Metformin is the most widely used oral antidiabetic drug worldwide. It inhibits hepatic glycogen isogenesis while increasing insulin sensitivity in peripheral tissues to lower blood glucose and insulin concentrations. The retrospective findings that metformin may reduce cancer risk and death in diabetic patients have prompted many preclinical and clinical studies to explore the anticancer activity of metformin. Collated below: Recently, Sil Kordes and colleagues reported one of the first results from a prospective study of metformin in the journal Lancet Oncology. Their randomized phase 2 study evaluated the primary survival endpoint of metformin in combination with gemcitabine and erlotinib in patients with advanced pancreatic cancer. The study was designed to find a significant benefit of metformin application in pancreatic cancer – one of the most deadly and aggressive malignancies. The defined sample size (129 patients) was based on detecting a 50% increase in survival at 6 months – from 50% to 75% – and a P value of 80%. The study found benefit beyond that of FOLFIRINOX compared with gemcitabine (58% to 75%) and gemcitabine + albumin-bound paclitaxel compared with gemcitabine (58% to 70%). With a total of 121 patients in the study cohort, the trial was not sufficient to detect a P value but still a clinically meaningful benefit from metformin. However, this study is very important and its results raise several points of reflection. It is reassuring that metformin was well tolerated in combination with gemcitabine and erlotinib. The report showed no increase in the occurrence of grade 3 or 4 toxicities, and non-diabetic patients treated with metformin did not progress to hypoglycemia. Nevertheless, treatment discontinuation due to toxicities was more common in patients treated with metformin compared with those treated with placebo (13/60 [22%] vs 8/61 [13%]), which may also have contributed to the shorter median treatment duration in the metformin group; however, progressive disease remained the most common cause of treatment discontinuation. Overall survival at 6 months was 63.9% (95% CI, 51.9 to 75.9) in the placebo group and 56.7% (44.1 to 69.2) in the metformin group; the hazard ratio [HR] was 1.056 ([95% CI 0.72 to 1.55]; P=0.78). The fact that the study failed to meet the primary endpoint of a 50% increase in overall survival is disappointing, but not surprising. Pancreatic cancer is a complex disease, and the addition of targeted agents to gemcitabine did not produce a significant survival benefit in the non-selected population. One of the main mechanisms of action for the antitumor activity of metformin is thought to be downregulation of insulin receptor signaling. To investigate this mechanism, this study investigated the correlation between dynamic changes in blood concentrations of insulin, IGF-1, and IGFBP-3 and patient survival. Although patients treated with metformin therapy for reduced insulin concentrations appear to have an improved survival prognosis, the results are too early to draw a conclusion. The lack of tumor tissue in the relevant studies hinders the opportunity to identify subgroups of patients who may benefit clinically from metformin. Metformin inhibits complex I of the mitochondrial respiratory chain, thereby reducing intracellular oxidative phosphorylation and ATP production. This inhibition strains energy production, potentially leading to arrest or death of cancer cells, especially in cells dependent on oxidative phosphorylation to provide energy requirements, or under certain conditions, such as kinase inhibitor-induced reduction of glycolysis. However, whether metformin produces a cytostatic or cytotoxic response in cancer cells, or other responses, is likely to be dependent on many factors, including how they are energized, the state of their microenvironment, the interaction between glycolytic and oxygen phosphorylation pathways, and intracellular metformin concentrations. Tumor heterogeneity is also important in this context, and tumor mutations need to be taken into account, especially STK11 (LKB1) and TP53 mutations, as well as mitochondrial DNA mutations. Despite this disappointing result, attempts to repurpose metformin for cancer treatment should not be dismissed. more than 100 studies evaluating metformin in different stages and cancer types are currently underway, and results from additional translational endpoints are yet to be reported. Patient selection and translational studies are critical to determine the success of attempts to add metformin to cancer treatment.