The hypoglycemic agent metformin failed to slow disease progression in men with low-risk localized prostate cancer undergoing active surveillance, according to the results of the randomized, controlled MAST trial reported at the 2024 ASCO Annual Meeting.1 In addition, the use of metformin was associated with increased gastrointestinal side effects and fatigue.
“Unfortunately, there was no benefit for metformin in this particular group of patients, and that is disappointing. During exploratory analysis, we noted that men with a higher body mass index [BMI] who received metformin had higher rates of disease progression and slightly more high-grade disease compared to men on placebo,” said Anthony M. Joshua, MBBS, PhD, FRACP, of Princess Margaret Cancer Centre, Toronto.
Men diagnosed with low-risk prostate cancer have three recommended options: watchful waiting, where interventions are event-driven; active surveillance, which includes periodic prostate biopsies and is designed to avoid short-term morbidity; and definitive therapy such as surgery or radiation therapy.
Metformin is approved for the treatment of type 2 diabetes but is thought by many to have an anticancer effect. In an observational study about 20 years ago, the use of metformin was associated with a reduced incidence of cancer in people with type 2 diabetes. Since then, numerous preclinical, epidemiologic, and meta-analytic studies suggested the drug has anticancer effects, including in prostate cancer. “This has given rise to a variety of off-label uses of the drug,” Dr. Joshua said. However, about 30% of patients taking metformin develop gastrointestinal side effects, he noted.
Glucose metabolism is involved in tumor angiogenesis, and metformin inhibits glucogenesis. Animal studies have suggested that metformin may slow cancer progression and make cells more sensitive to cytotoxic therapy; however, level 1 evidence is lacking in humans. The MAST trial was designed to determine whether metformin could slow prostate cancer progression in men with low-risk prostate cancer undergoing active surveillance.
MAST Details
Active surveillance is recommended by the American Urological Association for the management of low-risk, localized prostate cancer. This approach tracks disease progression by serial biopsies and/or imaging, and patients are treated at signs of disease progression, thus avoiding exposure to more toxic drugs.
The randomized, double-blind, placebo-controlled MAST trial was conducted at 12 health-care sites in Canada. A total of 407 participants undergoing active surveillance for low-risk localized prostate cancer were randomly assigned 1:1 to receive active surveillance with metformin (arm 1) or placebo (arm 2). Treatment was metformin at 850 mg twice daily or placebo for 3 years. The primary endpoint was time to primary prostate cancer therapy or pathologic disease progression, as identified by serial biopsies performed at baseline, 18 months, and 36 months.
Participants had low-risk or very low–risk prostate cancer, as documented on biopsy. Enrollment criteria stipulated fewer than one-third positive cores or less than 50% of positivity in one core; prostate-specific antigen (PSA) level of ≤ 10 ng/mL; and clinical stage T1c to T2a disease within 8 months of screening.
Key Results
Progression-free survival was similar between the groups. The unadjusted hazard ratio was 1.08 for therapeutic and pathologic disease progression combined; 1.07 for pathologic disease progression alone; and 1.75 for therapeutic disease progression alone. “In each case, the metformin arm did not do as well as the placebo arm,” Dr. Joshua said.
An exploratory subgroup analysis suggested that patients with higher BMI and a Gleason score of at least 8 at disease progression fared worse on metformin. In patients with a BMI greater than 30 kg/m2, those given metformin had worse progression-free survival compared with those given placebo (P = .01), “suggesting these men had a detriment from taking metformin,” he said.
In men who experienced disease progression who had a Gleason score of at least 7 on disease progression, a trend was observed toward greater disease progression in the metformin-treated group (19.9% vs 4.5%). Multivariate analysis identified three factors of pathologic disease progression: baseline PSA level, number of positive cores, and log prostate volume.
Patients in the study who received metformin had a higher incidence of diarrhea, bloating, abdominal pain, decreased appetite, and fatigue compared with the placebo group.
Expert Point of View
“Metformin is thought to elicit an anticancer effect [via several mechanisms]…. It is inexpensive, largely well tolerated, and widely available, thus driving interest in repurposing metformin as an adjunctive anticancer drug. However, we lack rigorous studies to support its use in patients with cancer,” stated invited discussant of the MAST trial, Shahneen Sandhu, MBBS, FRACP, of Peter MacCallum Cancer Centre and the University of Melbourne, Australia. “It is valuable to have a prospective study of metformin, but this study raises more questions than answers,” she added.
According to Dr. Sandhu, it might be possible to define subsets of patients who may benefit or be harmed by the use of metformin. “Proteomic and metabolic analyses of serial biopsies are likely to be informative. We need to consider whether there are baseline tumor metabolic phenotypes that could make metformin more or less likely to alter pathology and Gleason score or disease progression,” she noted.
The interaction between metformin and body mass index (BMI) suggested in the exploratory analysis is “intriguing,” Dr. 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?”
DISCLOSURE: Dr. Joshua reported no conflicts of interest related to this work. Dr. Sandhu has received research support or has financial relationships with AstraZeneca, Bristol Myers Squibb, Janssen, Merck, AbbVie, BMS/Roche, Merck Sharp & Dohme, Novartis, Skyline Diagnostics, Advanced Accelerator Applications/Novartis, Amgen, Pfizer, and Senhwa Biosciences.
REFERENCE
1. Fleshner NE, Bernardino RM, Lajkosz K, et al: A randomized, double-blind, placebo-controlled trial of metformin in reducing progression among men on expectant management for low-risk prostate cancer. 2024 ASCO Annual Meeting. Abstract LBA5002. Presented June 2, 2024.
