Statin and metformin use and outcomes in patients with castration-resistant prostate cancer treated with enzalutamide: A meta-analysis of AFFIRM, PREVAIL and PROSPER

Abstract

Background: Statins and metformin are commonly prescribed for patients, including those with prostate cancer. Preclinical and epidemiologic studies of each agent have suggested anti-cancer properties.

Methods: Patient data from three randomised, double-blind, placebo-controlled, phase III studies evaluating enzalutamide (AFFIRM, PREVAIL and PROSPER) in patients with castration-resistant prostate cancer were included in this analysis. This post hoc, retrospective study examined the association of statin and metformin on radiographic progression-free survival (rPFS), metastasis-free survival (MFS), toxicity and overall survival (OS). After adjusting for available clinical prognostic variables, multivariate analyses were performed on pooled data from AFFIRM and PREVAIL, all three trials pooled, and each trial individually, to assess differential efficacy in these end-points associated with the baseline use of these medications.

Results: In the multivariate analysis of the individual trials, OS and rPFS/MFS were not significantly influenced by statin or metformin use in AFFIRM or PROSPER. However, in PREVAIL, OS was significantly influenced by statin (hazard ratio [HR] 0.72; 95% confidence interval [CI] 0.59-0.89) and rPFS was significantly influenced by metformin (HR, 0.48; 95% CI 0.34-0.70). In pooled analyses, improved OS was significantly associated with statin use but not metformin use for AFFIRM+PREVAIL trials (HR 0.83; 95% CI 0.72-0.96) and AFFIRM+PREVAIL+PROSPER (HR 0.75; 95% CI 0.66-0.85).

Conclusions: The association between statin or metformin use and rPFS, MFS and OS was inconsistent across three trials. Analyses of all three trials pooled and AFFIRM+PREVAIL pooled revealed that statin but not metformin use was significantly associated with a reduced risk of death in enzalutamide-treated patients. Additional prospective, controlled studies are warranted.

Clinical trial registration: AFFIRM (NCT00974311), PREVAIL (NCT01212991) and PROSPER (NCT02003924).

Keywords: Castration-resistant prostate cancer; Enzalutamide; Metformin; Overall survival; Radiographic progression-free survival; Statin.

Conflict of interest statement

Conflict of interest statement AMJ declares consultant/advisory board member for Neokulin, Janssen Oncology, Ipsen, AstraZeneca, Sanfoi, Noxopharm, IQvia, Pfizer, Novartis, Bristol Myers Squibb, Merck Serono, Eisai. AMJ has received research funding from: Bristol Myers Squibb, Janssen Oncology, Merck Sharp & Dohme, Mayne Pharma, Roche/Genetech, Bayer, Macrogenics, Lilly, Pfizer, AstraZeneca, and Corvus Pharmaceuticals. AA is a paid consultant for and/or receives institutional funding from Astellas, Pfizer, Janssen, Bayer, Dendreon, Genentech/Roche, Bristol Myers Squibb, Merck, and AstraZeneca. AA provides research support to Duke University from Constellation, Beigene, Amgen, Celgene, and Forma. MC has received honoraria from Pfizer and Merck Healthcare. HIS declares consultant/advisory board member for Ambry Genetics Corporation, Amgen, Bayer, ESSA Pharma, Janssen Biotech, Janssen Research & Development, OncLive Insights, Menarini Silicon Biosystems, Physicians Education Resource, Pfizer, Sanofi Aventis, Sun Pharmaceuticals Industries, Inc. and WCG Oncology; Board of Directors’ Member of Asterias Biotherapeutics; Intellectual Property Rights BioNTech, Elucida Oncology, MaBVAX, Y-mAbs Therapeutics, Inc and institutional research funding from Epic Sciences, Illumina, Janssen Diagnostics, Menarini Silicon Biosystems, and ThermoFisher. JDB has served on advisory boards and received fees from Amgen, Astellas, AstraZeneca, Bayer, Bioxcel Therapeutics, Boehringer Ingelheim, Cellcentric, Daiichi, Eisai, Genentech Roche, Genmab, GlaxoSmithKline, Harpoon, Janssen, Menarini Silicon Biosystems, Merck Serono, Merck Sharp & Dohme, Orion Pharma, Pfizer, Qiagen, Sanofi Aventis, Sierra Oncology, Taiho, Terumo, Vertex Pharmaceuticals. He is an employee of the ICR, which has received funding or other support for his research work from Astellas, AstraZeneca, Bayer, Cellcentric, Daiichi, Genentech Roche, Genmab, GlaxoSmithKline, Harpoon, Janssen, Merck Serono, Merck Sharp & Dohme, Orion Pharma, Pfizer, Sanofi Aventis, Sierra Oncology, Taiho, Vertex Pharmaceuticals, and which has a commercial interest in abiraterone, PARP inhibition in DNA repair defective cancers and PI3K/AKT pathway inhibitors (no personal income). He was named as an inventor, with no financial interest, for patent 8,822,438. BT has financial or personal interests with AAA International, Astellas, Bayer, Ferring, Janssen, Myovant and Sanofi. MH over the last three years reports receiving lecture fees and travel support from Astellas Pharma, grant support, paid to Northwestern University, from AstraZeneca, grant support, paid to Northwestern University, and advisory board fees from Bayer, advisory board fees from Daiichi Sankyo, Bristol Myers Squibb, grant support, paid to Northwestern University, and advisory board fees from Genentech, grant support, paid to the University of Michigan, from Pfizer, and lecture fees from Sanofi and Genzyme. CNS is a consultant for Pfizer, Merck Sharp & Dohme, Merck, AstraZeneca, Astellas, Sanofi-Genzyme Roche-Genentech, Incyte, Clovis Oncology, Inc, Medscape, UroToday, Janssen Oncology, Foundation Medicine, Bristol Meyers Squibb, Immunomedics (now Gilead). SG in the last three years has received honoraria compensation from Janssen Cilag; served in a consulting or advisory role (including IDMC) to Astellas Pharma, Amgen, Roche, Pfizer, AAA International, Janssen, Innocrin Pharma Inst, Sanofi, Bayer, Orion Pharma GmbH, Clovis Oncology, Menarini Silicon Biosystems, Tolero Pharmaceuticals and Merck Sharp & Dohme; Patents, royalties, other intellectual property include Method for biomarker WO2009138392; Travel grant from ProteoMediX; Other relationships include Aranda. JC is a paid consultant with Amgen, Astellas, Bayer, Bristol Myers Squibb, Merck Sharp & Dohme, Johnson & Johnson, Sanofi, Pfizer; is a member of the Speakers Bureau for Astellas, Bayer, Johnson & Johnson; has engaged in institutional study collaboration with AB Science, Aragon Pharmaceuticals, Arog Pharmaceuticals, Inc, Astellas Pharma., AstraZeneca AB, Aveo Pharmaceuticals Inc, Bayer AG, Blueprint Medicines Corporation, BN Immunotherapeutics Inc, Boehringer Ingelheim España, S.A., Bristol Myers Squibb International Corporation, Clovis Oncology, Inc, Cougar Biotechnology Inc, Deciphera Pharmaceuticals LLC, Exelixis Inc, F. Hoffmann-La Roche LTD, Genentech Inc, Glaxosmithkline, SA, Incyte Corporation, Janssen-Cilag International NV, Karyopharm Therapeutics Inc, Laboratoires Leurquin Mediolanum SAS, Lilly, S.A., Medimmune, Millennium Pharmaceuticals, Inc, Nanobiotix SA, Novartis Farmacéutica, S.A., Pfizer, S.L.U, Puma Biotechnology, Inc, Sanofi-Aventis, S.A., SFJ Pharma LTD. II, Teva Pharma S.L.U. KF has participated on advisory boards and symposia for: Astellas, Bayer, Clovis, Curevac, Janssen, Merck Sharp & Dohme, Orion, Sanofi. PL declares no conflict of interest. WD is an employee of Pfizer and owns stock in the company. JS is an employee of Astellas. DR is an employee of Pfizer. TMB in the past year reports: institutional research funding from Alliance Foundation Trials, Astellas Pharma, Bayer, Boehringer Ingelheim, Corcept Therapeutics, Endocyte Inc., Freenome, Grail Inc, Harpoon Therapeutics, Janssen Research & Development, Medivation, Inc., Sotio, Theraclone Sciences/OncoResponse, and Zenith Epigenetics; has consulted for: Arvinas, Astellas Pharma, AstraZeneca, Bayer, Bristol Myers Squibb, Constellation, Grail Inc, Janssen, Myovant Sciences, Pfizer, and Sanofi, and holds stock in Arvinas Inc, and Salarius Pharmaceuticals.

Copyright © 2022 The Pfizer, The Author(s). Published by Elsevier Ltd.. All rights reserved.