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.
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."
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 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.
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