Original Study| Volume 17, ISSUE 2, e323-e328, April 2019

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Impact of Addition of Metformin to Abiraterone in Metastatic Castration-Resistant Prostate Cancer Patients With Disease Progressing While Receiving Abiraterone Treatment (MetAb-Pro): Phase 2 Pilot Study

Published:January 02, 2019DOI:



      There is evidence linking metformin to improved prostate cancer–related outcomes.

      Patients and Methods

      Twenty-five men with metastatic castration-resistant prostate cancer and prostate-specific antigen (PSA) progression while receiving treatment with abiraterone from 3 Swiss centers were included in this single-arm phase 2 trial between November 2013 and September 2016. Metformin was added to abiraterone continuously at 1000 mg twice daily in uninterrupted 4-week cycles. The primary end point was the absence of disease progression at 12 weeks (PFS12). The Fleming single-stage design was applied. With a 5% significance level and 80% power, 25 patients were required to test PFS12 ≤ 15% (H0) compared to ≥ 35% (H1). Secondary end points included toxicity and safety issues. The study was registered at (NCT01677897).


      The primary end point PFS12 was 12% (3 of 25 patients) (95% confidence interval, 3-31). Most patients had PSA progression, almost half had radiographic progression, but only 1 patient had symptomatic progression. Eleven (44%) of 25 patients had grade 1 and 2 patients each grade 2 (8%) or grade 3 (8%) gastrointestinal toxicity (nausea, diarrhea, loss of appetite). One patient discontinued treatment at week 5 because of intolerable grade 3 diarrhea.


      The addition of metformin to abiraterone for patients with metastatic castration-resistant prostate cancer and PSA progression while receiving abiraterone therapy does not affect further progression and has no meaningful clinical benefit. A higher-than-expected gastrointestinal toxicity attributed to metformin was observed.


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        • Gillessen S.
        • Omlin A.
        • Attard G.
        • et al.
        Management of patients with advanced prostate cancer: recommendations of the St Gallen Advanced Prostate Cancer Consensus Conference (APCCC) 2015.
        Ann Oncol. 2015; 26: 1589-1604
        • Attard G.
        • Belldegrun A.S.
        • de Bono J.S.
        Selective blockade of androgenic steroid synthesis by novel lyase inhibitors as a therapeutic strategy for treating metastatic prostate cancer.
        BJU Int. 2005; 96: 1241-1246
        • Jarman M.
        • Barrie S.E.
        • Llera J.M.
        The 16,17-double bond is needed for irreversible inhibition of human cytochrome p45017alpha by abiraterone (17-(3-pyridyl) androsta-5,16-dien-3beta-ol) and related steroidal inhibitors.
        J Med Chem. 1998; 41: 5375-5381
        • Ryan C.J.
        • Smith M.R.
        • de Bono J.S.
        • et al.
        Abiraterone in metastatic prostate cancer without previous chemotherapy.
        N Engl J Med. 2013; 368: 138-148
        • Chen Y.
        • Clegg N.J.
        • Scher H.I.
        Anti-androgens and androgen-depleting therapies in prostate cancer: new agents for an established target.
        Lancet Oncol. 2009; 10: 981-991
        • Hu R.
        • Denmeade S.R.
        • Luo J.
        Molecular processes leading to aberrant androgen receptor signaling and castration resistance in prostate cancer.
        Expert Rev Endocrinol Metab. 2010; 5: 753-764
        • Bitting R.L.
        • Armstrong A.J.
        Targeting the PI3K/Akt/mTOR pathway in castration resistant prostate cancer.
        Endocr Relat Cancer. 2013; 20: 83-99
        • Schayowitz A.
        • Sabnis G.
        • Njar V.C.O.
        • et al.
        Synergistic effect of a novel antiandrogen, VN/124-1, and signal transduction inhibitors in prostate cancer progression to hormone independence in vitro.
        Mol Cancer Ther. 2008; 7: 121-132
        • Schayowitz A.
        • Sabnis G.
        • Goloubeva O.
        • et al.
        Prolonging hormone sensitivity in prostate cancer xenografts through dual inhibition of AR and mTOR.
        Br J Cancer. 2010; 103: 1001-1007
        • Hundal R.S.
        • Krssak M.
        • Dofour S.
        • et al.
        Mechanism by which metformin reduces glucose production in type 2 diabetes.
        Diabetes. 2000; 49: 2063-2069
        • Evans J.M.
        • Donnelly L.A.
        • Emslie-Smith A.M.
        • et al.
        Metformin and reduced risk of cancer in diabetic patients.
        BMJ. 2005; 330: 1304-1305
        • Hwang I.C.
        • Park S.M.
        • Shin D.
        • et al.
        Metformin association with lower prostate cancer recurrence in type 2 diabetes: a systematic review and meta-analysis.
        Asian Pac J Cancer Prev. 2015; 16: 595-600
        • Colquhoun A.J.
        • Venier N.A.
        • Vandersluis A.D.
        • et al.
        Metformin enhances the antiproliferative and apoptotic effect of bicalutamide in prostate cancer.
        Prostate Cancer Prostatic Dis. 2012; 15: 346-352
        • Tsutsumi Y.
        • Nomiyama T.
        • Kawanami T.
        • et al.
        Combined treatment with exendin-4 and metformin attenuates prostate cancer growth.
        PLoS One. 2015; 10: e0139709
        • Bray G.A.
        The underlying basis for obesity: relationship to cancer.
        J Nutr. 2002; 132: 3451S-3455S
        • Venkateswaran V.
        • Haddad A.Q.
        • Fleshner N.E.
        • et al.
        Association of diet-induced hyperinsulinemia with accelerated growth of prostate cancer (LNCaP) xenografts.
        J Natl Cancer Inst. 2007; 99: 1793-1800
        • Zakikhani M.
        • Dowling R.
        • Fantus I.G.
        • et al.
        Metformin is an AMP kinase–dependent growth inhibitor for breast cancer cells.
        Cancer Res. 2006; 66: 10269-10273
        • Mamane Y.
        • Petroulakis E.
        • LeBacquer O.
        • et al.
        mTOR, translation initiation and cancer.
        Oncogene. 2006; 25: 6416-6422
        • Rothermundt C.
        • Hayoz S.
        • Templeton A.J.
        • et al.
        Metformin in chemotherapy-naive castration resistant prostate cancer: a multicenter phase 2 trial (SAKK 08/09).
        Eur Urol. 2014; 66: 468-474
        • Templeton A.J.
        • Dutoit V.
        • Cathomas R.
        • et al.
        Phase 2 trial of single-agent everolimus in chemotherapy-naive patients with castration-resistant prostate cancer (SAKK 08/08).
        Eur Urol. 2013; 64: 150-158
      1. ICH harmonized tripartite guideline: guideline for good clinical practice.
        J Postgrad Med. 2001; 47: 45-50
        • National Institutes of Health; National Cancer Institute; Division of Cancer Treatment and Diagnosis
        Common Terminology Criteria for Adverse Events (CTCAE) v4.0.
        (Available at:)
        • Scher H.I.
        • Halabi S.
        • Tannock I.
        • et al.
        Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group.
        J Clin Oncol. 2008; 26: 1148-1159
        • Nguyen H.G.
        • Yang J.C.
        • Kung H.J.
        • et al.
        Targeting autophagy overcomes enzalutamide resistance in castration-resistant prostate cancer cells and improves therapeutic response in a xenograft model.
        Oncogene. 2014; 33: 4521-4530
        • Liu Q.
        • Tong D.
        • Liu G.
        • et al.
        Metformin reverses prostate cancer resistance to enzalutamide by targeting TGF-β1/STAT3 axis-regulated EMT.
        Cell Death Dis. 2017; 8: e3007
        • Zingales V.
        • Distefano A.
        • Raffaele M.
        • et al.
        Metformin: a bridge between diabetes and prostate cancer.
        Front Oncol. 2017; 7: 243
        • Wang Y.
        • Liu G.
        • Tong D.
        • et al.
        Metformin represses androgen-dependent and androgen-independent prostate cancers by targeting androgen receptor.
        Prostate. 2015; 75: 1187-1196
        • Arora V.K.
        • Schenkein E.
        • Murali R.
        • et al.
        Glucocorticoid receptor confers resistance to antiandrogens by bypassing androgen receptor blockade.
        Cell. 2013; 155: 1309-1322
        • Zhao Y.
        • Gong C.
        • Wang Z.
        • et al.
        A randomized phase II study of aromatase inhibitors plus metformin in pre-treated postmenopausal patients with hormone receptor positive metastatic breast cancer.
        Oncotarget. 2017; 8: 84224-84236
        • Gillessen S.
        • Gilson C.
        • James N.
        • et al.
        Repurposing metformin as therapy for prostate cancer within the Stampede platform.
        Eur Urol. 2016; 70: 906-908