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Neeraj Agarwal: Welcome to UroToday. Today we have our guest, Dr. and Professor Silke Gillessen, who is the Director of the Institute of Oncology in Southern Switzerland. We will be asking Dr. Gillessen about her presentation at the 2024 ESMO Congress in Barcelona, where she discussed the results of her Phase 3 trial of adding metformin to androgen deprivation therapy in patients with metastatic hormone-sensitive prostate cancer. Welcome, Silke.

Silke Gillessen: Welcome, Dr. Agarwal, or I think we can say Neeraj. Very nice to be with you, and very nice that you asked me to also present the metformin data, because of course there was a lot of discussion about my P3 data presented in the plenary. But I'm very happy that you asked also about the metformin, which is really also very close to my heart. So thank you very much.

Neeraj Agarwal: Absolutely. Yeah, we're looking forward to it.

Silke Gillessen: So thank you again, Neeraj, and I'll just show you the slides that I also presented at ESMO, but I'm going to go a bit faster in some and in others a bit more slowly. So most of you probably know already the STAMPEDE trial, a trial for patients who are metastatic or high-risk localized and who receive standard of care in the hormone-sensitive setting or standard of care plus a new or not-so-new therapy. And in this case, it's metformin that we added to standard of care.

Here's my conflict of interest. I show them anyway. And I guess to this audience, I don't have to say that androgen deprivation therapy is the standard of care in advanced prostate cancer. And something that sometimes we forget, it has also a lot of metabolic adverse effects. And we know since a long time that metformin has anti-cancer activities. There's a lot of studies suggesting that in different malignancies and also in prostate cancer.

And our idea was that metformin may have these anti-cancer activities but also may have a positive effect against the adverse metabolic effects that we induce by ADT. And our hypothesis was that metformin therefore can improve overall survival maybe by two mechanisms: mitigating adverse metabolic effects and the anti-cancer effect.

And here you see the STAMPEDE trial scheme. I won't go into the details, but in yellow you see the standard of care arm, and the standard of care arm with metformin. And I will only present now the results of the metastatic patients because the other ones are not mature yet.

I'm not going too much into the statistical design, but the primary outcome measure was overall survival. I think that's important. And we looked for a 20% difference in overall survival. Another thing that's important to know is that seven subgroups were pre-specified for final analysis.

Here you see the study scheme. It's really easy, so it's patients with metastatic hormone-sensitive prostate cancer. They could not be diabetic, and they were randomized. And you see it was a big study; only the metastatic patients were more than 1,800 patients to standard of care versus standard of care with a target dose of twice 850 milligrams. And as I said, the primary endpoint was overall survival, and a key secondary endpoint was metabolic effects and safety. And patients could formally stay on metformin also beyond progression because of these suggested metabolic effects.

Here you see the baseline characteristics; they were very well-balanced between the arms. It's a big trial. I think important to understand is that because it was kind of an old trial, 80% of the patients had the combination ADT plus docetaxel, and only very few patients had an RP.

Here you see the primary endpoint overall survival in orange, the arm with metformin, in black, the standard of care arm. And we saw a hazard ratio of 0.91. As we said, we targeted 0.8, so this trial was negative, p-value was 0.142. If you look at the median OS in months, the standard of care almost 63 months and the standard of care arm plus metformin was 69 plus one months. This is the overall survival in months.

If you look at the forest plot, I think here it's quite interesting that if you look at the volume, and again this is only subgroup analysis. You see here also the p-value of interaction was not statistically significant, but there seemed to be a difference in the high versus the low-volume patients. And if you look at that in the Kaplan-Meier curves, you see here, it seems that if anything, the high-volume patients derive more benefit. But again, it's only a subgroup analysis. And the same is true also for progression-free survival. Here the p-value for interaction is much more interesting and statistically irrelevant. But anyway, it's only subgroup analysis and we need to look into that with further research.

Maybe more importantly, one of the key secondary endpoints was metabolic effects. We all know that patients really suffer from weight gain under ADT. And you see here in black, again the standard of care, you see that in median the patients had a weight gain of more than four kilos, whereas in the metformin arm in all ranges, the weight gain was only two kilos. So this was statistically significant. Also statistically significantly different were the glucose levels, the HbA1c level. The total cholesterol level was lower with metformin and the LDL cholesterol was lower with metformin. And all these parameters were statistically significantly improved at six months, at 12 months, and at 24 months.

The safety was as expected. We saw more GI toxicity with metformin. You see here, the all gray, also a small increase in renal urinary side effects grade 1 and grade 2. And in conclusion, I think we have to say there is no clear evidence that adding metformin to standard of care increases overall survival in unselected patients with metastatic hormone-sensitive disease.

There was some evidence of benefit for outcomes in the pre-specified but not pre-powered subgroup with high volume compared to low volume. But that requires further evaluation because it was only a subgroup analysis.

Most metabolic parameters improved significantly with metformin irrespective of disease volume. And that may translate hopefully to reduced cardiovascular death also in the future.

Further research is clearly warranted now for patients who are treated with an ADT androgen receptor pathway inhibitor doublet, because as we know, if you add the second hormonal treatment, we see even more metabolic side effects.

And yes, here I think I have to really thank all the patients as always and their families and friends, but also the funding bodies that helped us to do that study with of course a very old drug that nobody has interest in. So Cancer Research UK and specifically also Prostate Cancer UK have provided funding support for the metformin comparison. And of course, like a lot of things, also to, as always, the investigators because it's really a lot of hospitals, more than a hundred hospitals, who take part in the STAMPEDE trial.

Neeraj Agarwal: That was really wonderful. Thank you again for taking the time to share those data from the STAMPEDE metformin arm, and showing that even though overall survival was not improved by adding metformin to the ADT backbone in patients with metastatic hormone-sensitive prostate cancer, we do see some hint of efficacy. As you mentioned, although not powered for a specific subgroup, but there was definitely—we saw the Kaplan-Meier curve showing definitely some hint of benefit in patients with high-volume disease but not low-volume disease. And of course, these are all hypothesis-generating data, but I also found it very intriguing that the cholesterol levels, total cholesterol, LDL level, glucose levels, hemoglobin A1c, all those metabolic parameters, they seemed to be statistically significantly improved in patients who were in the metformin arm. So Silke, I'd like to ask you, what is your message regarding this aspect of the results for our colleagues out there across the world?

Silke Gillessen: That's a very good question, Neeraj, right? Because of course, as you said, we didn't hit the 20% reduction in death. But the other endpoint that we found that is really interesting is the metabolic changes. And there we saw a clearly significant improvement in a lot of parameters.

Now of course, it's the question, how do we communicate this data? It was the secondary endpoint. It was not the primary endpoint. I think, and it's not approved—metformin is not approved in that setting because these were all patients without diabetes, right? So there are now a lot of studies ongoing in pre-diabetes with metformin because we see there also a positive impact. So I guess we have to discuss now with the patients, is it worth for them, specifically maybe for the patients who have already a difficult profile for the cardiovascular parameters, and we start ADT and we know we are going to worsen it, right? So is it worth talking to the patients and say maybe we could try to start metformin? It's not approved in that situation. I think we have to really try to find out what we can do in that situation.

But only looking from a scientific standpoint, not talking about approval now, I think it's quite interesting. And some patients already are very interested. I heard from one colleague that in Hollywood already everyone is taking metformin anyway because it has that effect of anti-aging and lowering your glucose. You saw that. So I think it is a quite interesting drug. According to the endocrinologists, the patients who don't tolerate it well, like having the diarrhea, the GI effects, you see it quite early when you start giving it so you can adapt. But there's still some patients who don't continue it, so I would not give it to a patient who doesn't tolerate it. But I think it's quite interesting and we have to find out what we are doing out of it. And I think it's a one-to-one discussion because that drug is not approved in that situation.

Neeraj Agarwal: Yeah. As you said, ADT plus ARPI now increasingly being used as a considered standard of care, and we are expecting our patients to live much longer with these drugs on board. I personally expect, as like we all do, a surge in the metabolic syndrome, if you will, increasing weight, blood sugar levels, hemoglobin A1c, cholesterol, and our patients are going to increasingly feel the brunt of this metabolic syndrome, if you will, in the coming years. In this context, I'll be honest with you, when I saw the data, despite overall survival not being positive, I'm very tempted to use metformin in my patients, especially who I deem to be at a higher risk of developing metabolic syndrome. So I have patients who are overweight to begin with. I have patients who already are at the edge with hemoglobin A1c. They don't have diabetes yet. I am actually being asked by my patients about the value of metformin on a regular basis, and I tell them that I don't mind if they start metformin through their primary care doctor even though I cannot prescribe that. Do you think my approach is incorrect, if you will?

Silke Gillessen: I guess it's reasonable, right? Now you have also some data to back it up. And just last week, our patients really say they can't lose weight. They try, they try hard, they eat less, they exercise more, but it seems to be very difficult to lose the weight they gain by starting the ADT. And a lot of my patients, they really are hurt by it. They don't like their bodies, they don't like to be four kilos more. You saw it, right? After two years, they have more than two kilos more. That's quite a lot. And a lot of patients tell me, "Look, I really tried to not gain weight, but it doesn't work. I can't get rid of these plus kilos." So I think it's really also something that bothers our patients. It is not only a value, it's also something—at least my patients, they don't like it and they can't do anything against it.

And I think the good thing about the study now is that we have the data. We know very well the drug. The drug is very old. We have a lot of experience with it. It's very, very cheap. That's why we tried it in a trial, because it could then be used really worldwide because it's so cheap, even in Switzerland where normally everything is expensive. I don't know about the States.

So I guess it's not something that's going to hurt our costs for health. And what we don't know because we have a follow-up, I think about 60 months in that study. But in all the diabetes studies, you need to wait longer to see the effect on overall survival, because the diabetes drugs are approved by how much they lower the glucose, not for overall survival, but you see effects on overall survival. And hopefully we see that also in that study and we will do the follow-up for overall survival. Maybe we see that only in 10 years or 15 years. That is something for the moment we don't know.

And just to let you know that we are planning right now—we are discussing with STAMPEDE2, where we have an arm for the more like polymetastatic patients with lutetium, if we want maybe to add there two times two also with metformin. Let's see if we can find funding and so on. But I think that would be—and there we have the backbone of an ARPI plus ADT and we will see what's going on when we do that. So I think it's a worthwhile question, but we have to find funding. As you know, it's not easy.

Neeraj Agarwal: Absolutely. Absolutely. I agree with you. I think it will also help the investigators or clinicians across the world to hear from the panel of APCCC next year.

Silke Gillessen: Yes.

Neeraj Agarwal: When it is endorsed by multiple doctors. I know overall survival was not met and you also showed just now that pretty much all relevant metabolic parameters were significantly improved, which is quite meaningful to us as clinicians and patients. I think something coming from APCCC panel or guideline panels from the US and across the world, from ESMO, I think it'll really help clinicians across the world getting reimbursement for metformin and to see if they can use this on a regular basis. And of course, if this comes from the panel, it definitely is more convincing rather than me telling you on this panel that I want to use it. So I think everything helps. But APCCC is a widely regarded, respected consensus panel, so I think it'll really help if we can come up with some type of guideline in this regard. What do you say about this?

Silke Gillessen: Yeah. Of course, I'm completely biased and I don't want to drive the decision in any direction, but I guess to have a question would be very interesting, right? To see maybe people say, "No, we are not doing it." So we made a survey with English investigators and we asked the question, "So would you use it now in no patients, in the patients with high volume, the patients with risk factors as you said, right, for cardiovascular disease?" And interestingly, not so many of the investigators would say to not use it. Some of them—and one of my friends already wrote me, "Oh, I started giving metformin to one patient because he asked me and we looked at the data together and he wanted to have it."

But again, I think we have to say it's not approved in that condition. I would feel much better if we would do a second trial and confirm the hypothesis with the high volume and also confirm that that's quite clear. But also the effect in the doublet, like the ARPI plus ADT. So it will be cleaner if you have another trial, but it will take some time of course.

Neeraj Agarwal: Yeah. It'll be years, years, another many years. Yeah.

Silke Gillessen: Maybe not, because then you go only to the high volume, maybe no—you will see a bit earlier.

Neeraj Agarwal: Yeah.

Silke Gillessen: And in parallel, we'll do the update, the survival update from this study. And there may be less cardiovascular deaths in five years. We don't know, right?

Neeraj Agarwal: Yeah.

Silke Gillessen: So I think we are going to follow up on these data as well. And then you will have a lot of translational research. So we will have all the blocks of the patients who have been treated with metformin. We will see if patients, let's say with PTEN mutations react differently, and so on. So we have a lot of translational research ongoing. We have a subgroup, a metabolic also subgroup in STAMPEDE, and we are going to do a lot of other investigations there, looking for sarcopenia, for all these important things for our patients.

Neeraj Agarwal: That sounds like a wonderful plan. While we are waiting for the trial to complete, I think it will really help still to hear from the experts across the world on this panel about what they think it should be, whether metformin should be used on a regular basis or not. Again, there is not going to be evidence, level one evidence, for every single situation we have in the clinic. And that's why these panels are so valuable to all of us.

With that, I'd like to thank you, Silke, for taking the time to join us today. Again, congratulations for completing this study with so many patients asking such a pertinent question of use of metformin in patients with metastatic hormone-sensitive prostate cancer. As we saw, even though overall survival was not positive, the multiple metabolic parameters and weight gain were significantly improved with the help of metformin. So we'll see how the data pans out down the line. For now, the question remains whether we should offer metformin on a regular basis to our patients or not. And use your clinical judgment, and we look forward to some guidelines from the APCCC consensus panel in this regard in coming years. Thank you very much.

Silke Gillessen: Those are recommendations, not guidelines. But anyway, yeah, we will do that. And thank you very much, Neeraj, and thank you also for your positive feedback, very nice. Thank you.