Bayer, Orion Seek Darolutamide’s Approval in Europe for Non-metastatic CRPC

Bayer and Orion have successfully submitted an application to the European Medicines Agency seeking the approval of darolutamide for men with non-metastatic castration-resistant prostate cancer (nmCRPC).

The application follows promising results from the ARAMIS Phase 3 trial (NCT02200614), where a combination of darolutamide and androgen deprivation therapy (ADT) delayed cancer spread by 22 months, compared to ADT only.

The findings were presented during the 2019 Genitourinary Cancers Symposium in San Francisco and have been published in The New England Journal of Medicine.

Currently, Erleada (apalutamide) and Xtandi (enzalutamide) are the only two androgen receptor inhibitors approved to delay cancer’s spread in CRPC patients. However, both therapies are associated with toxicities that may affect patients’ quality of life.

Darolutamide is an oral androgen receptor inhibitor, meaning that it prevents the binding of testosterone to the androgen receptor, blocking the signals that fuel prostate cancer growth. Its structure, however, is distinct from other inhibitors of the androgen receptor, potentially being less toxic to patients.

ARAMIS was designed to determine whether darolutamide could safely delay metastasis in CRPC patients at high risk. It included 1,509 patients with non-metastatic CRPC whose prostate-specific antigen (PSA) levels were rapidly rising while receiving androgen deprivation therapy.

During the trial, all participants continued to receive hormone therapy and were randomly either assigned oral darolutamide (955 patients) or a placebo (554 patients) twice daily.

Investigators found that patients given a combination of darolutamide and ADT lived a median 40.4 months without their cancer spreading, compared to 18.4 months for ADT alone. This 22-month delay represented a 59% reduction in the risk of disease spread or death.

While more than half of patients were alive at the time of the analysis, the interim analysis pointed toward a 29% reduction in the risk of death for patients taking darolutamide. Also, the treatment extended the time patients lived without disease progression — 36.8 months versus 14.8 months — representing a 62% reduction in the risk of disease worsening or death.

Other secondary measures were also met, with darolutamide delaying the time to pain worsening — from a median 25.4 months on placebo to 40.3 months — and lowering the risk of needing a chemotherapeutic medication by 57%.

The time to first skeletal event — deemed radiation therapy to the bone, bone fractures, spinal cord compression, or bone surgery — was also longer with darolutamide.

The adverse events of any grade were similar in both groups, with darolutamide treatment not causing an increase in critical adverse events such as seizures, fractures, falls, high blood pressure, or cognitive disorder.

“Darolutamide is highly effective in the patient population with non-metastatic castration-resistant prostate cancer, and it has a side effect profile that parallels that of placebo. Patients who received darolutamide had substantially longer [metastasis-free survival] in the ARAMIS trial, and there was also a strong trend for improved overall survival,” Christer Nordstedt, MD, PhD, senior vice president of research and development for Orion, said in a press release. “These results are truly exciting. We are looking forward to taking the next steps in bringing darolutamide to men with nmCRPC and their treating physicians.”

Darolutamide’s developers, Bayer and Orion, have also submitted a request for darolutamide approval to the U.S. Food and Drug Administration (FDA) and to the Ministry of Health, Labor and Welfare (MHLW) in Japan.