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Alicia Morgans: Hi. I'm so excited to be here today with Professor Anthony Joshua, who is joining me from Sydney, Australia, as well as joining me at ASCO 2024, where you presented the MAST trial really investigating metformin in a prostate cancer population to understand how this may influence outcomes for patients. It's been a very hot topic for many, many years. Thank you for being here. Can you tell me a little bit about how we got to where we are? How did we get to this trial?

Anthony Joshua: Well, it's great to be here. So there's actually a lot of work that went into this study. The study recruited from October 2013. So even before that time, we were actually thinking about metformin intensively, and even in the first few years of the study, publishing on a number of orthogonal analyses that suggested that metformin had benefits.

So just to speak to a few of those that gave us hope that metformin may have an effect on men with active surveillance: At Princess Margaret, we did a retrospective analysis of men undergoing radiotherapy who took metformin versus those that didn't in a cohort of 500 people. We found there was a 10-year reduction in biochemical-free recurrence for men undergoing radiotherapy. We did an analysis of COU-301 and 302, and we found a hazard ratio of 0.77 for men that took metformin on that study compared to those that didn't in a pooled analysis for overall survival.

We looked at diabetic men, David Margel's paper, where for every six months of metformin use subsequent to diagnosis, the hazard ratio is 0.76 for a reduction of prostate cancer mortality. So there was some of the epidemiological data, and there was a wealth of biological data on the role of metformin being an mTOR inhibitor, activating AMPK, having an effect on the tumor immune microenvironment and a variety of other effects on the microbiome, et cetera, et cetera, that may have suggested that actually this effect is real.

Then probably the cherry on top was the neoadjuvant study that we published on neoadjuvant metformin that showed that there was a 30% reduction in Ki-67 between a standard of care biopsy and then the subsequent radical prostatectomy in 24 patients who took metformin prior to their radical prostatectomy. So those pieces of information gave us enough rationale to think, well, you know what? If it's going to have an effect anywhere, it's going to have an effect in active surveillance, so Gleason 6 disease, et cetera, et cetera.

So we built a study. The study was funded initially by the Prostate Cancer Foundation, who you know well, and then subsequently funded by the Canadian Cancer Society. It turned into a randomized Phase III study. So it was 408 men in total, 204 in each arm with sufficient power, a hazard ratio that was generous, but nevertheless would give us some inclination and understanding of the role of metformin in this setting. So that study accrued at 12 Canadian centers over a 10-year period from October 2013 to December 2023, so an incredibly long study. But it took that long to get through the pandemic, find men, and there are some obvious weaknesses over a 10-year accrual time. There was the use of MRI came into play, and we couldn't control for the use of MRI between arms, et cetera, et cetera. So there's some limitations to the study, obviously, but it is probably a very tight cohort of men undergoing active surveillance in a contemporary period, half of whom took metformin and half of whom didn't.

Obviously, those men had to have what was essentially NCCN very low or low-risk prostate cancer. So for people listening, that's basically Gleason 6 disease with low volume, less than 50% in any one core, they needed at least 10 cores to go in, less than one-third of cores had to be positive, up to T2a. Those sorts of criteria had to be inherent in going into the study. Obviously, they had not to be diabetic, so we didn't want to see diabetics on metformin coming into the study. They had to be people who were not diabetic who took metformin.

As I presented the study, there was no difference between the two arms for either pathological progression, which is progression defined by the biopsy at 18 months or 36 months, nor in therapeutic progression, which is getting prostate cancer treatment for whatever reason, or those combined. It was essentially a negative study from that point of view. But then what came out in some subsequent analyses were some subgroups that gave us some pause for thought. So one of those was men with a high BMI. In men with a BMI under 30, there did not seem to be any meaningful signal, but with men with a BMI over 30, there was potentially a detriment to taking metformin. Now, we don't quite understand why. I was even, subsequent to the talk, text messaging with a few of the prostate cancer people that you know trying to nut that out to work out why is it those men have a detriment to taking metformin.

What do we know about diabetic men taking metformin? Well, generally speaking, not diabetic men, but men with a high BMI taking metformin, generally speaking, those men have lower PSAs at a population level. The reason for that is unknown. But if we take that as fact that obese men have lower PSAs, maybe one could hypothesize that the tumors are less androgen-driven and maybe more driven by AMPK signaling. Maybe if you inhibit that, that would then somehow accelerate the cancer in some way because you get a rebound in terms of AR signaling and that may provide more intraprostatic testosterone or testosterone activation or AR transcriptome to drive more progression. That's extraordinarily on thin evidentiary grounds, and I can't say that's a fact. That's one hypothesis as to why this happened.

There are a variety of other reasons that we've talked through, including changing the microbiome, butyrate production in the bowel, and a few other things that we're looking at. It will take some sub-analyses to understand what happens to those men who progressed pathologically who had a high BMI. I won't use the word obese, but who had a high BMI to understand what was the nature of that at the time that they progressed. Did they have high PSAs and perhaps what were some of the genomics of the tumors that were removed?

There are some biomarkers that show promise in predicting benefit from metformin subsequent to our trials, such as NKX3.1. There's been some excellent work done on that. And so we might look at some of those biomarkers to understand what they may reveal about that population. Maybe there was an unintended bias in terms of the number of patients with certain biomarkers that went to certain subgroups. So that was one subgroup of concern.

The other one was there did seem to be, unrelated or not, more men, although not statistically significant but certainly a trend, more men that progressed with Gleason 8 plus disease who took metformin compared to those that didn't. Men progress pathologically for a number of reasons. So cores being greater than 50% or more than a third of the cores. But the issue about men progressing with Gleason 8 disease is a little bit of a concern, and that seemed to occur more frequently. Again, not statistically significant, but there was a signal there again, that gave some pause for thought.

So I think the onus is now on us as the investigators to work out why this happened and do a whole lot of downstream analyses, most of which are planned, covering the metabolome, the proteome, biomarkers, genomics, and imaging. We are going to suck in as much data as we can over the next six to nine months to really understand what it is about non-diabetic men taking metformin that led to either no outcome and no effect other than the fact that the men who took metformin lost approximately 1.5 kg in weight, which they generally did. No effect on their tumor microenvironment or there are some other confounders that we are not aware of just yet. We're trying to put that all together.

The only other thing I would say is so far in randomized studies in prostate cancer, metformin hasn't really done much. There's been a number of studies which are now coming out in the literature, and there's at least one more study to come, which is a radical prostatectomy study, 50 men in each arm from England. So I think that will also provide some insights. Not to mention obviously the STAMPEDE study with the metformin arm, which my understanding is that's coming out later this year. So that will, I think those final two studies will really be the sort of nail in the coffin as to whether metformin has any use in men with prostate cancer.

In breast cancer though, it's interesting that there was a very large study MA.32, which looked at five years of adjuvant metformin versus placebo, and that didn't find any benefit either in women, despite similar rationale and similar epidemiological and scientific studies. We've been in contact with the authors of that manuscript, and I guess both similarly flummoxed about why it is that despite all this preliminary evidence that we're not seeing signals in men or women with relevant cancers that metformin may benefit. So I think there's a lot of work which is in progress, but at the end of the day, it's a negative study. I cannot in any way endorse that men take metformin when they're on active surveillance. It's not an evidence-based practice.

If you are diabetic, you probably should be taking metformin. If you're not diabetic, then I would not be using metformin. I would talk to your local physician about other health measures that certainly ... I know you've talked about the importance of exercise and the importance of weight loss, controlling other cardiovascular risk factors. Those things seem entirely appropriate, but metformin is not one of them.

Alicia Morgans: It's fascinating, isn't it? I think this sort of speaks from my perspective to the importance of randomized trials to answer some of these questions where the confounding should fall out in that randomization. Epidemiologic studies, as we know, are going to be watching, is essentially natural history and standard of care. Perhaps people who have been on metformin have had more touches with the healthcare system, perhaps they are catching things more quickly, perhaps they're having interventions more quickly similar to patients on a clinical trial, perhaps that earlier ability to have an intervention or that additional support from a clinical trials team in a trial or from a patient who's now touching many healthcare providers because of their diabetic management.

Perhaps that has something to do with this. Who knows? Just a hypothesis. But I think it's really fascinating, especially in this randomized study where we see that patients who may be more likely to develop diabetes over the course of follow-up actually had a detriment to exposure to metformin. I wonder, did you capture the development of diabetes throughout the course of treatment to understand if this was something that was unbalanced because of the relatively small-ish numbers of your randomized patient population?

Anthony Joshua: I'm sure we did capture BSL in terms of as a diagnostic tool for diabetes and HbA1c. I don't have that information right now. I think it's certainly something that we would look at. It's quite plausible that a certain percentage of men in the placebo arm did develop diabetes during the course of the study. Certainly didn't have it when they entered.

Alicia Morgans: No, of course.

Anthony Joshua: They did put on a half kilogram during the course of the study, and maybe that's associated with the high risk of diabetes. But that's sort of the data that we will be looking at to understand what happened on study to those men.

Alicia Morgans: Absolutely. There's so much to dig in, but I think it's so important, your main message, if you don't have diabetes, metformin is not an anti-prostate cancer treatment.

Anthony Joshua: Yes.

Alicia Morgans: It is not something to prevent prostate cancer. And this study is really so helpful and important in defining that. So if you had to give a final, very clear statement to patients, to clinicians about the findings from your study and congratulations on doing the work, what would that be?

Anthony Joshua: The final statement I think is going to have to be that active surveillance is a standard of care for men with NCCN, very low or low-risk prostate cancer. There are other standards of care that you can discuss with your local urologist and/or family doctor. But if you undertake a course of active surveillance for your NCCN, very low or low-risk prostate cancer, then at this stage, I cannot recommend metformin as a medication that's going to alter the natural history of the prostate cancer for which you're undergoing active surveillance.

Alicia Morgans: Wonderful. Well, there we have it. Such important work. Thank you so much, and congratulations on what I'm sure was a labor of love throughout a pandemic across continents. A fantastic job on a really important study. Thank you.

Anthony Joshua: Thank you.