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

Anthony M. Joshua; Andrew Armstrong; Megan Crumbaker; Howard I. Scher; Johann de Bono; Bertrand Tombal; Maha Hussain; Cora N. Sternberg; Silke Gillessen; Joan Carles; Karim Fizazi; Ping Lin; William Duggan; Jennifer Sugg; David Russell; Tomasz M. Beer

doi:10.1016/j.ejca.2022.04.005

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

Anthony M. Joshua^*, Andrew Armstrong, Megan Crumbaker, Howard I. Scher, Johann de Bono, Bertrand Tombal, Maha Hussain, Cora N. Sternberg, Silke Gillessen, Joan Carles, Karim Fizazi, Ping Lin, William Duggan, Jennifer Sugg, David Russell, Tomasz M. Beer

^*Corresponding author for this work

Medicine, Hematology Oncology Division

Research output: Contribution to journal › Article › peer-review

18 Scopus citations

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).

Original language	English (US)
Pages (from-to)	285-295
Number of pages	11
Journal	European Journal of Cancer
Volume	170
DOIs	https://doi.org/10.1016/j.ejca.2022.04.005
State	Published - Jul 2022

Funding

This study was sponsored by Pfizer Inc. (New York, NY, USA) and Astellas Pharma, Inc . (Northbrook, IL, USA), the co-developers of enzalutamide. Medical writing and editorial support funded by the sponsors were provided by Stephanie Vadasz, PhD, and Dena McWain of Ashfield MedComms (an Ashfield Health company), Lauren Rainer, BSc, and Julie B. Stimmel, PhD, of Onyx (a Prime Global agency).

Keywords

Castration-resistant prostate cancer
Enzalutamide
Metformin
Overall survival
Radiographic progression-free survival
Statin

ASJC Scopus subject areas

Oncology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ejca.2022.04.005

Cite this

Joshua, A. M., Armstrong, A., Crumbaker, M., Scher, H. I., de Bono, J., Tombal, B., Hussain, M., Sternberg, C. N., Gillessen, S., Carles, J., Fizazi, K., Lin, P., Duggan, W., Sugg, J., Russell, D., & Beer, T. M. (2022). Statin and metformin use and outcomes in patients with castration-resistant prostate cancer treated with enzalutamide: A meta-analysis of AFFIRM, PREVAIL and PROSPER. European Journal of Cancer, 170, 285-295. https://doi.org/10.1016/j.ejca.2022.04.005

@article{6c19bedafd02479db0dd3e1a97474bd5,

title = "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",

author = "Joshua, {Anthony M.} and Andrew Armstrong and Megan Crumbaker and Scher, {Howard I.} and {de Bono}, Johann and Bertrand Tombal and Maha Hussain and Sternberg, {Cora N.} and Silke Gillessen and Joan Carles and Karim Fizazi and Ping Lin and William Duggan and Jennifer Sugg and David Russell and Beer, {Tomasz M.}",

note = "Publisher Copyright: {\textcopyright} 2022 The Pfizer, The Author(s)",

year = "2022",

month = jul,

doi = "10.1016/j.ejca.2022.04.005",

language = "English (US)",

volume = "170",

pages = "285--295",

journal = "European Journal of Cancer",

issn = "0959-8049",

publisher = "Elsevier Ltd",

}

Joshua, AM, Armstrong, A, Crumbaker, M, Scher, HI, de Bono, J, Tombal, B, Hussain, M, Sternberg, CN, Gillessen, S, Carles, J, Fizazi, K, Lin, P, Duggan, W, Sugg, J, Russell, D & Beer, TM 2022, 'Statin and metformin use and outcomes in patients with castration-resistant prostate cancer treated with enzalutamide: A meta-analysis of AFFIRM, PREVAIL and PROSPER', European Journal of Cancer, vol. 170, pp. 285-295. https://doi.org/10.1016/j.ejca.2022.04.005

TY - JOUR

T1 - Statin and metformin use and outcomes in patients with castration-resistant prostate cancer treated with enzalutamide

T2 - A meta-analysis of AFFIRM, PREVAIL and PROSPER

AU - Joshua, Anthony M.

AU - Armstrong, Andrew

AU - Crumbaker, Megan

AU - Scher, Howard I.

AU - de Bono, Johann

AU - Tombal, Bertrand

AU - Hussain, Maha

AU - Sternberg, Cora N.

AU - Gillessen, Silke

AU - Carles, Joan

AU - Fizazi, Karim

AU - Lin, Ping

AU - Duggan, William

AU - Sugg, Jennifer

AU - Russell, David

AU - Beer, Tomasz M.

PY - 2022/7

Y1 - 2022/7

N2 - 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).

AB - 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).

KW - Castration-resistant prostate cancer

KW - Enzalutamide

KW - Metformin

KW - Overall survival

KW - Radiographic progression-free survival

KW - Statin

UR - http://www.scopus.com/inward/record.url?scp=85130310825&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85130310825&partnerID=8YFLogxK

U2 - 10.1016/j.ejca.2022.04.005

DO - 10.1016/j.ejca.2022.04.005

M3 - Article

C2 - 35643841

AN - SCOPUS:85130310825

SN - 0959-8049

VL - 170

SP - 285

EP - 295

JO - European Journal of Cancer

JF - European Journal of Cancer

ER -

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

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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