Enzalutamide‐Induced Host Metabolic Reprogramming Is Associated with Treatment Outcomes in Patients with Castration‐Resistant Prostate Cancer: A Hypothesis‐Generating Study

Host metabolic changes in response to drug treatment may shape individual pharmacological outcomes. This study aims to identify serum metabolomics signatures potentially associated with individual responses to enzalutamide treatment in metastatic castrate-resistant prostate cancer (mCRPC) patients. Targeted metabolomic profiles in serum collected from 18 mCRPC patients treated with 160 mg/day of enzalutamide were measured at baseline, after 3 months of treatment, and until disease progression by a validated liquid chromatography tandem mass spectrometry analytical platform. The difference in the serum metabolomic profiles during enzalutamide treatment between good and poor responders was investigated by both multivariate and univariate statistical analysis. Primary mouse hepatocytes and Caco-2 cell models were employed to gain mechanistic insights into the most relevant changes detected. Enzalutamide induced a significant and sustained increase in several amino acids, with taurine displaying the most significant change. The in vitro data suggest that enzalutamide-induced elevation of systemic taurine results from both increased intestinal absorption and decreased hepatic extraction. Finally, serum metabolomic changes observed after 3 months of treatment were found to be significantly associated with the pharmacological response. This hypothesis-generating study reveals that enzalutamide significantly alters the host serum metabolome, inducing changes that correlate with therapeutic response over time. These results highlight the importance of host-drug metabolic interactions during androgen receptor inhibitor treatment and, although further validation is required, they support the hypothesis that metabolic profiling could eventually aid in the personalized management of enzalutamide therapy.