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Exposure-Response Assessment of Enzalutamide and Its Major Metabolites in a Real-World Cohort of Patients with Metastatic Castration-Resistant Prostate Cancer.

Authors
  • van Nuland, Merel1, 2
  • Bergman, Andries M3
  • Rosing, Hilde1
  • de Vries, Niels1
  • Huitema, Alwin D R1, 2, 4
  • Beijnen, Jos H1, 2, 5
  • 1 Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands. , (Netherlands)
  • 2 Division of Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands. , (Netherlands)
  • 3 Division of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands. , (Netherlands)
  • 4 Department of Clinical Pharmacy, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands. , (Netherlands)
  • 5 Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands. , (Netherlands)
Type
Published Article
Journal
Pharmacotherapy
Publication Date
Dec 01, 2019
Volume
39
Issue
12
Pages
1137–1145
Identifiers
DOI: 10.1002/phar.2339
PMID: 31596947
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Enzalutamide is an oral agent for the treatment of metastatic castration-resistant prostate cancer (mCRPC); N-desmethyl enzalutamide is its active metabolite, which has clinically relevant anti-androgen capacities similar to enzalutamide, and carboxylic acid enzalutamide is an inactive metabolite. The aim of our study was to investigate the relationship between enzalutamide and N-desmethyl enzalutamide exposure and treatment response in a real-world cohort of patients with mCRPC. Retrospective, observational, pharmacokinetic study. Outpatient clinic at a tertiary cancer center in Amsterdam, the Netherlands. Sixty-five patients with mCRPC who were treated with enzalutamide 160 mg daily and had at least one steady-state enzalutamide plasma concentration between May 2015 and June 2018; of these patients, 38 were prostate-specific antigen (PSA) responders and 27 were nonresponders. Plasma concentrations, determined by using liquid chromatography with tandem mass spectrometry (LC-MS/MS), were compared between PSA responders and nonresponders. Three clinical end points were evaluated separately in this study: PSA-independent progression-free survival (PFS), time to PSA progression (TTPP), and rate of PSA response (defined as ≥ 50% decrease in PSA level from baseline). Enzalutamide toxicity was defined as discontinuation due to adverse events, dose reductions due to adverse events, or temporary treatment interruption. For these analyses, plasma concentrations of enzalutamide and N-desmethyl enzalutamide were divided into quartiles. Mean ± SD plasma concentrations in the 65 patients were as follows: enzalutamide 11.2 ± 2.8 μg/ml, N-desmethyl enzalutamide 9.9 ± 2.9 μg/ml, and carboxylic acid enzalutamide 6.1 ± 4.3 μg/ml. Plasma concentrations were not significantly different in the PSA responder versus nonresponder groups for enzalutamide (11.5 vs 10.6 μg/ml, p=0.20), N-desmethyl enzalutamide (10.1 vs 9.6 μg/ml, p=0.48), and carboxylic acid enzalutamide (6.5 vs 5.5 μg/ml, p=0.34). Univariate and multivariate analyses did not show a relationship between plasma concentrations and PSA-independent PFS, TTPP, or toxicity. This study confirmed that enzalutamide plasma concentrations were not related to PSA-independent PFS, TTPP, or toxicity in patients with mCRPC, and demonstrated that plasma concentrations of its major metabolites were also not associated with treatment response. Based on these findings, there is no role for therapeutic drug monitoring of enzalutamide in patients with mCRPC in daily practice. © 2019 Pharmacotherapy Publications, Inc.

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