Dr. Jehonathan Pinthus presented at the 26th International Prostate Cancer Update on Friday, January 22, 2016 on “Cardiovascular Complications of ADT: Reviewing Pre-clincal and Clinical Data and Introducing the RADICAL-PC Trial.”
Keywords: prostate cancer, cardiovascular disease, ADT, FSH, RADICAL-PC Trial
How to cite: Pinthus, Jehonathan.”Cardiovascular Complications of ADT: Reviewing Pre-clincal and Clinical Data and Introducing the RADICAL-PC Trial.” Grand Rounds in Urology. January 22, 2016. Oct 2019. https://grandroundsinurology.com/prostate-cancer-jehonathan-pinthus-cardiovascular-complications-of-ADT/.
Cardiovascular Complications of ADT: Reviewing Pre-clincal and Clinical Data and Introducing the RADICAL-PC Trial
Cardiovascular disease simply should be divided into two main domains. In the arteries there is a buildup of plaque that narrows the lumen but this is usually a stable plaque and what it can cause and here you can see the stable plaque on the cross section. It can cause what we call unstable angina meaning that a man would have normal function but when he exerts, there would be a demand for more oxygen and more blood flow and symptoms will come. But this is stable cardiovascular disease or stable atherosclerotic plaques. The problem comes when these plaques are unstable and rupture and cause a thrombus on top of the fibrous cap, which is now torn, as you can see here, it completed occluded the vessels causing acute ischemic attack, MI, stroke, et cetera.
Now, we need to realize that the epidemiology of cardiovascular disease is actually very interesting in prostate cancer patients. Prostate cancer patients, I will show you, being diagnosed with prostate cancer puts them at risk, at high risk, to have cardiovascular event. The American Heart Association defines a significant risk for cardiovascular disease if one has more then 2% a year – – to develop cardiovascular event.
Now, look what happens with prostate cancer. This is from the Swedish Registry Trial. You can see patients with prostate cancer on no ADT so those are hormone naïve prostate cancer patients and you can see already that there is a very high over and above 2% a year chance of developing cardiovascular events so being a prostate cancer patient puts you at risk from the get go to have cardiovascular event.
We are investigating through so that this will be presented in the upcoming AUA and just to be short and for the sake of time, what I can show you here is that when one has prostate cancer, which is a high prostate cancer, those are the prostate cancers that are destined potentially to receive ADT at one trajectory of their disease, one would have other diagnoses already – – in hormonal and metabolic profiles such as the fasting C-peptide, leptin, adiponectin, and so forth.
So prostate cancer patients are at right risk for cardiovascular disease. This exceeded the 2% a year that is considered high risk by the American Heart Association. Indeed the chance of that in patients on ADT is even more than 4% so at a very high risk and you can see it here.
The Swedish Registry again, very high risk with GnRH agonists and important point that I wanted to make. This does not only true for the bread and butter ADT – – , GnRH agonist, potentially GnRH antagonist. This is also true for patients that are undergoing now on novel ADT agents and this is a very nice paper which we commented on that in European Urology can see it I think this month and this relates to the risk metaanalysis for the risk within. This significantly increased the risk for cardiovascular disease morbidity or even mortality. But this comes into conflict with so to speak randomized control trial, which are not randomized and not controlled. This is data from patients that underwent radiation with hormones – – group compared to patients that received radiation and often time a delayed hormonal therapy or short course of hormonal therapy, which was considered as control. So, this are not very clean comparison and obviously the endpoints of those studies were not cardiovascular disease.
So essentially the take home message number one is cardiovascular disease and it’s risk factors are very common in prostate cancer patients, high risk, potentially more aggressive disease and observational data suggested the risk is significantly increased with all forms of ADT.
Now, how is that happening? So one needs to understand and I’ll show you two models. First patients with no cardiovascular risk factors in which ADT would promote the development of metabolic syndrome, glycemia deposited, dyslipidemia, which would build up plaque and patients and as I show you this is very common with already established cardiovascular disease in which the hormonal intervention would induce plaque and event.
Now, for the sake of the talk, I will, and for the novelty I would focus on FSH. Now FSH is a very topical hormone, okay? In males, what it does, it stimulates the seminiferus tubules but it has also effects that, or has very important biological significance in tumor genicity and also in obviously in metabolism in cardiovascular disease include steroid genesis and calcium intake and so forth and so on. And the important thing and I think this is a very important message to you is that the regulation of FSH secretion is not similar to LH. So if we come with GnRH analogs for example, we do not have the same suppression of FSH and LH. It’s not that they both dropped down. And what’s interesting is that the FSH receptors are not just on the testicles alone. Actually they are very, and this is analysis that we did, they are very, very common on many tissues including tissue that are very important in the metabolic syndrome and cardiovascular disease such as cardiac myocytes here, skeletal muscles, adipocytes, and so forth.
And not all ADT forms result in the same FSH levels. For example, orchiectomy would result in very high levels of FSH because we lose the – – that is secreted from the testes and cause some – – inhibition. GnRH analogs and agonists actually cause a reduction in FHS but this reduction is only to 50%. The most significant and sustained reduction in FHS levels is achieved by GnRH antagonists and here you can see data from the CS21 and 21 extension trial where you can see the difference between agonist and the degarelix in terms of FSH suppression and you can see that if you switch from agonist to antagonist you do get a significant further suppression of FSH.
So why is that important? Think of females, okay? Let’s go out of the world of prostate cancer patients or even males. Females, when they get into the menopause, what happens is that they start to gain weight. And they gain weight in different depots such as the subcut, the visceral fat, ectopic fat, and also very interestingly, premenopausal females don’t have that high risk of cardiovascular disease but when they get to the menopause or into the premenopause, very early menopause period, they catch up with the rates of males. And what’s the hallmark of menopause? It’s the FSH. And the FSH dries up significantly in menopause. And you can see indeed that you can correlate the FSH levels to the body fat and there is a direct correlation. The more FSH you have, the more fat you have.
Now, as I told you, there is a conflict within observational trials that shows a significant positive effect of ADT on cardiovascular disease and one meta analysis of randomized or – – randomized trials in radiation that did not show that. So what we decided is to manipulate mice, which are actually an ideal model. Why? Because mice do not have cardiovascular disease. They don’t smoke. All of them have the same diet. They live in the same cage. They all have the same genetic background. None of them take statins and so forth. So what we did is that we manipulate them with different modes of ADT such as castration, sham control, and sham control with leuprolide, and sham control with degarelix.
And what you can see and this is a very pure analysis of data. You can see and this is a city measurements of body composition you can see that indeed mice that are treated with ADT gained fat and lose lean body mass, i.e., muscles and you can see it with from your patients, you can see that they get weaker, they have muscle atrophy but the least so, when the FSH levels are low, this is with degarelix and more so or even equally in patients that have orchiectomy and leuprolide, some holds true with dysglycemia.
Here is fasting glucose levels, this is – – under the care for glucose tolerance test and you can see indeed, yes, ADT does induce hyperglycemia and dysglycemia but in a more specific manner, okay? The list is with the antagonist related potentially to the FSH that is very low and more so with the other forms of therapy.
So, what’s very important is that mice are actually very atheroprotective. So the ADT intervention by itself proved to be a very atherogenic factor. What’s very interesting is that we could take the arteries of these mice and actually measure the atherosclerotic plaques and what you can see again that if you look at the area of the plaque, okay, the plaque size, you can see that indeed with all forms of ADT, it increased, less so with antagonist but equally with agonist and orchiectomy.
What’s more important is the area of the necrotic core. I don’t know if you remember, but when I showed you the unstable plaque, they have a necrotic core. This is an area of inflammation that is very unstable and tend to rupture and you can see here in the wide bars that there is a significant difference between the ADT modes with respect to the tendency to make plaque unstable.
So in subjects without preestablished atherosclerosis, I believe that ADT causes the metabolic syndrome – – prepare the plaque, the stable plaque if you will causing a deposit dysglycemia, dyslipidemia, hypertension, in a – – specific extent, orchiectomy more equal to GnRH agonist and this is more than in GnRH antagonist that seems to be more athero friendly if you will. But in subjects with established atherosclerosis and remember a lot of your prostate cancer patients do have cardiovascular disease. What happens? ADT induces plaque instability and hence cardiovascular events and this is a very interesting paper from JCO last year. It’s a very complicated one so I’ll just give you the message.
When they look at the rates of cardiovascular event from the – – of ADT and you can see that it already within six months, one can see a significant incidence of cardiovascular events in patients that you place on ADT. Why is that? This is because you take patients with established atherosclerosis, okay? And you intervene with your hormonal therapy and you causes this plaque instability that obviously rupture, blocks the artery, MI, stroke, death, et cetera. And that relates exactly to this wide bars. To the amount of lipid core and the carotid core and you can see that there is a difference between the different hormonal therapy favoring antagonists probably because of FSH and I’ll show you some data on that. This is just some, additional data.
For the sake of time I will skip that but you can see here. This is data from the Swedish group growing again on mice and you can see a very significant change in the necrotic core and an inflammatory response in those that are treated with an agonist compared to antagonist. This is data from the Albertsen data that did a – – of six leuprolide, the degarelix trials comparative trials for the cardiovascular endpoint. The patients were even in terms of their cardiovascular risk profile at the time of ADT commences and you can see that in patients with established cardiovascular disease, there is a significant difference even within a year, a year with the respect of cardiovascular events.
So why does that happen? And this is a little bit data from my lab. I wouldn’t release everything but I think it’s just to give you a notion that there is some science behind that. So, the atherosclerotic process or the plaques are actually an inflammatory process. And the main drivers are macrophages, monocytes that are recruited into the plaque and they start their entire machinery of lipid accumulation and inflammation and so forth but macrophages are not just one type. Very simplistically, there are two types of macrophages: The good macrophages and the bad macrophages. The bad macrophages, the M1 macrophages are trouble. They secrete factors for example that degrades the fibrous cap that tries to conceal the plaque and prevent rupture, okay? They secrete pro inflammatory cytokines. The good macrophages are actually trying to settle down the fire, okay? They secrete factors that are inhibitory to the inflammatory reaction somehow that are actually building a fibrous cap and what we can see is that, and that relates to the FSH, that when we compare our mice that were treated with agonist and antagonist for example, with the antagonist, we had more good players than with the agonists and this relates to the effect of FSH.
This is just for the sake of time again, this shows you the lipid accumulation in what so to speak foam cells and you can see, we take the macrophages from the bone marrow of this same mice. We can – – from there here. We are treating them either with control, which actually has no testosterone in the serum or we add FSH, you can see here that they accumulate fat. So FSH has – – on the macrophages as you can see here and this FSH in the presence of no androgens increased the accumulation of fat within these macrophages, i.e. foam cells. I’ll skip that of the sake of time.
Interestingly, and this is a little bit of a hard concept, when you have mice that are genetically engineered to have significant diabetes, no insulin, actually ADT protects from cardiovascular effect, compared to their control mice where ADT actually increased the plaque size and you can see it here on cross sectioning of the aorta with staining with red lipids but what interesting in these mice, that you can actually take the coronary, cross section them and see how much they are occluded. Now remember and I don’t have time to get into the explanation why it happens, but in this model, it’s preestablished that ADT actually, only in these mice, protects against cardiovascular disease and this is hard core data of mortality of these mice, more than 10 mice group and you can see again there are differences in mortality rate, cardiovascular mortality between mice that are treated with agonists and antagonists.
So, take home message number two: ADT induced obesity, metabolic syndrome, and atherosclerosis, cardiovascular disease to a more specific extent, an FSH level may have a role in this effect. In patients with preexisting atherosclerosis, ADT may induce plaque instability and potentially this gives us an opportunity to consider that there may be some more cardio friendly modes of ADT. We have to look into that clinically but this is a very strong preclinical suggestion for that.
So, I’m privileged to be the PI on a study that has just been launched called the RADICAL-PC. It was funded by Movember, hence you can see this logo I expect will appear a lot in the coming years. So you can see the – – you can see the blue color of the prostate cancer in the moustache but what this study is and this is done in collaboration with Klotz and Lucia, and two very leading cardiologists, and what that look is it’s actually two studies. First prospective trial for cardiovascular endpoints in prostate cancer patients and that would look at A, there are two studies that are nested within each other. The role of androgen deprivation therapy in cardiovascular disease a longitudinal prostate cancer study. So this is the perspective cohort study and within that, there is the buildup, another study is built, and this is a randomized intervention for cardiovascular and lifestyle risk factor in prostate cancer patients and this is a randomized control prevention trial. So, again the key epidemiological observation is that men with prostate cancer are at high risk for cardiovascular disease.
The role of ADT in promoting cardiovascular disease remains uncertain clinically yet. So, the unanswered questions are what are the most important determinants of cardiovascular disease in men with prostate cancer and how we can prevent it. Because obviously we will not stop giving ADT for patients that needs it combined with radiation or patients with metastatic disease.
So how can we predict who is going to get cardiovascular disease and how we can intervene and try to prevent that. It’s a perspective trial of 6,000 men. The objective of RADICAL PC1 will be to determine the representative contemporary sample of men, the prevalence of cardiovascular disease risk factor and disease as well as the incidence particularly among patients who starts ADT.
So, alright so, the RADICAL PC2 will determine modes, – – in a second, modes for prevention, I’ll skip that. I think I’ll skip that. There will be a huge component of bio-bank, which will be also for R and D and we are going to look at several markers for cardiovascular disease. One interesting marker is the troponin. We had, I was a coauthor on that but that study was obviously lead by cardiologist PJ Devereaux, who showed on 40,000 men that, so troponin levels can predict a very hard core endpoint which is cardiovascular modality within 30 days. So we will look into that in patients that are undergoing ADT and prostate cancer patients and I think that the significant finding of that, and we already started to recruit, so we have the data on the initial patients, 100 patients. This is the first prospective cohort study of prostate cancer ADT with defined cardiovascular disease endpoints. We will be able to potentially discover risk factors to stratify patients who are at risk, have a large bio-bank, and hopefully will determine roles for prevention.
So, just thank you for my collaborators, Geoff Werstuck, Helga Duivenvoorden, and Sarah Hopmans for the lab work they did. Thank you.