Andrew Hahn: Thank you, Neeraj. It's my honor to be here, and I've learned a ton from you, and excited to have the conversation.
Neeraj Agarwal: So Andy, you have done a lot of work regarding cardiovascular outcomes in patients with metastatic prostate cancer or advanced prostate cancer. Just taking a step back for our worldwide audience today, we know that as patients are living longer with great new medications like ADT plus ARPI and many more coming, they're living longer with prostate cancer, which is great news, but then we have to really worry about other non-prostate cancer causes of mortality and morbidity. And cardiovascular issues are one of the most important causes of that. So first of all, we are interested in learning what you presented in the ASCO GU 2026 meeting, and then we can talk about the implications of those findings and what as community of medical oncologists and urologists, what we can do in our busy clinics for our patients.
Andrew Hahn: Yeah, absolutely. No, I think cardiovascular events are an extremely important and under-addressed need in the community for men living with prostate cancer. And so for this study, this was a real-world study that we did. The background for this is that, and you know this well, but in the HERO trial, they showed that use of relugolix, an oral GnRH antagonist, was associated with a significantly lower risk for developing major adverse cardiovascular events, which I'll refer to as MACE moving forward. And that was in 2021. Around that same time the PRONOUNCE trial came out, which brought up some other cardiovascular issues and items and really suggested that having a cardiologist involved made a very meaningful difference in lowering your risk of having MACE events. So we went to the market share commercial and Medicare databases. We used an index date of the date that ADT was prescribed, whether that was GnRH agonist or antagonist. And then that was your index date. And the primary endpoints that we were looking at were two- and three-point MACE.
And then we had a secondary analysis where we were also looking at incident or prevalence of MACE, pre and post-2021, when both of those studies came out. So kind of a few highlights from a baseline characteristics perspective. We had about 17,000 patients who met the criteria. About 90% of those or so received a GnRH agonist such as leuprolide. And then about 10% received a GnRH antagonist, either degarelix, and that was about two-thirds of the antagonist or relugolix, about a third of the antagonist. And this time period went up to May 2024. So not some of the more recent data where we've seen really increased uptake of relugolix. Now, there were three, in my mind, key differences between the people receiving agonist and antagonist. The patients receiving agonists were older median age. Patients receiving agonist were less likely to have commercial insurance, more likely to have Medicare, and had a longer median follow-up. That being said, I think there were three or four key takeaways from a results' perspective. The first one is that the relative prevalence of MACE across all patients was relatively low. It was about four major adverse cardiovascular events per 100 person years. You can think of that as either a hundred people followed for a year, 50 for two years, et cetera. So four there. And when we compared agonist to antagonists, we saw a numerically lower prevalence of MACE in the patients who are receiving antagonists by about 37% compared to those receiving agonists.
And then for me as a medical oncologist, one of my key takeaways, and one that I think we're going to revisit here in a few minutes, is that patients who had preexisting cardiovascular disease before starting either agonist or antagonist had a substantially higher prevalence of MACE, about 11 events per 100 person years. So there's this really about threefold increase that happened for those patients. Final component from the study when I was thinking about it was that we looked at pre-2021 versus post-2021, and we saw a modest reduction in the prevalence of MACE in the post-2021 period compared to the pre-2021 period, suggesting that there probably is some increasing awareness developing as these different studies have come out, but there's clearly some unmet needs as well.
Neeraj Agarwal: Really pertinent data, I think. Large patient population, real world. And again, one year, it's great to measure anything you can, but in the lifespan of a patient with metastatic prostate cancer, six months and one year, a relatively short time period as these patients, our patients are living much longer. And as these MACE events, which are the extreme form of cardiovascular events, but they don't necessarily capture the earlier time points of metabolic syndrome, diabetes, atherosclerosis, kidney dysfunction, or many other cardiovascular issues which are not necessarily captured by MACE definition. They are very prevalent. We know that. And this study and many other studies have consistently shown they are present and they may be better with the GnRH antagonist over agonist. And again, juries out there for relugolix versus degarelix, we don't want to get into that. Relugolix has most clear data that MACE decreases by multifold, especially in those patients who have MACE in the past, had MACE in the past, or major cardiovascular events in the past. So thanks for doing all this.
Thanks for bringing this to the attention of the community out there, to us. How do we approach this? How do we approach tackling this challenge in the clinic? And I'd just like to add, you are busy, Andy. I am busy. We are happy to be able to solve the prostate cancer problem if we can, take care of our patient's prostate cancer, and these related complications. And now we have this major cardiovascular issue facing us. How do we tackle this?
Andrew Hahn: Yeah, I mean, absolutely, Neeraj. I think there's a natural inclination for clinicians treating men living with prostate cancer to focus on prostate cancer, especially when it's going well. It's great to walk in a room and have good news and just focus on your PSAs down, you're doing well with therapy and leave it at that. And I think there is that natural inclination. We need to be addressing the rest of the cancer health for the patient, and that's not just their PSA and their disease, that is their cardiometabolic health beyond just major adverse cardiovascular events, their bone health. There's a lot to this. I think a reasonable beginning approach of what we're trying to do is just increase awareness for clinicians of how to identify patients who need to be escalated from just being seen by an oncologist and followed there to seeing either their primary care doctor or ideally, PRONOUNCE showed us this, seeing a cardiologist because if we have cardiologists doing preventative health, we can really lower the burden of MACE that our patients are experiencing.
So we have, you know this well, but with Dr. Gupta from Medical College of Georgia, he has led this work with Prostate Cancer Foundation as well of putting together a consensus statement from a group of industry and experts, including a number of cardio-oncologists to identify the patients who are at the highest risk, this kind of red category and say, for this group of patients, we need to be instantly putting referrals into cardiology or primary care and ensuring those visits occur for those patients. What are things that we can be doing to try to identify those patients? Some of it's really simple things, reviewing vital signs, reviewing concomitant medications, reviewing past medical history, where patients live, what race they are. These all contribute to your risk of developing cardiovascular events. But then if you want to take a step further, there are more things that we as medical oncologists and clinicians can do, and that includes things such as measuring lipid panels to calculate different cardiovascular risk scores if we want to be a little more sophisticated in our approach, evaluating hemoglobin A1C.
And if you want to round out the picture a little bit beyond MACE or cardiovascular events is looking at DEXA scans and evaluating bone health for these patients as well. This can be a lot, and this is where really I think this consensus statement is just making an argument for increased awareness and a workflow, potentially even a website so that patients can understand when they're at a higher risk and ensure that they're going to see the right providers so they have good long-term outcomes and live well, and live for as long as possible with prostate cancer.
Neeraj Agarwal: So well said. So we are really looking forward to the statement which you and Dr. [Inaudible] are leading to make sure we have very clear guidelines on what we should be doing as medical oncologists, taking care of patients with prostate cancer, and also for my urology colleagues, they are very busy. So what we should be doing in the clinic, I really hope to get a very clear message from that consensus statement coming from the PCF clinical industry roundtable. I look forward to reading that paper very soon.
Andrew Hahn: Yes, I do too. Thank you, Neeraj.