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 ClinicalTrials.gov (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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- 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
- 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
- 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
- Abiraterone in metastatic prostate cancer without previous chemotherapy.N Engl J Med. 2013; 368: 138-148
- Anti-androgens and androgen-depleting therapies in prostate cancer: new agents for an established target.Lancet Oncol. 2009; 10: 981-991
- Molecular processes leading to aberrant androgen receptor signaling and castration resistance in prostate cancer.Expert Rev Endocrinol Metab. 2010; 5: 753-764
- Targeting the PI3K/Akt/mTOR pathway in castration resistant prostate cancer.Endocr Relat Cancer. 2013; 20: 83-99
- 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
- Prolonging hormone sensitivity in prostate cancer xenografts through dual inhibition of AR and mTOR.Br J Cancer. 2010; 103: 1001-1007
- Mechanism by which metformin reduces glucose production in type 2 diabetes.Diabetes. 2000; 49: 2063-2069
- Metformin and reduced risk of cancer in diabetic patients.BMJ. 2005; 330: 1304-1305
- 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
- Metformin enhances the antiproliferative and apoptotic effect of bicalutamide in prostate cancer.Prostate Cancer Prostatic Dis. 2012; 15: 346-352
- Combined treatment with exendin-4 and metformin attenuates prostate cancer growth.PLoS One. 2015; 10: e0139709
- The underlying basis for obesity: relationship to cancer.J Nutr. 2002; 132: 3451S-3455S
- Association of diet-induced hyperinsulinemia with accelerated growth of prostate cancer (LNCaP) xenografts.J Natl Cancer Inst. 2007; 99: 1793-1800
- Metformin is an AMP kinase–dependent growth inhibitor for breast cancer cells.Cancer Res. 2006; 66: 10269-10273
- mTOR, translation initiation and cancer.Oncogene. 2006; 25: 6416-6422
- Metformin in chemotherapy-naive castration resistant prostate cancer: a multicenter phase 2 trial (SAKK 08/09).Eur Urol. 2014; 66: 468-474
- 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
- ICH harmonized tripartite guideline: guideline for good clinical practice.J Postgrad Med. 2001; 47: 45-50
- Common Terminology Criteria for Adverse Events (CTCAE) v4.0.(Available at:)https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htmDate accessed: January 12, 2019
- 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
- Targeting autophagy overcomes enzalutamide resistance in castration-resistant prostate cancer cells and improves therapeutic response in a xenograft model.Oncogene. 2014; 33: 4521-4530
- Metformin reverses prostate cancer resistance to enzalutamide by targeting TGF-β1/STAT3 axis-regulated EMT.Cell Death Dis. 2017; 8: e3007
- Metformin: a bridge between diabetes and prostate cancer.Front Oncol. 2017; 7: 243
- Metformin represses androgen-dependent and androgen-independent prostate cancers by targeting androgen receptor.Prostate. 2015; 75: 1187-1196
- Glucocorticoid receptor confers resistance to antiandrogens by bypassing androgen receptor blockade.Cell. 2013; 155: 1309-1322
- 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
- Repurposing metformin as therapy for prostate cancer within the Stampede platform.Eur Urol. 2016; 70: 906-908
Published online: January 02, 2019
Accepted: December 26, 2018
Received in revised form: December 23, 2018
Received: October 29, 2018
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