Alicia Morgans: And now we have Dr. Fred Saad who's going to talk about how to take care of the heart. I also want to mention, he was knighted in his province, which I think is phenomenal. Let's give him a little round of applause. Thank you, Knight Saad. Nice.

Fred Saad: Thank you very much for that, Alicia. And I'd like to... Pardon me? Sir... No, it's not like in England. So I don't know if I should thank [inaudible] and [inaudible] for this lecture because it's far from my expertise. But they challenged me and I enjoyed preparing this very much. And hopefully it'll be practical and allow us to review what I think is still controversial.

And so prostate cancer is obviously a major cause of death. But there are competing risks of death. We are not treating pediatric patients. And not dying from prostate cancer is a good thing, as long as our treatment is not causing death from other causes than prostate cancer. And cardiovascular disease remains the number one cause of death, even in our prostate cancer patients.

What's interesting though, is that there are competing risks of death, even in metastatic prostate cancer. And this is a nice paper that came out recently looking at causes of death in metastatic prostate cancer. And actually about 16, 17% of deaths are not prostate cancer or cancer-related deaths. And of those, 41% are cardiovascular causes of death even in our metastatic patients where we would all assume that they're going to die of prostate cancer. And this problem becomes even more profound if we keep patients alive more than five years, where 35% of deaths are not due to prostate cancer. So by increasing our efficacious treatments, we might actually be having to think about competing causes of death, even in our metastatic patients.

So, number one question, does ADT increase the risk of cardiovascular events? And probably the answer is yes. So Alicia Morgans was part of this very impressive paper from the AHA looking at the impact of hormonal therapies in the treatment of breast and prostate cancer. And in terms of ADT, there are metabolic changes due to hypogonadism that are going to lead to clearly metabolic syndrome type phenotype that will increase the risks of cardiovascular risk.

In observational studies, there looks like there is a clear association between the use of ADT and cardiovascular mortality when looking at multiple real world datasets and a meta-analysis of these data sets. But when we look at randomized clinical trials, that association is not so clear, probably because of selection of patients that go into clinical trials, probably the fact that these patients are followed more closely while they're in the clinical trials. But the evidence is not as clear that ADT is related to cardiovascular mortality.

So the question is are there patients more at risk and what can we do about it? And so clearly, one of the papers that opened our eyes to this cardiovascular mortality came out of the radiation oncology literature. With even a short course of neoadjuvant hormonal therapy, given to patients going on to brachytherapy, you see that if you had no comorbid cardiovascular history or only one cardiovascular risk factor, there was really no difference between patients who got hormonal therapy or not. But once you got into patients with known coronary artery disease or patients with heart failure or history of MI, then all of a sudden, even with a short course of hormonal therapy, you see a separation of the curves in terms of cardiovascular mortality.

So how can we help our patients in the clinic? Well, first we have to be aware and we have to try to identify patients at risk of cardiovascular disease. And this stamp is something that is proposed in different varieties. We propose this in Canada. Asking whether there's a history of stroke, transient ischemic attacks, history of aortic aneurysms, or other sites of aneurysms, history of MI, angina, peripheral, arterial disease. These are ways that we can easily try to identify patients at risk.

And then the other question is do antagonists have less cardiovascular risk than the agonist? And so here, if you look at multiple studies and a meta-analysis, this would suggest that antagonists might have less cardiovascular risk than an agonist in patients on ADT. And Neil Shore and myself and [inaudible] led this study that was published in the New England Journal a couple of years ago, using an oral antagonist versus Leuprolide, that showed that in terms of major adverse cardiovascular events, looked like it was more profound in patients who got the agonist than the antagonist. And actually, if patients had a history of a major event in the past, these are the patients that were most at risk in driving this difference of having another major cardiac event.

But, and this is a big but, with only one T, in the real world evidence, the conclusion is not so clear. Degarelix in the real world, this is a paper that also came out recently, that there was no association between Degarelix and lower risk of cardiac events. And this might be a selection bias where the highest risk patients were put on Degarelix for whatever reason. But what we all would like to see is a randomized control trial between an antagonist and an agonist. And this was actually published over the last year where patients, where put into this pronounced study looking at cardiovascular events in patients getting an antagonist versus an agonist.

And there are several things in this that were very interesting. The cardiovascular event rate was very, very low overall. And this is probably because of better awareness and attention to cardiovascular risk factor controls, because these were not only urologists or radiation oncologists or oncologists treating these patients, there was a team of expertise, including cardiac expertise. And there was no difference in MACE at one year between patients assigned to Degarelix or Leuprolide. So the question is still out. At least in randomized control trials, doesn't look like there's a difference. What about the real world?

What about new generation hormonal therapies, which are being used widely now? And there is at least one study that was published by colleagues in Quebec looking at patients on Abiraterone or Enzalutamide. And there did appear to be a higher cardiovascular risk in patients on Abiraterone versus Enzalutamide, but only in patients with known cardiovascular risk factors. If you didn't have any, there was no difference.

So very briefly, to end with some recommendations on how to reduce cardiovascular risk. One, be aware that these exist. This is undeniable that there is a risk. Aspirin antiplatelet therapy, if you are considered high risk of an event, this should be considered or referred to someone who can actually manage this. Make sure blood pressure, I don't think there are many urologists that do blood pressure testing, but we have to check that the blood pressure is maintained. Statin use. Patients, this is a systematic review presented just a couple of months ago, that it suggested an overall mortality reduction of 27% and a cancer-specific mortality of 35% in patients with hormone sensitive metastatic disease, and even castration-resistant metastatic disease in patients going on ADT or ARAT. So, my reflex in the past was this is a drug we can get rid of. You don't need the statin, you're going to die of prostate cancer. But I'm re-questioning this simplicity of what patients need.

Encourage patients to stop smoking. Diet and weight management. Diabetes prevention and treatment. This is another area that I had the opportunity to review by doing this study. And I was very surprised at how strong the Metformin data is. And there is a very nice paper in scientific reports showing an overall survival reduction, cancer-specific reduction, and radiographic progression free survival in patients on Metformin in this study. Obviously this is real world data. But over a million and a half patients were part of this analysis. So something that needs to be reflected on. And exercise, and we're going to talk about exercise. Clearly, this is one of the best ways to reduce cardiovascular risk.

So I'll conclude by saying that ADT clearly looks like there's an association with cardiovascular events and cardiovascular death in observational studies, but not consistently observed or reproducible in RCTs. You should institute preventative strategies in all patients. Every patient on ADT should be encouraged to at least stop smoking, exercise. Whether or not the statin is at level one, to consider statin use, aspirin, Metformin. These are things that I think we might need help to decide if patients would be appropriately treated. Identify patients with cardiovascular history or risk. Whatever method you use, you need to identify those patients. And if they're considered moderate or high risk, involve other expertise. We cannot do everything alone. And it's unclear if there is clearly a benefit of an antagonist over an agonist. And I just end by saying that our therapies for advanced prostate cancer are becoming more and more effective. Patients are living longer and longer with prostate cancer. So taking care of the heart becomes even more relevant. Thank you very much.