Lisa Horvath: Thank you. It's very kind of you to invite me to talk.
Neeraj Agarwal: So we really enjoyed your presentation at the 2026 APCCC meeting where you discussed aspirin and statins in our patients with advanced prostate cancer who are on these androgen deprivation therapy with the androgen receptor pathway inhibitors. So Lisa, first of all, great talk. So can we start with cardiovascular events first? I know we all see this in our clinic, increasingly prevalent as our patients are living longer with low testosterone. So could you please tell us about the prevalence of cardiovascular disease in our patients with advanced prostate cancer?
Lisa Horvath: Certainly. And I think it's a huge problem. It's a problem of success with all of the great new drugs that our patients are getting. Patients are living so much longer with their prostate cancer. But what I think is really fascinating, but also disturbing, is that we know that testosterone suppression has lots of metabolic effects. It increases the risk of elevated cholesterol, the risks of elevated LDLs. It causes obesity and in particular visceral adiposity, which predisposes to insulin resistance and again, all of those issues around lipids. And of course, it increases the incidence of hypertension and it also has some effects on the actual vascular wall.
So all of these things happen just by switching off testosterone with androgen deprivation therapy. We all know that it's a little better with drugs like Degarelix and so that certainly, the AR antagonist certainly decreased the risk, but what is most profound when you look at the trials, in particular in mHSPC, all of our large randomized trials, that no matter what measure of cardiovascular events you look at, by going from the monotherapy to the doublet therapy, you double the incidence of hypertension, cardiovascular events, and all the other issues related to these metabolic side effects. And I think this is really profound. If we take the patient with de novo low-volume metastatic prostate cancer in particular diagnosed with a PSMA-PET scan, because I am an Australian, so I can't have a discussion without mentioning it.
That patient is going to live more than five years and possibly 10 years on doublet treatment, which is fantastic for prostate control, but progressively their risk of cardiovascular events increases. What I also think is really, really interesting is looking at the real world data. And the PIONEER database, while it shows wildly different incidences of these events, so it's difficult to compare, the key thing I think is looking at the baseline incidents of comorbidities. The data I've referred to in the randomized trials refers to patients with very strict eligibility criteria. Once you get into the real world, the incidence of going on these drugs already having significant comorbidities is much, much higher, often over 50%. So the rate that I've just talked about in the randomized trials is likely to be a huge underestimate compared to what we're seeing in the real world.
Neeraj Agarwal: That's such a great point you raised. Most of the patients are ineligible for these trials if QTC interval is slightly prolonged. So in real world, we don't have such restrictions and all these patients are being treated with these deeper androgen blockade.
Lisa Horvath: And what is also going to get very interesting down the track with the de-escalation studies that are being looked at particularly in the low volume space is how will we affect this risk if patients are having periods, testosterone holidays where they get back a level of testosterone for a period of time. So I think there's a whole pile of information that we don't have that will also help us down the track. But getting back to the discussion around how do we deal with this? I think the first thing, and I would say that a lot of this literature has been written by Alicia Morgan, so I feel like I'm heavily quoting her and want to acknowledge her.
We need to understand this. We need to go looking for these cardiovascular events, but we need to go looking for the risk factors. So every patient should be being assessed at baseline. We talk a lot in APCCC about ECGs, but actually when you look at hormonal treatment doesn't actually affect the QTC very much. I mean, we've all been doing it in all these trials, but in fact, the ARPIs, once you look at that, it's not been a major issue. The big issue is what are the patients' cardiovascular side effects? Do they already have elevated lipids? What is their blood pressure? Have we ever checked? If they already have significant risk factors, are they seeing a cardiologist? Have they been properly assessed? The other thing is we should also not only be looking at lipids, but also fasting glucose and hemoglobin A1C because the insulin resistance associated with these drugs is quite substantial and early identification and treatment of diabetes will be really, really helpful.
Neeraj Agarwal: I'm going to segue to the next question I was going to bring up. Obviously, if somebody already has elevated hemoglobin A1C or high lipid profile, is going to get worse with low testosterone. So that brings me to the next question, Lisa, which was one of the focus of your presentation. That is the role of statin and aspirin in our patients with these, advanced prostate cancer patients who are starting ADT with ARPI. What should we be doing? What we should be looking at? What are the data in favor of statins and aspirin? And should we be starting all these patients on these two drugs?
Lisa Horvath: I think the data really is about assessing the risks and starting early, especially with statins. So primary prevention with statins is well established in the cardiovascular literature with significant decreases in the incidence of cardiovascular events and the incidence of death from those events. So, primary prevention absolutely with statins. We need to be looking at the cholesterol and climbing into it early. And I think importantly, and I really emphasize this, we need to not be so scared of the side effects. I don't know if it's the same in the US, but in Australia there's been a media scare campaign about statins and there's a group that has been looking at this in some detail and shown that the myalgias that people are very worried about and scared about. In fact, there's only a 7% excess of myalgias in the first year with treatment with statins and there's no excess in subsequent years.
So myalgias can occur, but they're actually an infrequent side effect and they shouldn't stop people from going on statins because the benefits far outweigh the risk of muscle pain. However, statins also have an incidence of increased diabetes, so they do add to that. But again, these things can be worked on. So we should be aggressively pushing statins for our patients. We shouldn't be telling them to go and go on low cholesterol diets and it will all get better. Once they start ADT, they're likely to put on weight. The insulin resistance will worsen that cholesterol. We just need to be getting in there and putting them on it. The other question is what should we do if they don't have any abnormalities? Well, I don't think that the data is there yet to say that we should just be putting everyone broadly on statins, certainly for cardiovascular risk.
It's really about treating the metabolic abnormalities, but of course we cannot think that these things are static. We've got to check every year because every year that risk gets worse. In terms of aspirin, the data is really around patients with high risk of cardiovascular disease using aspirin as a primary prevention. The data for aspirin is much stronger for secondary prevention. So I think really it's about looking for people's lipids, looking for their blood pressure, making sure we control it, getting on top of any incipient or established diabetes, and making sure that we start the statins early and don't give patients false hope that this can all be controlled through diet and exercise because fundamentally with the changes we're making in people's metabolic function, that's highly unlikely.
Neeraj Agarwal: Great. And Lisa, if I may interrupt you, there's often a discussion about who should be starting these medications. Is it the primary care? Is it the oncologist? Aspirin is safe. 80 milligram daily virtually has no interaction with other anti-prostate cancer medications we use, but statins do pose some challenges from that perspective. So what is your practice in your clinic regarding starting aspirin and statins in your patients with advanced prostate cancer?
Lisa Horvath: So my practice is that I do like to partner with the primary care physician and I think it's very important. They have a lot more experience in primary practice and in cardiovascular prevention than I do these days. It's been about 30 years since that's been my primary focus. However, I do acknowledge that there are interactions with the statins and some of the ARPIs that we use. There are concerns about changes in the statin levels and will that change how well they're working? I would emphasize we have a fabulous pharmacodynamic marker. If your cholesterol's in the normal range, you're on enough of the drug.
So I'm very comfortable in terms of monitoring that on lipids. What I will tend to do is I might start the statin if I find that on my routine bloods, but I would then always partner with the primary care physician because they will see the patient more regularly and they need to be involved. The other thing I would also say that what we don't know yet is things like Ozempic, and Wegovy, and Mounjaro and how they're going to affect this. These drugs, yes, we're using them for weight loss, but we also, and that's very helpful in prostate cancer, but they have quite profound effects on insulin sensitivity. They do affect lipid profiles and with increased availability, it will be interesting to see how they also fit into the paradigm that we use for cardiovascular prevention.
Neeraj Agarwal: That's great. So just to summarize for our viewers today, primary prevention in patients who have elevated lipid profile with statin is very important for our patients with advanced prostate cancer starting ADT plus ARPI. Patients who do not have high lipids or lipid profile is completely unremarkable, we don't have the data to support. Maybe PEACE-4 trial. We can talk about the PEACE-4 trial in a moment, but that will probably answer that. And then regarding aspirin, it's a pretty simple drug, no drug interaction and patients with elevated cardiovascular risk profile should be strongly considered for starting aspirin at 80 milligram daily. And cooperation or close interaction and partnership with primary care physician is very important because they are the ones who are more experienced than us regarding use of these medications. Is that a correct summary of the discussion?
Lisa Horvath: Absolutely. Completely agree with everything you've just said.
Neeraj Agarwal: And could you elaborate more on the PEACE-4 trial?
Lisa Horvath: Well, I might start off by just briefly talking about the fact that statins in particular and to a lesser degree aspirin have had a long history in prostate cancer randomized trials and there have been several sub-analyses from a number of these trials to see if patients who are already on these drugs for cardiovascular prevention, either primary or secondary do better. The data is much stronger for statins and in particular around the ARPIs. The data for aspirin is probably more around primary prevention from screening studies or patients that have had localized prostate cancer treatment. The data at the moment is not, it's not hard data. What PEACE-4 is aiming to do is to look at this in a randomized control fashion. This is a study out of France and it is patients with metastatic castration-resistant prostate cancer, having first-line treatment, standard of care, and being randomized to either aspirin or a statin or the combination.
So it is the first really rigorous study to see if the post-hoc data that we've been looking at can be translated forward. And it's not about whether you've got an elevated cholesterol or your cardiovascular risk, it's a simple randomization. So I think it has the potential to give us some really powerful data. It's also very interesting based on some of the plasma biomarker work that we've been doing out of [inaudible 00:15:47] where we've identified immunometabolic phenotypes. We can see patients who have high lipids. These are not cholesterol or LDL, they're things called ceramides, but they're associated with poor prognosis. And we see patients that have this elevation called PCPro, and our clear compliance signature. And then we also have looked at pro-inflammatory cytokines, which are associated with those ceramides and we can see four distinct groups.
There are patients that have lots of inflammation, abnormal lipids. They are the most poor prognosis group. There is a large group that have no aberrations and I really think will be very interesting whether they're a really good group for de-escalation, but then there are groups that have inflammation without lipid changes, lipid changes without inflammation. And these subgroups we're going to be looking at in PEACE-4, it's been incorporated into the protocol and we may actually find that we have some plasma biomarkers that can help us guide who would be most likely to benefit from the statins and the aspirins. So I'm interested in PEACE-4 from a purely clinical standpoint, and then I have a slightly selfish scientific interest as well.
Neeraj Agarwal: Well, we look forward to result of the trial. In the meanwhile, we can be quite proactive with screening our patients for cardiovascular risk and talking to them about aspirin and statins.
Lisa Horvath: Can I put one more plug in? Which is-
Neeraj Agarwal: Of course.
Lisa Horvath: All of these things should also include exercise because another potent factor to improve cardiovascular risk is exercise. So I'll just plug that at the end.
Neeraj Agarwal: Very well said. Thank you. Well, Lisa, thank you very much for sharing your wisdom. And as always, it's a pleasure to have you on board.
Lisa Horvath: Thank you so much. It's been a pleasure talking to you, Neeraj.