A review of prostate cancer treatment impact on the CNS and cognitive function

Background: Androgen deprivation therapy (ADT) is the backbone of systemic therapy for men with prostate cancer (PC); almost one-half of patients receive treatment during their disease course. However, a range of cognitive and other central nervous system (CNS) changes have been associated with ADT. In this review, we discuss extant data describing these complications and the mechanisms through which medications used to deliver ADT may affect them. Methods: We performed a MEDLINE search for appropriate papers published between January 2000 and December 2018. Relevant papers were selected and reviewed; additional publications were identified by manually assessing references from included papers, and recent congress abstracts. Results: Of ~230 search outputs, 33 were selected for inclusion. Some studies suggested a clear association between ADT and CNS effects in men with PC, whereas others did not. Accurate assessment is limited by test instrument variability, inadequate sample sizes, short follow-up duration, and limited prospective longitudinal studies. The approved second-generation androgen receptor (AR) inhibitors enzalutamide and apalutamide were associated with some CNS-related adverse events (AEs) in clinical studies, including fatigue (which can interfere with cognitive function). The androgen synthesis inhibitor abiraterone acetate was associated with a low CNS AE profile when compared with enzalutamide. The AR antagonist darolutamide demonstrated a comparable incidence of cognitive disorder in clinical trials to that of ADT alone. Conclusions: Adequately caring for men receiving ADT requires an understanding of the symptoms, incidence and magnitude of cognitive effects, and a feasible approach to cognitive assessment and management in clinical settings. Some CNS effects could relate to blood–brain barrier penetration and direct AR inhibitor activity; drug safety profiles may differ by the degree of blood–brain barrier penetration of particular agents. Ongoing clinical trials seek to define the CNS tolerability of newer AR pathway-targeted therapy options more clearly.