Significant localized reduction in cerebral blood flow (CBF) in regions relevant to cognitive function with enzalutamide (ENZA) compared to darolutamide (DARO) and placebo (PBO) in healthy volunteers.

Abstract

326 Background: DARO is an oral androgen receptor antagonist with a unique structure and a low blood–brain barrier penetrance noted in rodents. Here we compare CBF following administration of DARO, ENZA, and PBO using arterial spin labelled magnetic resonance imaging (ASL-MRI) in humans. Methods: This phase I, randomized, PBO-controlled, 3-period crossover study investigated drug-induced changes in CBF for brain grey matter and for specific regions related to cognitive function in healthy males (age 19–44). Twenty-three participants received a single oral dose of DARO, ENZA, or PBO at 6-week intervals at similar unbound concentrations . An ASL-MRI scan was performed ~4 hours after each dose. Blood samples for drug analysis and physiological measures were collected prior to drug administration and immediately post-scan. ASL data were preprocessed and statistical parametric modelling was used for treatment comparisons (paired t-tests). Whole-brain results were considered significant after correction for multiple comparisons. A linear mixed effects model was used for predetermined region of interest (ROI) analysis, with physiological parameters as nuisance regressors. Results: Drug-concentration data confirmed similar unbound exposure during MRI scans and a complete washout between treatments. No unexpected safety concerns were noted in the study. Whole-brain analysis showed a significant localized 5.2% reduction in CBF for ENZA in temporo-occipital cortices but no significant CBF reduction with DARO compared to PBO. A significant 5.9% localized reduction in CBF was measured for ENZA vs DARO. ROI analysis showed a significant reduction in CBF for ENZA vs PBO (p = 0.045) and for ENZA vs DARO (p = 0.037) in the left and right dorsolateral prefrontal cortices, respectively. A significant reduction was noted in CBF for ENZA vs PBO in right amygdala (p = 0.047). Conclusions: Compared to PBO and DARO, significant localized reductions in CBF were noted for ENZA. These results may be relevant to cognitive function (executive function, memory, and anxiety) with extended treatment and warrant further investigation. Clinical trial information: NCT03704519.