ASCO 2019: TAXOMET: A French Prospective Multicenter Randomized Controlled Phase II Study Comparing Docetaxel Plus Metformin Versus Docetaxel Plus Placebo in mCRPC - Medical Oncologist Perspective

Chicago, IL (UroToday.com) Docetaxel is an approved therapy for the treatment of both metastatic hormone sensitive prostate cancer (mHSPC) and metastatic castration-resistant prostate cancer (mCRPC). CHAARTED demonstrated that patients receiving docetaxel for mHSPC with high volume disease had a median overall survival (OS) of 57.6 months compared with 47.2 months for those who did not receive upfront chemotherapy.1 In the mCRPC setting, TAX 327 demonstrated that when compared with mitoxantrone, docetaxel improved median overall survival from 16.5 months to 18.9 months.2


In preclinical models, metformin, a commonly used oral diabetes medication, has demonstrated anti-neoplastic effects in many solid tumors including colon cancer, pancreatic cancer, and breast cancer.3 Its mechanism of action is thought to be related to activation of the AMP-activated protein kinase (AMPK) pathway, inhibiting the expression of genes involved in cell cycle regulation and mitosis. The relationship between metformin and prostate cancer is controversial. Preclinic studies in prostate cancer cell lines have suggested that metformin is able to reduce cyclin D1 activity, activate the AMPK pathway, and inhibit mTOR signaling.
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In the clinical setting, retrospective data is mixed. Two large retrospective studies have not found any prostate cancer-specific survival benefit. However, a recent large meta-analysis which included 30 different studies and 1.6 million patients suggested that metformin use improved overall survival (HR = 0.72), prostate cancer-specific survival (hazard ratio (HR)= 0.78), and recurrence-free survival (HR=0.60). Prospective data in this setting is lacking. In this study, Marc Martin, MD and colleagues describe the results of a prospective multicenter randomized controlled phase II study comparing docetaxel plus metformin versus docetaxel plus placebo in mCRPC.
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This abstract provides data on 99 non-diabetic patients with mCRPC who were randomly assigned in a 1:1 ratio to docetaxel 75mg/m2 every 21 days + prednisone 5 mg twice a day and either metformin 850mg twice a day (arm A) or placebo (arm B), up to 10 cycles. (Arm A = metformin A, Arm B = placebo arm). The primary endpoint of this study was PSA50 (≥50% decrease).
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Patients were well balanced in both arms.

In terms of the primary endpoint, there was no difference in PSA50 (72% in both arms). In terms of the secondary objectives, there was also no difference in objective response rates (28% in both arms), clinical median progression-free survival (mPFS) (7.3 months vs 5.8 months p = 0.848), and no difference in median overall survival (24.2 months vs 19.7 months, p = 0.53). Patients receiving metformin had a higher incidence of diarrhea which is a known side effect of metformin.
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The quality of life was measured with the QLQ-C30 questionnaire and there was no difference here either.
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For patients with mCRPC without diabetes, the addition of metformin to docetaxel chemotherapy does not improve PSA50, objective response rates, mPFS, or OS. This could suggest that either metformin is not clinically active for patients with CRPC, or that docetaxel may not be the right partner drug to be used in combination with metformin, or that the CRPC setting may not be the right disease state. The authors also suggested that perhaps if metformin had been continued at progression instead of discontinued at the same time as chemotherapy, this may have made an effect as the benefits may be more long term.

Presented by: Marc Pujalte Martin, MD, Centre Antoine Lacassagne, Nice, France 

Written by: Jason Zhu, MD. Fellow, Division of Hematology and Oncology, Duke University, @TheRealJasonZhu, at the 2019 ASCO Annual Meeting #ASCO19, May 31- June 4, 2019, Chicago, IL USA

References:
  1. Kyriakopoulos CE, Chen Y-H, Carducci MA, et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer: long-term survival analysis of the randomized phase III E3805 CHAARTED trial. Journal of Clinical Oncology 2018;36:1080.
  2. Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus Prednisone or Mitoxantrone plus Prednisone for Advanced Prostate Cancer. New England Journal of Medicine 2004;351:1502-12.
  3. He K, Hu H, Ye S, Wang H, Cui R, Yi L. The effect of metformin therapy on incidence and prognosis in prostate cancer: A systematic review and meta-analysis. Scientific reports 2019;9:2218.
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