Apalutamide

Drug Overview

Apalutamide (Johnson & Johnson) is an orally available androgen signaling inhibitor. The drug exhibits high binding affinity to the ligand-binding domain of androgen receptor (AR) and subsequently inhibits its nuclear import, as well as its ability to bind to DNA. Apalutamide has a similar mechanism of action to Xtandi (enzalutamide; Pfizer/Astellas). However, in preclinical development, apalutamide exhibited reduced binding to plasma proteins, which resulted in increased efficacy at lower exposure rates than those required for Xtandi. Brain-levels (the concentration of the drug in brain tissue) were lower for apalutamide than for Xtandi, which could indicate a lower seizure-induction risk with apalutamide.

Apalutamide is poised to become the next AR inhibitor to reach the market following the submission of a New Drug Application (NDA) to the US Food and Drug Administration (FDA) in non-metastatic castration-resistant prostate cancer (nmCRPC) patients. The submission to the FDA was based on the Phase III SPARTAN trial, which met its primary endpoint of metastasis-free survival (MFS). Approval in this population would expand Johnson & Johnson’s prostate cancer treatment portfolio and pair an AR inhibitor with its blockbuster 17 alpha-hydroxylase (CYP17) inhibitor Zytiga (abiraterone acetate). However, if approved, apalutamide may face direct competition from the established AR inhibitor Xtandi, which also improved MFS in nmCRPC patients in the Phase III PROSPER study.