Neal Shore: Thank you very much Silke and Aurelius, fabulous program as always and thanks for everything that you're doing as well as all the faculty in enhancing global care for our prostate cancer patients.

Here are my disclosures. What's of note is that I couldn't be here without Tanya Dorff, Julie Graff, and Alicia Morgans, so I think that ups the women female component to the program. I'm wearing blue. Cue the Joe Sullivan band. I'm done. Okay. All right.

So I'm charged with looking complications of ADT, specifically cardiovascular disease and diabetes in 10 minutes, and I think I'll try to do that. ADT is the mainstay, or the centerpiece of the foundation, and if you Google word search this in PubMed, there's about 5 billion associations of the word mainstay with ADT. And so that has been the sine qua non as Martin Gleave showed us with the Huggins and Hodge's Nobel Prize in 1966 for prostate cancer management. Maybe one day it will not be, but clearly it delays progression, it prolongs survival, but there is obvious significant attendant risks. That's why we're having this particular session.

So is our current management adequately addressing these risks? I would argue that giving ADT and the management is not what your father or your grandfather urologists, medical oncologists thought of. We're in a totally new era. This is the demographics of where we see this escalation of the aging population, all forms of cancer. And you see this in the United States. What's particularly, it's probably true for the rest of the world... But what's particularly notable is the octogenarian and nonagenarian groups that will be living longer. So this is the graying of the world or the "Silver Tsunami" effect.

We often talk about how cardiovascular disease versus terminal advanced prostate cancer, it's a race between the uromedical oncologist versus the cardiologist. But actually we may be fooling ourselves and actually contributing to our competitors in keeping people from being alive longer or what we euphemistically call dying of old age or a cardiovascular event. As you can see in this pie chart, at age 85 and over, the cardiovascular causes are markedly increased, and of course, cancer is the second leading cause.

So what's the protective role of androgens in the cardiovascular system? You can read through this outline, but at the end of the day, there has some impact on QT prolongation, clearly potentially on vasodilatation, and we'll talk a little bit more about body composition. What's notable in this particular slide is this issue around visceral adiposity and particularly sarcopenic obesity, which is abdominal obesity and reduced muscle mass with an increase in all-cause mortality. So does it have an effect on true coronary vasculature? Does it also lead to fatigue, falls, and associated co-morbidities with those problems?

So ADT, or testosterone suppression as Chris Sweeney calls it is and the dyslipidemic effects is basically, it's a quasi-metabolic syndrome. All of it is consistent with the metabolic syndrome except for this sort of counterintuitive increase in HDL levels. But the net effect is for it to be pro-atherogenic and therefore a risk for coronary plaque development, dislocation, and there's a lot of interesting research that's going through that looking at cardiac myocytes in particular on FSH levels. But I don't have time to really review that in detail.

So the ADT and the metabolic syndrome, as you see up in the upper corner diagram, these are the things you see, visceral obesity, insulin resistance, elevated triglycerides, and hypertension. But you don't see the lowering of the HDL. Of note, anywhere from a third to more than half of men who are on ADT for greater than a year will develop this form of metabolic syndrome independent of age, race, and stage of the prostate cancer.

So why is this important? This is pretty well known, it should be also intuitive, is that patients with cardiovascular disease have frequently additional comorbidities, as you can see reading through the highlighted bars. And then when I touch on diabetes, you'll see about this as well. So why does that make a difference? Well, it makes a difference because when you increase the number of comorbidities, it's a very nice correlative to your likelihood for a less than 10-year survival. Again, very intuitive, but here is the obvious, the data that supports it.

The third bullet is important here because cardiovascular disease risk is highest in the first six months of ADT by this report from O'Farrell in JCO in 2015 in men who have experienced two or more previous cardiovascular events. So getting a good baseline history is important, and this leads to another theme which is probably more significant for urologists than medical oncologists, but I think it was Tia who said it is that you have to sort of channel your inner internal medicine and so with the complication of managing advanced prostate cancer patients, and in fact all advanced cancer patients, we have to be broader in our appreciation of their evaluation.

So does ADT cause cardiovascular disease? This is a pioneering seminal work by Nancy Keating and senior author Matthew Smith, who's here and on the faculty and this was really an important look. It was a VA study, retrospective of close to 40,000 patients where they saw clear statistically significant correlation with ADT use and myocardial infarction, sudden cardiac death, as well as diabetes. This was a retrospective look back in the VA healthcare system.

In this paper by Tsai and Carroll using capture data, they looked at neo and adjuvant ADT for a prostatectomy cohort and had similar conclusions. But then lo and behold, this meta-analysis of about eight prospective trials by Nguyen and Choueiri basically said they disagreed, and in fact there wasn't a correlation with ADT and increasing cardiovascular disease.

And then this paper by Alibhai and the Canadian group over about a six-year period, a look back of a large cohort of Canadian patients didn't see so much of a cardiovascular correlation but an increase in diabetes mellitus.

So what did this lead to? Essentially this conclusion and the JCO paper by O'Farrell really is that cardiovascular outcomes were not studied as a primary endpoint, and not surprisingly secondary analyses from these trials have failed to show an association, a finding that has been consistently shown in these otherwise large scale observational studies.

Well that said, it didn't prevent the FDA in 2010 for putting a black box warning to all of the GnRH agonists that are on the market today and basically suggesting we need more prospective trials and we need to be warned when we start patients on ADT.

So what are the guidelines? Everyone's probably seen this, but I think it's actually good because of its simplicity and cost effectiveness, it is the A B, C, D, E effect. And that is awareness of cardiovascular prior comorbidities or history, family history, possibly using aspirin. Quick show of hands, how many in the audience are taking a baby aspirin daily? Am I the only one? Wow. Okay. I'm wearing blue, I asked a question, I'm looking for chocolates. Okay. So monitor blood pressure, cholesterol, obviously monitor that, smoking cessation. We'll get to diabetes and touch on diet and exercise as well.

So this is a very nice paper also in JCO, Jacobs, but the bottom line here is that there clearly seems to be in this large cohort of patients a protective effect from taking daily aspirin in a prostate cancer cohort. Most recently you've seen the data, large scale studies prospective that men over 70 or with any sort of bleeding diathesis the use of daily aspirin has now been not recommended by the American Cardiology Association, but we really don't have additional studies in the at risk cancer population. So I think that that's still something that needs further research.

As it gets back to the FDA warning in 2010 for agonists and the increased risks of coronary vascular or major adverse cardiovascular events known as MACE, is it possible that the antagonist could be safer? This was a paper published by Albertsen and others looking at a series of a pooled analysis and essentially demonstrated that it might be possible, again, retrospective pooled analysis, that perhaps there was something less inflammatory in using an antagonist versus an agonist, and so with that there is an ongoing study (PRONOUNCE). It's prospective and multinational and Howard Scher was very involved in the semination of this. Degarelix, an antagonist versus an agonist looking at these MACE timepoint effects.

So let's talk about... Here's a busy algorithm, and I apologize it's busy, but this is the notion here is around "Can we do better?". And that would be bringing into our multidisciplinary family, the cardiologist or the cardio-oncologist. And so what exactly does that mean? So that would be to refer a patient who would have cardiovascular disease, who would have potentially family history issues of cardiovascular risk, to bring that person to your cardio-oncology clinic, which is probably something only at tertiary centers and major metropolitan centers, certainly not something that would be applicable in rural or let alone in the developing world, but nonetheless something that we need to be thinking about.

So what would you be checking for for someone who has preexisting CV disease or undertreated metabolic CV risk factors? Can you check a hemoglobin A1c, can you check a lipid panel? Obvious... oh, the bovine chime.

All right. I'm going to move. All right, so the emergence of cardio-oncologist. This paper just this year, about half the cardiovascular training programs don't do any form of oncology training. So that needs to be corrected. You can read through these for purposes of time, but I just... This speaks to hyperinsulinemia. Metformin, this paper supported it. Ninety thousand patients retrospective said Metformin had a hazard ratio of about 0.9 in diabetics versus diabetics who didn't take Metformin. This recently double ACR disputes it with a really nice basic science work in PBMCs looking at levels of both glucose, insulin and waist circumference.

So nutrition, obviously important. I'll skip through that for purposes of time. Exercise. Exercise is obviously a good thing. It's probably one of the best things to stave off worsening Alzheimer's when it's diagnosed and clearly it's better for performance status so patients can go on to all of the CRPC therapies that we have.

Shout out to Fred Saad who's doing the gap for a trial, it's a prospective phase three trial on exercise sponsored by Movember. I think one of our questions for the panel will be subsumed in this. This was a panel that we put together a full day looking at optimization of androgen deprivation therapy and prostate cancer, a practical guide for clinicians. So we asked and this is a combination of academic and community medical oncologists and urologists, and either the urologist or the PCP should monitor blood pressure, etc in patients receiving ADT. Consensus for this was 10 out of 14, that would have been over 70%. Prior to initiating ADT, CVD comorbidity should be referred to a cardiologist for co-management, 100% yes.

Final two slides. There's no evidence to support taking Metformin, 86% said yes, no evidence, adequate. Urologists should communicate better, clearly they should or channel their internal medicine vibe. Hemoglobin A1c should certainly be looked at. And exercise and weight reduction is extremely important, and I think it's a low hanging fruit.

So I just wanted to end by saying this has nothing to do with my talk, but it has to do with drinking wine. So this is for the faculty tonight. Men without cancer who drink alcohol have a lower risk of lethal prostate cancer, and this was just reported by Downer. He's really not... the name belies the message. And this was in 2019 of this year.

So my conclusion is treatment with ADT is a mainstay in one of the most common cancers among men, the "Silver Tsunami" effect. We can do better as Johann de Bono told us yesterday, prostate cancer, the management from start to end is remarkably complex, and we need to understand that, particularly in the community. So again, thanks to Silke and Aurelius for having me here.