MAST: Metformin to Reduce Progression in Men on Management for Low-Risk PCa

In the Oral Abstract Session dedicated to genitourinary cancer (prostate, testicular, and penile cancers) held on Saturday, June 1, 2024, at this year’s American Society of Clinical Oncology Annual Meeting in Chicago, Dr. Anthony Joshua presented results of the MAST trial evaluating the role of metformin to reduce progression among men undergoing active surveillance for low-risk prostate cancer (PCa).

Over the past 2 decades, active surveillance has become not just an accepted approach, but the preferred treatment approach for men diagnosed with low-risk PCa. While the goal of active surveillance is to avoid the toxicity associated with curative-intent PCa treatments, patients are at risk of disease progression. Researchers have previously studied a number of approaches—ranging from dietary manipulations to pharmaceuticals, including 5-alpha reductase inhibitors and enzalutamide—with the goal of reducing the risk of progression. Metformin, a biguanide oral hypoglycemic widely used in the treatment of diabetes, has been associated with favorable oncologic effects for patients with PCa.

In the MAST trial (NCT01864096), Dr. Joshua and colleagues sought to assess the effect of metformin on PCa progression with low-risk localized PCa on active surveillance. To do so, they performed a multicenter, randomized trial among 14 Canadian centers. Enrolled patients must have already opted for active surveillance for low-risk, biopsy-proven PCa, defined as Gleason score <6 observed in one-third or less of the total cores, less than 50% positivity in any one core, prostate-specific antigen level ≤10 ng/ml, and a clinical stage between T1c-T2a. Importantly, patients could not have a diagnosis of diabetes, elevated hemoglobin A1c, or prior PCa treatment.

Eligible patients were randomized (1:1) to receive either metformin 850 mg BID or placebo for 3 years. All patients underwent repeat prostate biopsy at 18 and 36 months in keeping with active surveillance protocols. The primary end point was time to progression, defined as the earliest occurrence of primary PCa therapy (eg, prostatectomy, radiation, hormonal therapy) or pathological progression (less than one-third of total cores involved, at least 50% of any one core involved, or Gleason pattern ≥4). The authors also assessed each of these end points individually.

A total of 407 patients were enrolled in the study, of whom 204 were administered metformin and 203 received placebo. The median age of the overall cohort was 63 years.

Among the 407 enrolled patients, 141 experienced disease progression. No statistically significant difference in progression-free survival (PFS) was observed between patients treated with metformin and those receiving placebo (hazard ratio [HR], 1.06; 95% CI, 0.78-1.50; P=.63). There were no differences in either pathological progression (HR, 1.07; 95% CI, 0.76-1.52; P=.69) or therapeutic progression (HR, 1.75; 95% CI, 0.99-3.06; P=.05) when these end points were examined independently. Of interest, when examining the pathological progression end point, rates of progression due to an increased number of involved cores (48.4% vs 47.8%), maximum core involvement (45.2% vs 44.8%), and upgrading to Gleason score ≥7 (69.4% vs 65.7%) were similar, though patients receiving metformin were somewhat more likely to have upgrading to Gleason score ≥8 (12.9% vs 4.5%; P=.082).

Subgroup analyses showed that receipt of metformin was associated with a significantly increased risk of disease progression in men with a body mass index (BMI) of 30 or greater (HR, 2.39; 95% CI, 1.20-4.75; P=.01), though this effect was notably not significant for those with a BMI less than 30.

Dr. Joshua concluded that, in spite of suggestive preclinical and epidemiological data supporting metformin as a treatment to reduce PCa progression, the MAST trial failed to show a benefit in progression for men on active surveillance for low-risk PCa.