Impact of hormone-therapy used in CRPC patients: Evaluation of abiraterone acetate/prednisone or enzalutamide on activity and cognitive functions in aged castrated mice.

Abstract

e16526 Background: Prostate cancer (PC) is a major public health problem and represents the most frequent cancer in elderly male patients. Although most patients initially respond to androgen deprivation therapy (ADT) through inhibition of gonadal testosterone biosynthesis, the majority of these patients will progress to metastatic castration-resistant PC (mCRPC). Novel oral agents targeting androgen signaling axis, abiraterone acetate (AA)+prednisone (P) and enzalutamide (ENZ) are available and used in mCRPC patients in addition to ADT, but their impact on cognition is not well understood. Recently, the AQUARiUS study (Thiery-Vuillemin et al., ESMO Open, 2018) showed that after treatment, median Quality of life score improved with AAP. Additionally, results from a phase 2 trial showed that a worsening of depression symptoms were more often detected in ENZ- than in AAP-treated patients (Khalaf et al., Eur Urol, 2018). Methods: Here we developed a preclinical animal model to clarify the potential impact of AAP or ENZ on emotional reactivity and cognitive functions including spontaneous activity, anxiety-like and depression-like behaviors or spatial memory and learning. Results: In aged castrated mice receiving per os vehicle or AAP or ENZ, we showed that, in contrast to AAP, exposure to ENZ reduced spontaneous activity and increased depressive-like behaviors. AAP-treated mice displayed diminished self-grooming suggesting lower arousal in a novel environment. None of the treatments provoked anxiety-like behavior, learning and memory deficits. However, the swimming strategies (Morris-water maze) in AAP and ENZ groups were slightly altered. Analysis of plasma from treated mice revealed a detectable level of corticosterone only in AAP group. Conclusions: These data establish the impact of ENZ on emotional reactivity and of both ENZ and AAP on subtle cognitive functions in castrated aged male subjects. It paves the road for future effective research that could lead to better management of quality of life in mCRPC.