Alicia Morgans: Hi, my name is Alicia Morgans, GU medical oncologist and Associate Professor of Medicine at Northwestern University. I'm so pleased to introduce today, Dr. Javid Moslehi, who's a cardio-oncologist at Vanderbilt University and an Associate Professor of Medicine. He's going to talk with us about cardiovascular risks, as they relate to ADT in men with prostate cancer, from a cardio-oncologist perspective. Thank you so much, Dr. Moslehi.

Javid Moslehi: Thank you very much for the invitation Alicia, it's always a pleasure working with you, Dr. Morgans, and great to be here. Just as a way of background, I'm a cardiologist by training, but over the last decade, the focus of my clinical practice has been on this new area of cardio-oncology.

And in fact, a few years I was asked to kind of say, what is cardio-oncology to the general group? Is it oncology? Is it cardiology? And this is a review I wrote for The New England Journal of Medicine, sort of summarizing the field. But in many ways, much of what's written here, which is more general and really applies to every type of cancer that there is, and every cancer patient, really particularly applies to the prostate cancer population.

So much of this field is driven by the middle, where there are drugs that affect the heart and vessels. And we've seen this with every type of cancer that exists, whether it's breast cancer, where you get Adriamycin® and Herceptin®, to other forms of cancer. And of course, this, as you will see, pertains to therapies we give our prostate cancer population.

But I think it's also important to note that the intersection of cardiology and oncology, which is the basis of cardio-oncology, really extends beyond that. We recognize now, there are common risk factors that predispose to both cancer and heart disease and this is particularly true with prostate, whether it's obesity, whether it's hyperlipidemia, whether it's diabetes, or even genetic predispositions that can predispose to both. And this is an important observation that in the emerging, really emerging data coming in this space, and it speaks volumes in terms of how we can intervene for all of our patients, but especially our cancer survivors, and how we can prevent cardiovascular disease in this population.

In the US, we have 17 million Americans, that's the population, and more than 3 million prostate cancer survivors. Everybody thinks of prostate cancer being the thing you have to worry about in the patients, which you should, but right next to that is cardiovascular risk in this population. And so, strategies that get at assessing and treating cardiovascular disease and risk, particularly in the prostate cancer population, would be very important.

So what does this all have to do with the prostate? Well, I think the first paper that really nailed this on the head, now 15 years ago, more than 15 years ago, was this work by Nancy Keating in Boston looking at Medicare population. These are by definition greater than 66 years of age with localized prostate cancer. And when these patients received ADT, that's GnRH agonist, they had an increased risk of diabetes, increased risk of coronary artery disease, increased risk of myocardial infarction, and increased risk of sudden cardiac death.

And given that orchiectomy patients only had the risk of diabetes, that argued in this retrospective analysis, that in fact, there was something about GnRH agonist use or ADT use that really predisposed to these adverse cardiovascular events that went beyond hormonal effects and the metabolic effects that we can see in the spot when we treat patients.

Now, there have been a series of papers over the last 10 years and I've summarized them on this slide. I think we all recognize that ADT has generally unfavorable effects on cardiovascular risk factors, that's kind of a given. Observational studies, which are often retrospectives, point that beyond the association with risk factors, there's actually an association between ADT and cardiovascular disease, that is heart attack and sudden cardiac death. So it goes, at least observational studies, argue this goes beyond the patients with just cardiovascular risk factors.

However, there have been a number of randomized clinical trials in oncology that showed that this extension, this association really only extends to patients who have a high risk of cardiovascular disease at baseline. And I think it's also important, as we look at all of these data, which I've summarized basically in this one slide, it's important to note that in the general population, in many of the prostate cancer studies, in fact, the cardiovascular risk at baseline is not collected.

The other thing is, I think it's pretty obvious that when you do observational studies when you see the real-world population, that's probably very different than patients that are enrolled in oncology clinical trials that specifically have a lower risk of cardiovascular disease. Because if you want to have a trial where you just focus on prostate cancer or a treatment strategy, you want to take all the other issues out of the picture.And so by definition, the oncology trials often include healthy cancer patients. I know that sounds like an oxymoron, but that's what's happening and something that doesn't extend to the real-world population.

And I think the other important issue is that we're just kind of grouping all these patients in one bucket and I'll talk about that momentarily. About 10 years ago, there was this statement that came by the American Heart Association, combined with the American Urological Association at the American Society of Radiation Oncology, that did say that ADT clearly has these risks with cardiovascular risk factors. Although they somewhat de-emphasized in my opinion, the association with the disease itself.

So what are these effects that we're talking about? Well, I think first, it's important to know, and this is nicely summarized by one of our fellows and this is a nice work done by Dr. Morgans in collaboration, that we published a few years ago. We talk about increased effects on sugar, so diabetes. Increased effects on bad cholesterol, but also interestingly, the good cholesterol as well. There are effects of metabolic syndrome, these are all effects by ADT.

And I think the other part that gets de-emphasized, that Dr. Bertrand nicely pointed out, is that among patients who start on ADT, they lose muscle mass and they gain fat, something we know that can have adverse cardiovascular effects. And I think these two studies done out of Boston by Dr. D'Amico and his colleagues actually really nicely point, that even in the oncology trial population with respect to cardiovascular risk with ADT and or other treatments, not all patients are treated equally. That is if you have patients that have increased cardiovascular risk, or if you have increased cardiac disease at baseline, when you treat them with ADT, there are differences in terms of events that can occur in this population. Something we'll see nicely as we look at the HERO studies.

And so, as we think about all these issues it's important to take, and this is a general comment, with all of our patients, I think the field of prostate cancer and treatments really now extends into taking patients' co-morbidities in one side and also assessing the various risk factors. And I hope I can convince you over the next few slides that this is going to be particularly important for patients who get started on ADT and really also paying attention to the baseline cardiovascular risk factors.

And so, in the backdrop of all of this, I think the emerging area has been, well, are all ADTs technically, are they all the same? Is a GnRH agonist, for example, the same as an antagonist in terms of cardiovascular risk? And the intriguing data by the HERO trial, suggest that there is a distinct difference that we really need to understand biologically better. So my colleagues in the prostate space here now, have sort of brought you up to speed on what the HERO trial is and how it compared Lupron® versus relugolix, with respect to effects on cancer outcomes or hormonal effects, but also cardiovascular risk effects that came about.

So if you look at the overall population, overall in this study, in this large study, more patients on the Lupron® arm had major adverse cardiovascular events, 7.1% compared to 3.9%. This definition of adverse cardiovascular events included major adverse cardiovascular events and ischemic heart disease. And as you can see, these major events were considerably higher on the Lupron® arm. To me, however, one of the more telling stories and consistent with what I told you up to this point, this relative increased risk of MACE or major adverse cardiovascular events, really increases more when we take patients who have already had a history of cardiovascular disease. The relative risk goes from 1.5 to 5.8 in this study. And although this study, and this observation, is a retrospective analysis and not predefined, again, it's consistent with the barrage of data that have come in the last few years, outlining the importance of cardiovascular risk, baseline cardiovascular risk, in terms of the events that can occur while patients are on therapy.

I think the other part that for me is interesting, is the differences in curves that we observe within weeks after starting either therapy. In many of the large cardiovascular studies, you have to follow patients for years to see a difference. But in this study, you can see a clear distinction within weeks after starting therapy. And in fact, the curves, if you will, separate right off the bat. And I think this is another area I think we need to understand better, in terms of why the effects are so acute and what we can do during this defined window to prevent cardiovascular disease in all of our patients.

And I think the conclusions of the HERO trial is, as well, there was this distinct difference in the suppression of the testosterone levels. I think there's 54% lower risk of major adverse cardiovascular events that are important. I think some of the outstanding issues as they come about are, what are the mechanisms behind these distinctions? Is it similar due to simply FSH/LH surge? And then, can we really understand these cardiovascular effects better? Is it an effect on the myocyte? Is it an effect on the endothelial cells or is it an effect on some fat cells or some other cells?

And I think it's important, and I think the HERO trial opens up a lot of questions that we should, I think, can maybe probe, in the setting of academic practices. But the other question comes about, well, what do we do for our patients? And again, I think, I want to kind of stress this point that there are distinctions seen with GnRH agonist versus antagonist, right off the bat. So in this case, relugolix wasn't the drug study, but rather degarelix, which is an earlier agent. And in this very nice paper done by a small Israeli group, a group of urologists, they apply the number of cardiovascular testing on the patients, but didn't see any effects. However, one thing that was telling and consistent with what we've seen before, within a short period, one year of observing patients who get started on either Lupron® or degarelix, there's a big distinction in terms of cardiovascular effects that occur in these patients.

And as you can see, 39 of these events really occur in one group with many of them happening in the agonist group. And there's a big difference in terms of cardiovascular events. These are pretty hard endpoints, if you think about it, with patients. And I think this becomes, again, sort of important as we think about the next steps.

Well, in collaboration with Dr. Alicia Morgans and others, we have developed basically some cardiovascular steps that I think are important to apply to every cancer patient, but especially our prostate cancer population. These guidelines are now adapted by the NCCN in the survivorship arm. And although we've written these guidelines such that they apply to every single cancer group, they are particularly important for the prostate cancer population.

Any prostate cancer patients, I think we have to assess their baseline cardiovascular risk and follow these ABCD steps that in many cases really apply to understanding, knowing what the patient's blood pressure is, whether they smoke, what their cholesterol is, whether they have diabetes, whether they exercise. And these are, I think, all steps that we can intervene on, on all of our patients, but particularly our cancer survivors.

And finally, I would just want to finish off by saying, it really takes a group effort to help our patients. This is our group at Vanderbilt a few years ago with Dr. Morgans heading this great multidisciplinary group that includes urologist David Penson and radiation oncology colleagues, as well as cardiologists. And only through this team effort, can we really bring what's the best care for our patients. Thank you again for this invitation.