Anthony M. Joshua, MBBS, PhD, on Low-Risk Prostate Cancer and Metformin: New Trial Data

We designed the study back in 2012. It was a study of metformin, men with active surveillance for prostate cancer, and there was a lot of rationales as to why metformin would be useful in prostate cancer. There's laboratory studies that we've done speaking to the importance of metformin inhibiting mTOR as well as having epigenetic effects. There's data from other groups looking at the beneficial effect of metformin on the tumor microenvironment. There's epidemiological studies that suggest that diabetic men who take metformin do better for their prostate cancer treatment. There's combination studies that we've done demonstrating that, in some of the pivotal prostate cancer studies, the men who took metformin did better in the studies with abiraterone. So we put all those things together. We thought, well, metformin may be the perfect medication to give men undergoing active surveillance of prostate cancer. So from the period of 2013 to 2023, we randomised 400 men, approximately 204 on each arm to take metformin versus a matched placebo when they were undergoing active surveillance. And active surveillance is briefly, as per NCCN, very low to low risk criteria. Basically men with low volume Gleason 6 disease, and there's more details in the presentation, but those men were randomised over that period, and the endpoint was defined as either being therapeutic progression or pathological progression. The pathological progression was biopsies done at 18 and 36 months, and their therapeutic progression was any treatment for prostate cancer. And in brief, we found no difference between the arms, and in fact, there was a couple of concerning trends. One trend was that men who had a high BMI actually seemed to do worse on metformin for reasons we don't understand. And a priori, you would think those men would do better on metformin because they may lose weight, but that was not the case. And also there seemed to be a slight trend towards men progressing with higher Gleason scores who took metformin compared to those men who took placebo. This is a little bit worrying, and certainly we need to do more research to understand why this is the case. But this study was an academic study across 12 centers in Canada, funded through, essentially philanthropy, the Prostate Cancer Foundation, and the Canadian Cancer Association. So taken together, I think this has been a great academic effort. It will seed a lot of future research to understand the role of metformin and those types of drugs in men with and without diabetes for prostate cancer undergoing active surveillance.