The U.S. Food and Drug Administration ( FDA ) has approved a supplemental New Drug Application ( sNDA ) for the oral androgen receptor inhibitor ( ARi ) Darolutamide ( Nubeqa ) in combination with Docetaxel for the treatment of patients with metastatic hormone-sensitive prostate cancer ( mHSPC ).
The approval is based on positive results of the phase III ARASENS trial that has demonstrated Darolutamide plus androgen deprivation therapy ( ADT ) and Docetaxel has significantly reduced the risk of death by 32.5% compared to ADT plus Docetaxel.
These results were published in The New England Journal of Medicine ( NEJM ).
Prostate cancer remains the second leading cancer-related cause of death among men in the U.S., with up to one-third of patients developing metastatic disease.
The incidence of mHSPC has increased by 72% in the U.S. over the past 10 years.
Approximately one in three patients who are diagnosed with mHSPC survive the disease five years or longer, with most eventually experiencing progression to castration-resistant prostate cancer ( CRPC ).
The ARASENS trial is the only randomized, phase III, multi-center, double-blind, trial which was prospectively designed to compare the use of a second-generation oral androgen receptor inhibitor Darolutamide plus ADT and chemotherapy Docetaxel to ADT plus Docetaxel ( a standard-of-care ) in metastatic hormone-sensitive prostate cancer.
A total of 1,306 newly diagnosed patients were randomized in a 1:1 ratio to receive 600 mg of Darolutamide twice a day or matching placebo, plus ADT and Docetaxel.
The primary endpoint of this trial was overall survival ( OS ). Secondary endpoints included time to castration-resistant prostate cancer, time to pain progression, time to first symptomatic skeletal event ( SSE ), time to initiation of subsequent anticancer therapy, all evaluated at 12‐week intervals, as well as adverse events as a measure of safety and tolerability.
The ARASENS trial has demonstrated that Darolutamide plus androgen deprivation therapy and Docetaxel has significantly reduced the risk of death by 32.5% compared to ADT plus Docetaxel.
Improvements in the secondary endpoints supported the benefit observed in the primary endpoint, overall survival.
At the time of diagnosis, most men have localized prostate cancer, meaning their cancer is confined to the prostate gland and can be treated with curative surgery or radiotherapy.
Upon relapse, when the disease will metastasize or spread, the disease is hormone-sensitive and androgen deprivation therapy is the cornerstone of treatment.
Current treatment options for men with metastatic hormone-sensitive prostate cancer include hormone therapy, such as ADT, androgen receptor pathway inhibitors plus ADT or a combination of the Docetaxel chemotherapy and ADT.
Despite these treatments, a large proportion of men with mHSPC will eventually experience progression to metastatic castration-resistant prostate cancer, a condition with high morbidity and limited survival.
Darolutamide is an oral androgen receptor inhibitor with a distinct chemical structure that binds to the receptor with high affinity and exhibits strong antagonistic activity, thereby inhibiting the receptor function and the growth of prostate cancer cells.
The low potential for blood-brain barrier penetration for Darolutamide is supported by preclinical models and neuroimaging data in healthy humans.
This is supported by the overall low incidence of central nervous system ( CNS )-related adverse events compared to placebo as seen in the ARAMIS phase III trial and the improved verbal learning and memory observed in the Darolutamide arm of the phase II ODENZA trial. ( Xagena )
Source: Bayer, 2022