Comparison of Cerebral Blood Flow in Regions Relevant to Cognition After Enzalutamide, Darolutamide, and Placebo in Healthy Volunteers: A Randomized Crossover Trial

TY - JOUR

T1 - Comparison of Cerebral Blood Flow in Regions Relevant to Cognition After Enzalutamide, Darolutamide, and Placebo in Healthy Volunteers

T2 - A Randomized Crossover Trial

AU - Williams, Steven C R

AU - Mazibuko, Ndaba

AU - O'Daly, Owen

AU - Zurth, Christian

AU - Patrick, Fiona

AU - Kappeler, Christian

AU - Kuss, Iris

AU - Cole, Patricia E

N1 - Funding Information: This work was supported by Bayer HealthCare. Funding Information: The authors thank Dr. Hille Gieschen (Bayer Pharmaceuticals, Berlin, Germany) and colleagues for the images from the rat autoradiography study. Medical writing support was provided by Open Health Medical Communications (London, UK), supported by Bayer. Steven C. R. Williams wishes to thank the Wellcome Trust and the National Institute for Health Research (NIHR) Maudsley Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London for their continued provision of facilities and support of our neuroimaging research. Publisher Copyright: © 2023, The Author(s).

PY - 2023/5

Y1 - 2023/5

N2 - Background: Off-target central nervous system (CNS) effects are associated with androgen receptor (AR)-targeting treatments for prostate cancer. Darolutamide is a structurally distinct AR inhibitor with low blood–brain barrier penetration. Objective: We compared cerebral blood flow (CBF) in grey matter and specific regions related to cognition after darolutamide, enzalutamide, or placebo administration, using arterial spin-label magnetic resonance imaging (ASL-MRI). Methods: This phase I, randomized, placebo-controlled, three-period crossover study administered single doses of darolutamide, enzalutamide, or placebo to 23 healthy males (aged 18–45 years) at 6-week intervals. ASL-MRI mapped CBF 4 h post-treatment. Treatments were compared using paired t-tests. Results: Drug concentrations during scans confirmed similar unbound exposure of darolutamide and enzalutamide, with complete washout between treatments. A significant localized 5.2% (p = 0.01) and 5.9% (p < 0.001) CBF reduction in the temporo-occipital cortices was observed for enzalutamide versus placebo and versus darolutamide, respectively, with no significant differences for darolutamide versus placebo. Enzalutamide reduced CBF in all prespecified regions, with significant reductions versus placebo (3.9%, p = 0.045) and versus darolutamide (4.4%, p = 0.037) in the left and right dorsolateral prefrontal cortices, respectively. Darolutamide showed minimal changes in CBF versus placebo in cognition-relevant regions. Conclusions: Darolutamide did not significantly alter CBF, consistent with its low blood–brain barrier penetration and low risk of CNS-related adverse events. A significant reduction in CBF was observed with enzalutamide. These results may be relevant to cognitive function with early and extended use of second-generation AR inhibitors, and warrant further investigation in patients with prostate cancer. Trial Registration Number: NCT03704519; date of registration: October 2018.

AB - Background: Off-target central nervous system (CNS) effects are associated with androgen receptor (AR)-targeting treatments for prostate cancer. Darolutamide is a structurally distinct AR inhibitor with low blood–brain barrier penetration. Objective: We compared cerebral blood flow (CBF) in grey matter and specific regions related to cognition after darolutamide, enzalutamide, or placebo administration, using arterial spin-label magnetic resonance imaging (ASL-MRI). Methods: This phase I, randomized, placebo-controlled, three-period crossover study administered single doses of darolutamide, enzalutamide, or placebo to 23 healthy males (aged 18–45 years) at 6-week intervals. ASL-MRI mapped CBF 4 h post-treatment. Treatments were compared using paired t-tests. Results: Drug concentrations during scans confirmed similar unbound exposure of darolutamide and enzalutamide, with complete washout between treatments. A significant localized 5.2% (p = 0.01) and 5.9% (p < 0.001) CBF reduction in the temporo-occipital cortices was observed for enzalutamide versus placebo and versus darolutamide, respectively, with no significant differences for darolutamide versus placebo. Enzalutamide reduced CBF in all prespecified regions, with significant reductions versus placebo (3.9%, p = 0.045) and versus darolutamide (4.4%, p = 0.037) in the left and right dorsolateral prefrontal cortices, respectively. Darolutamide showed minimal changes in CBF versus placebo in cognition-relevant regions. Conclusions: Darolutamide did not significantly alter CBF, consistent with its low blood–brain barrier penetration and low risk of CNS-related adverse events. A significant reduction in CBF was observed with enzalutamide. These results may be relevant to cognitive function with early and extended use of second-generation AR inhibitors, and warrant further investigation in patients with prostate cancer. Trial Registration Number: NCT03704519; date of registration: October 2018.

UR - https://www.scopus.com/pages/publications/85153715181

U2 - 10.1007/s11523-023-00959-5

DO - 10.1007/s11523-023-00959-5

M3 - Article

C2 - 37103658

SN - 1776-2596

VL - 18

SP - 403

EP - 413

JO - Targeted Oncology

JF - Targeted Oncology

IS - 3

ER -