851P - Pharmacokinetic/pharmacodynamic relationship of enzalutamide and its active metabolite N-desmethyl enzalutamide in metastatic castration-resistant prostate cancer patients

Abstract

Background: Enzalutamide (ENZA) is an oral androgen receptor inhibitor approved for the treatment of metastatic Castration-Resistant Prostate Cancer (mCRPC). ENZA is extensively metabolized by CYP 3A4 into N-desmethyl enzalutamide (NDE). Based on in vitro assays, NDE has been identified as pharmacologically active metabolite. We aimed to explore the relationship between ENZA, NDE plasma concentration and progression-free survival (PFS) in mCRPC. Methods: Trough plasma concentrations of ENZA and NDE were measured at steady-state one month after treatment start, using liquid chromatography. Trough ENZA and NDE plasma concentrations were dichotomized into 2 groups (high and low) according to their median value. Progression was defined as clinical progression, PSA increase or imaging progression according to the prostate working group criteria 3 or death. A survival analysis was used to explore relationship between PFS and plasma drug exposure. Results: From January 2015 to May 2017, 18 mCRPC patients treated with ENZA (median age 77.5 years, Interquartile range (IQR) 67.2-82.7) were prospectively included. Median follow-up was 10.6 months (ms) (IQR 5.1-21.3 ms). Median trough plasma concentration of ENZA and NDE were 10.5 ± 3.7 µg/mL (Coefficient of variation (CV) = 33.8%; IQR 8.2-13.2) and 8.1 ± 4.2 µg/mL (CV = 52.7%; IQR 5,4-10,1), respectively. Pearson correlation coefficient value was 0,3 (p = 0.21). Eleven patients (61%) achieved a PSA response. Median PFS in the whole cohort was 11.2 ms (IQR 3.4-12.4). High trough plasma concentration of ENZA was associated with a shorter PFS (9 ms vs 22.6 ms respectively in the high and the low group) (Hazard Ratio (HR) 0.2; 95% CI 0.04-0.57; p = 0.005). Conversely, a high trough plasma concentration of NDE was associated with a longer PFS: 12,8 ms vs 7.2 ms respectively in the high and low group (HR 3.04; 95% CI 1.19-48.45; p = 0.03). Conclusions: Overall, these results suggest that NDE could be more pharmacologically active than ENZA in vivo. Plasma monitoring of ENZA and NDE could lead to early identification of patients who will not benefit from ENZA as well as to optimize their treatment choice. Legal entity responsible for the study: Department of Medical Oncology, Cochin Hospital, Paris Descartes University, Pr Goldwasser. Funding: Has not received any funding. Disclosure: O. Huillard: Consultant/advisor: Astellas Pharma, Sanofi, Janssen Oncology, Bristol-Myers Squibb; Travel, accommodations reimburse: Roche/Genentech, Astellas Pharma, Pfizer; Sanofi. F. Goldwasser: Consultant/advisor: Fresenius Kabi, Baxter. J. Alexandre: Consultant/advisor: Novartis, Roche; Honoraria: Novartis, AstraZeneca, Roche, Ipsen; Research funding: Jansen; Travel, accommodations reimburse: Jansen. All other authors have declared no conflicts of interest.