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ASCO 2019 Annual Meeting

ASCO 2019: TAXOMET: Docetaxel Plus Metformin Versus Docetaxel Plus Placebo in Metastatic Castration Resistant Prostate Cancer

Chicago, IL (UroToday.com) Docetaxel is a standard of care in metastatic castration-resistant prostate cancer (mCRPC), however it is still a palliative treatment with a median overall survival of ~3 years in the first line setting. Thus, innovative strategies to improve survival outcomes are needed. The rationale for using metformin as an anti-cancer drug is such that since it decreases glucose metabolism in the cell, there is an effect on the mitochondria leading to cell cycle arrest.   There is also further rationale for combining docetaxel and metformin:

  • Metformin decreases prostate cancer incidence in a large cohort study (OR 0.84, 95% CI 0.74-0.96)1
  • Metformin improves time to castration-resistance and survival in prostate cancer diabetic patients compared to non-metformin users2
  • Metformin may be an effective chemosensitizer for docetaxel in preclinical models3
  • It is a well-known antidiabetic molecular, low cost, and with minimal side effects
As such, the addition of metformin could enhance docetaxel efficacy in mCRPC patients. Marc Martin, MD, and his colleagues from France presented results of their trial assessing the efficacy of metformin in combination with docetaxel.

TAXOMET is a phase II prospective multicenter randomized controlled trial. Non-diabetic mCRPC patients were assigned 1:1 to receive docetaxel 75 mg/m2 every 21 days plus prednisone 5 mg twice a day and either metformin 850 mg twice a day (arm A) or placebo (arm B), for up to 10 cycles. The primary endpoint was PSA response rate (≥50% decrease). Main secondary endpoints included objective response rate (ORR, according to RECIST v1.1), clinical and biological progression-free survival (PFS), overall survival (OS), toxicity and quality of life (QoL). Comparisons between arm A and B were performed using Chi² test for qualitative data and Log-rank test for survival data.
ASCO 2019 TAXOMET study design

From January 2013 to December 2015, there were 99 patients randomized in TAXOMET (50 pts in arm A and 49 pts in arm B) at 10 French centers, of which 95 patients were evaluable. The median age in arm A was 70 years (range 54-84) and 69 years (range 49-83) in arm B. The majority of patients in each arm were ECOG 0-1, and visceral metastases were well balanced between the two arms (14% in each). Over a median follow-up of 41.1 months (range 38.5-54.1), there was no difference observed between arm A and arm B in PSA-response rate (arm A 66%, arm B 63%; p=0.94), ORR (28% in both arms), clinical or biological mPFS (7.4 months vs 5.6 months p = 0.848) and median OS (24.6 months vs 19.7 months, p = 0.53), respectively.
ASCO 2019 TAXOMET survival ITT

There was no difference between arms in adverse events, except a trend for diarrhea to be more common with metformin (70% in arm A vs 50% in arm B, p = 0.072), but few grade 3-4 events. Furthermore, there were no hypoglycemic events and no toxic deaths. There was no difference in QoL according to QLQ-C30 score between the two arms during the treatment period.

Dr. Martin concluded his study with several take-home messages:
  • This is the first randomized controlled phase II trial testing the combination of metformin with docetaxel in mCRPC
  • The addition of metformin to docetaxel did not seem to have a meaningful clinical benefit in this setting
  • We are awaiting pending results of the standard of care + metformin in the STAMPEDE hormone-sensitive prostate cancer arm, which will likely report in 2024
Clinical trial information:  NCT01796028

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

Written by: Zachary Klaassen, MD, MSc, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md at the 2019 ASCO Annual Meeting #ASCO19, May 31-June 4, 2019, Chicago, IL USA

References:
  1. Preston MA, Riis AH, Ehrenstein V, et al. Metformin use and prostate cancer risk. Eur Urol 2014Dec;66(6):1012-1020.
  2. Spratt DE, Zhang C, Zumsteg ZS, et al. Metformin and prostate cancer: reduced development of castration-resistant disease and prostate cancer mortality. Eur Urol 2013 Apr;63(4):709-716.
  3. Mayer MJ, Klotz LH, Venkateswaran V. Evaluating metformin as a potential chemosensitizing agent when combined with docetaxel chemotherapy in castration-resistant prostate cancer cells. Anticancer Res 2017 Dec;37(12):6601-6607.