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CHICAGO -- Use of metformin didn't prevent progression of low-risk localized prostate cancer in patients on active surveillance, according to data from the randomized MAST study.

There was no statistically significant difference in progression-free survival (PFS) between patients treated with metformin and those receiving placebo when analyzing PFS using various definitions:

• Pathologic progression: HR 1.07 (95% CI 0.76-1.52, P=0.69)
• Therapeutic progression: HR 1.75 (95% CI 0.99-3.08, P=0.05)
• Therapeutic plus pathologic progression: HR 1.08 (95% CI 0.78-1.50, P=0.64)

"In each case clearly the metformin arm was not doing as well as the placebo arm," said Anthony Joshua, MBBS, PhD, of St. Vincent's Hospital in Sydney, who presented the findings at the American Society of Clinical Oncology (ASCO) annual meeting.

Moreover, Joshua said that exploratory subgroup analyses indicated there could be a potential detriment with metformin in patients with high body mass index (BMI) at study entry, as well as patients with Gleason score 8 or higher at progression.

The rationale for using metformin in prostate cancer "is persuasive," Joshua said. For example, a suggested that the use of metformin and statins, particularly in combination with abiraterone acetate (Zytiga) plus prednisone/prednisolone, resulted in prolonged overall survival and an improved prostate-specific antigen (PSA) response rate.

In addition, Joshua said, research has "documented such phenomena as metformin improving the local immune microenvironment in prostate cancer, improving overall survival in the SEER database, and reducing progression and improving overall survival in hormone-sensitive prostate cancer."

was a randomized double-blind trial conducted in 14 sites across Canada. Eligible patients had biopsy-proven, low-risk, localized prostate cancer diagnosed within the past 6 months, with a Gleason score ≤6 in no more than a third of the total cores, less than 50% positivity in any one core, a PSA level of ≤10 ng/mL, and a clinical stage between T1c-T2a.

The trial included 407 patients (median age 63) who chose active surveillance as their primary treatment. They were randomly assigned to receive metformin 850 mg twice daily or placebo for 3 years, with all patients undergoing repeat prostate biopsy at 18 and 36 months.

The primary endpoint was time to progression, defined as the earliest occurrence of primary prostate cancer therapy or pathological progression (more than a third of total cores involved, at least 50% of any one core involved, or Gleason pattern 4 or higher).

When looking at pathological progression endpoints, the researchers found that the first two were generally equivalent between groups, as was the percentage of patients who had a Gleason score ≥7 on progression.

However, in men who progressed with a Gleason score of ≥8, there was a trend toward an imbalance in men who took metformin, Joshua noted, at 12.9% versus 4.5% in the placebo group.

There also was an apparent interaction between BMI and metformin, as men with a BMI greater than 30 who took metformin had a worse PFS probability (unadjusted HR of 2.91, 95% CI 1.20-4.75, P=0.01).

On multivariable analysis, baseline PSA (HR 1.08, 95% CI 1.02-1.14), number of positive cores (HR 1.46, 95% CI 1.19-1.80), and log prostate volume (HR 0.68, 95% CI 0.53-0.88) were predictors of pathologic progression.

Toxicities were as expected, Joshua reported, with higher rates of diarrhea and other gastrointestinal symptoms in the metformin arm. Men in the metformin arm were also more likely to lose weight (1.8 and 1.4 kg, at 12 and 14 months) while men in the placebo arm gained about 0.5 kg.

Joshua acknowledged several study limitations, including the fact that accrual took place over a 10-year period, during which MRI use -- which was not controlled for during the study -- changed routine practice.

"The study raises more questions than answers," observed ASCO discussant Shahneen Sandhu, MD, PhD, of the Peter MacCallum Cancer Center and the University of Melbourne in Australia.

"We need to consider whether there are baseline tumor metabolic phenotypes that could make metformin more or less likely to alter pathology Gleason score/disease progression," she said. "Can we define, can we select a subset of patients that are likely to benefit or be harmed by this intervention?"

In addition, the BMI/metformin effect is "intriguing," Sandhu said. "Is increased BMI associated with some advantageous features within the tumor in this context that are altered by metformin, or is there a bigger impact from metformin on systemic metabolism in those with increased BMI?"

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