Higher blood–brain barrier penetration of [14C]apalutamide and [14C]enzalutamide compared to [14C]darolutamide in rats using whole-body autoradiography.

156Background: Darolutamide ([14C]Daro) is an investigational oral androgen receptor antagonist, structurally distinct from enzalutamide ([14C]Enza) and apalutamide ([14C]Apa). In a retrospective analysis of the ARADES database, central nervous system (CNS)-related adverse events (AEs) were not linked with Daro (Fizazi, et al. 2015). CNS-related AEs have been observed with Enza and Apa, eg, fatigue, mental impairment, and seizure (Hussain et al, 2018; Smith et al, 2018). In preclinical studies, low blood–brain barrier (BBB) penetration of Daro was observed, suggesting low impact on the CNS. To understand the different CNS effects, we report in vivo tissue distribution data in rats with [14C]-labeled Apa compared to previously presented [14C]Enza and [14C]Daro distribution data (Zurth, ASCO GU 2018) using quantitative whole-body autoradiography (QWBA). Methods: Male rats were orally dosed with 10 mg/kg [14C]Apa under similar experimental conditions as previously reported for [14C]Daro or [14C]Enza, prior t...