpassed placebo for all secondary end points.

"When looking at overall survival, the hazard ratio was 0.71 and a p value of .045, favoring darolutamide," he said. "This is an early analysis, and the median has not yet been reached. But still at three years, survival rates were 73% for placebo and 83% for darolutamide."

After 136 deaths (78 in the darolutamide group and 58 in the placebo group), darolutamide was associated with a lower mortality risk compared to placebo (HR for death, 0.71; 95% CI, 0.50 - 0.99; P = .045). Time to pain progression also favored darolutamide (median, 40.3 months vs 25.4 months; HR, 0.65; 95% CI, 0.53 - 0.79; P < .001) as did time to first cytotoxic chemotherapy and time to the first symptomatic skeletal event.

Fizazi and colleagues also looked at several exploratory endpoints. Median progression-free survival favored darolutamide (36.8 months vs 14.8 months; HR for disease progression or death, 0.38; 95% CI, 0.32 - 0.45; P < 0.001), as did median time to PSA progression (33.2 months vs 7.3 months; HR for PSA progression or death, 0.13; 95% CI, 0.11 - 0.16; P < .001).

Patients who discontinued therapy due to adverse events were similar in both groups, 8.9% with darolutamide vs 8.7% with placebo. Grade 3 or 4 adverse events occurred in 24.7% of the darolutamide group vs 19.5% of those receiving placebo; grade 5 adverse events were similar in both groups (3.9% and 3.2%, respectively).

Fizazi noted that grade 3 and 4 events were rarely observed, which is important for patients who are largely asymptomatic. "The rates of drug discontinuation were remarkably similar in the darolutamide and placebo groups," he noted.

Experts Weigh In

In a discussion of the paper, Ian D. Davis, MBBS, PhD, FRACP, FAChPM,​ Monash University Eastern Health Clinical School, Australia, was cautious about whether these results are practice changing.

This condition does need treatment, and the study shows "a meaningful endpoint and acceptable toxicity," he said.

However, Davis noted that "we don’t have a survival benefit yet," and so it is not possible yet to say if this treatment is cost effective.

Medscape Medical News reached out for an independent comment from Bobby Liaw, MD, clinical director of genitourinary oncology at Mount Sinai Health System in New York City. He said this study 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 said.  "Darolutamide would be competing with two other androgen receptor antagonists in the nmCRPC clinical space, which prior to 2018 had no approved therapeutic agents."

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

These data showing an MFS benefit led to new approvals by the US Food and Drug Administration — for apalutamide as a new drug and for enzalutamide 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."

The study was funded by Bayer HealthCare and Orion Pharma. Fizazi reports honoraria from Astellas Pharma, Janssen, Merck, Sanofi; consulting for Amgen, Astellas Pharma, AstraZeneca, Bayer, Clovis Oncology, Curevac, ESSA, Janssen Oncology, Orion Pharma GmbH, Roche/Genentech, Sanofi; and travel, accommodations and expenses from Amgen and Janssen. Several coauthors also report relationships with industry. Davis has disclosed multiple relationships with industry. Liaw has disclosed an investigator-initiated clinical trial for prostate cancer that is sponsored by Bayer and Sanofi.

Genitourinary Cancers Symposium (GUCS) 2019: Abstract 140. Presented February 14, 2019.

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