Pharmacokinetic/Pharmacodynamic relationship of Enzalutamide and its active metabolite N-desmethyl Enzalutamide in metastatic castration-resistant prostate cancer patients

Abstract Introduction Enzalutamide (ENZA) is an oral androgen receptor inhibitor approved for the treatment of metastatic and non-metastatic Castration-Resistant Prostate Cancer (CRPC). ENZA is extensively metabolized by CYP 3A4 into N -desmethyl enzalutamide (NDE), an active metabolite. We aimed to explore the pharmacokinetic/pharmacodynamic relationship for ENZA and NDE in metastatic CRPC patients from real world setting. Methods Trough plasma concentrations (C trough ) of ENZA and NDE were assayed using liquid chromatography coupled with UV-detection. The relationship between ENZA, NDE and composite (ENZA plus NDE) plasma concentration and requirement of ENZA dose reduction was investigated using Mann Whitney test. A survival univariate analysis was conducted to explore association between progression-free survival (PFS), overall survival (OS) and plasma C trough (ENZA, NDE and composite). Results Twenty-two metastatic CRPC patients treated with ENZA (median age 75.5 years, 59% of patients with ECOG Status 0-1) were prospectively included. Mean plasma C trough of ENZA and NDE were 12.4 ± 3.0 μg/mL and 8.8 ± 2.1 μg/mL, respectively. Neither PFS nor OS were statistically associated with ENZA, NDE or composite plasma C trough . In four patients (18%) who required ENZA dose reduction because of severe clinical toxicity, an increased ENZA plasma C trough was observed compared to 18 remaining patients (16.1 ± 2.4 μg/mL vs 11.6 ± 2.6 μg/mL, respectively; p=0.027). Conclusion The low interindividual variability in ENZA and NDE C trough and the lack of relationship with survival do not support the need of plasma drug monitoring. Severe asthenia may be related to higher exposure and could be improved by decreasing ENZA dosing.