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

Abstract

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 secondgeneration 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.

Patient and caregiver benefit‐risk preferences for nonmetastatic castration‐resistant prostate cancer treatment

“…[11][12][13] Rates of central nervous system related AEs vary among the SGARIs due to different penetration of the bloodbrain barrier. 19 Given that nmCRPC is fairly asymptomatic, an important treatment goal is to minimize AEs, as they can interfere with patients' daily activities, affecting quality of life (QoL), and may lead to treatment discontinuation. 20 Hence, careful weighing of the efficacy and AEs of treatment is crucial in nmCRPC treatment decision-making.…”

Analysis of Brain Functions in Men with Prostate Cancer under Androgen Deprivation Therapy: A One-Year Longitudinal Study

“…ADT was not associated with an increased risk of cognitive impairment than patients with PCa who had not received ADT in the general population [ 55 ]. A systematic review and a meta-analysis of cognitive impairment in men with PCa receiving ADT also found no statistically significant risk of overall cognitive impairment after ADT [ 20 , 56 ]. As in these studies, we detected no statistically significant decreases of the cognitive performance in the sample, but this finding should be considered cautiously, as the decline of the scores might need a bigger sample size or a longer period to appear.…”

A Clinical Evaluation of Enzalutamide in Metastatic Castration-Sensitive Prostate Cancer: Guiding Principles for Treatment Selection and Perspectives on Research

“… 62 CNS exposure to AR antagonists is postulated to produce cognitive deficits and fatigue. 63 Furthermore, negative feedback on the GnRH axis results in testosterone upregulation and increased estrogen levels (via peripheral aromatization) which eventually leads to gynecomastia and breast tenderness. 64 Darolutamide, a third-generation AR antagonist, does not appear to suffer from this pharmacokinetic limitation with a distinct chemical structure that likely restricts blood–brain barrier penetration and binding affinity for γ-aminobutyric acid type A receptors.…”