ASCO GU 2018: Blood-brain barrier penetration of darolutamide compared with enzalutamide using whole body autoradiography

San Francisco, CA ( Christian Zurth and colleagues presented results of their rat model study assessing blood-brain barrier penetration of darolutamide vs enzalutamide using whole body autoradiography at GU ASCO 2018. Darolutamide (ODM-201) is an investigational oral and high-affinity androgen receptor antagonist. In preclinical studies, penetration of darolutamide through the blood–brain barrier is negligible and in a retrospective safety analysis of the ARADES database for CNS-related adverse events, only one report of urinary incontinence was linked to darolutamide [1].

Various clinical trials on enzalutamide have reported CNS adverse events, including seizures, falls, fatigue, pain. Thus, in order to understand the differences in CNS outcomes between these two agents, the objective of this study was to report an in vivo tissue distribution assessment with [14C]-labelled enzalutamide and darolutamide in a head-to-head study in rats by means of quantitative whole-body autoradiography. 

For this study, male rats were orally dosed with 10 mg/kg [14C]-darolutamide or [14C]-enzalutamide in the same formulation, administration volume, and radioactive dose. The animals were then sacrificed at each drug’s specific tmax (time to reach the maximum concentration) in blood and the brain and processed for whole body autoradiography. The authors found that at early time points, [14C]-darolutamide and [14C]-enzalutamide derived radioactivity was rapidly absorbed from gastrointestinal tract and distributed throughout the body. By 8 hours after the medication, [14C]-darolutamide was significantly eliminated from almost all organs/tissues, whereas [14C]-enzalutamide remained constant within the body. In contrast to [14C]-darolutamide, high and persistent radioactivity was observed in the brain for [14C]-enzalutamide. At tmax, the brain/blood-ratio of [14C]-enzalutamide was ~0.765, while [14C]-darolutamide was ~10-fold lower at ~0.074. 

The authors concluded that post-treatment, there was a 10-fold lower blood-brain barrier penetration of [14C]-darolutamide compared with [14C]-enzalutamide. At 8 h, [14C]-darolutamide was rapidly eliminated and almost undetectable in all tissues, including brain, in contrast to [14C]-enzalutamide which remained constant. These results suggest that darolutamide may have a lower risk of inducing CNS-related adverse events compared to enzalutamide, which will ultimately be decided/confirmed in ongoing clinical studies. 

Presented by: Christian Zurth, Bayer AG, Berlin, Germany 

Co-Authors: Steffen Sandmann, Dagmar Trummel, Dietrich Seidel, Hille Gieschen

Written by: Zachary Klaassen, MD, Urologic Oncology Fellow, University of Toronto, Princess Margaret Cancer Centre  @zklaassen_md at the 2018 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, February 8-10, 2018 - San Francisco, CA

1. Fizazi K, Massard C, Bono P, et al. Activity and safety of ODM-201 in patients with progressive metastatic castration-resistant prostate cancer (ARADES): an open-label phase 1 dose-escalation and randomized phase 2 dose expansion trial. Lancet Oncol. 2014;15(9):975-985.