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Alicia Morgans: Hi, I'm so excited to be here today with Dr. Omar El-Taji and Dr. Ashwin Sachdeva, who are joining me from the University of Manchester and The Christie Hospital to talk about some interesting work that's continuing along the lines of what they've been doing over the last few years, which is investigating complications of hormonal therapy for prostate cancer. Now, these two have done some exciting work that's now published in JAMA Oncology, which is further evaluating the contribution of AR pathway inhibitors to cardiovascular risk in patients with prostate cancer. So thank you both so much for being here. And Omar, why don't you share some slides telling us a little bit about your data.

Omar El-Taji: Thank you so much, Dr. Morgans, and thanks for giving me the opportunity today to present some of the work that we've been doing in Manchester. Today I'm going to give a brief presentation on a systematic review and meta-analysis that we presented that was published in JAMA Oncology only yesterday. We were looking at cardiovascular events in patients with advanced prostate cancer treated with androgen receptor signaling inhibitors.

We looked at all randomized control trials that included at least one arm that randomized patients to androgen receptor signaling inhibitors and compared those with patients who received standard of care, which could have been ADT with or without docetaxel. And we identified 24 studies, and these studies included patients who are on abiraterone, enzalutamide, darolutamide, or apalutamide. There was one study from STAMPEDE, the J comparison of STAMPEDE, which looked at abiraterone with enzalutamide. Now, these studies comprised patients who had non-metastatic hormone-sensitive prostate cancer all the way through to metastatic castrate-resistant prostate cancer. So the whole disease spectrum.

Our primary outcome was cardiovascular events. We looked at any-grade cardiovascular events and high-grade cardiovascular events. Our secondary outcomes looked at specific cardiovascular conditions within the cardiovascular disease spectrum, including MI, so myocardial infarctions, stroke, cardiac dysrhythmia, venous thromboembolism, and we also looked at cardiovascular death.

What we found was with the addition of an androgen receptor signaling inhibitor, patients had a 1.8-times increased risk of a cardiovascular event of any grade compared to standard of care. For high-grade cardiovascular events, we found a two-fold increased risk of such an event occurring with the addition of an androgen receptor signaling inhibitor compared to standard of care. And this was seen across the whole disease spectrum. Now, there was some heterogeneity within our data and we performed a sensitivity analysis as well as meta-regression to further elucidate what was causing this heterogeneity.

Now, our subgroup analysis, we looked at androgen receptor signaling inhibitors in isolation, and what we found was that the highest cardiovascular risk was with abiraterone and enzalutamide, and this was up to a fourfold increased risk for a high-grade cardiovascular event. What's important to also note is that darolutamide only had one study available for comparison where we had access to the cardiovascular event rates. Our secondary outcomes were very interesting, and what we found was that there was an increased cardiovascular risk across all the secondary outcomes apart from venous thromboembolism. What was more interesting was that there was a two-fold increased risk of a grade 5 cardiovascular event, meaning a cardiovascular-related death, and that's something that we didn't expect.

The important take-home messages are that ARSI agents are associated with an increased risk of cardiovascular events across the whole prostate cancer disease spectrum and that the addition of an ARSI can double the risk of cardiovascular-related death when compared with standard of care and the greatest toxicity was with double ARSI, and that was seen within the STAMPEDE arm J data. What we do recommend is both screening and monitoring for cardiovascular events when ARSIs are initiated in addition to conventional androgen deprivation therapy. Thank you.

Alicia Morgans: Really, that was fantastic. Thank you so much, Omar, for sharing that and certainly congratulations on doing the work, pulling all of that data together. Now, this has been something that I think we've all considered as we've tried to practice, but this is some of the most compelling compilation of all of this data from my perspective and really nicely done in terms of trying to quantify that risk. I wonder, from your view, does this impact your clinical decision making? You are a urologist, you think about these agents, I'm sure, for many patients in your clinic. Do you think about this and this risk as you're choosing to potentially start an agent or maybe hold off, and how do you balance this risk with the benefit that we know could be fairly universal in many settings for these agents?

Omar El-Taji: Yeah, no, I think you're right and I think the important thing here is to understand that the use of ARSI agents, there's quite a clear OS benefit. But what we must take into consideration here is that patients are at increased risk of a cardiovascular event, and that can occur as early as within the first couple of weeks. And we saw that within the HERO trial, which looked at GnRH agonist versus antagonist or with the relugolix, but we saw that within the first couple of weeks, within four weeks, the first cardiovascular event happened.

So what we need to do as clinicians is we need to assess patients when they are at the point of diagnosis and risk assess them so that we can have a better understanding of which patients may develop cardiovascular events in the future and which patients may not. And there are certain ways that we can assess that risk. The European Society of Cardiology, for example, has a really good risk stratification tool and what they recommend is that patients who are at high risk based on their calculator, should be seen by a cardiologist or a cardio-oncologist.

Alicia Morgans: I think, certainly, that that makes sense. And I wonder if that may be contributing to the difficulty in ongoing more recent trials than the HERO trial to actually capture that cardiovascular signal that we saw. I'm sure that the two of you recall that PRONOUNCE, first, was unable to actually enroll, it really got over just about half of the patients planned, but then in the analysis, the event rate was substantially lower than expected. Do you think that our acknowledgment of the cardiovascular risk in our intervention in these ways, sending people to cardiology, working as urologists, medical oncologists, and others to try to mitigate risk factors and reversible risk factors of cardiovascular disease, do you think that's having an effect and perhaps leading to some of the changes that we might see in everyday management and in more recent clinical trials? Ashwin, I'll give this one, which is a little more of a difficult question, over to you.

Ashwin Sachdeva: Yeah, absolutely. I'm glad you mentioned the PRONOUNCE trial because one of the key things we learned from there was that a guideline-directed secondary preventative strategy can dramatically reduce the event rate. And I guess that we were a victim of our own success by stipulating that we should do our best to minimize cardiovascular events using lifestyle interventions, using the pharmacological interventions to better control these risk factors. And this resulted in a very low event rate, which made that trial pretty much impossible to complete.

So I think taking that message away from the PRONOUNCE trial and applying it to a clinical practice, if we are a bit more astute about assessing baseline cardiovascular risks, doing simple things like perhaps better managing diabetes and glycemic control, better managing blood pressure, hypertension, and perhaps even advising patients to consider interventions such as exercise may help reduce some of this baseline cardiovascular risk, which we know is a significant factor in a substantial proportion of patients presenting with prostate cancer. And largely this gets ignored and instead we prioritize largely on the cancer-related outcomes. So I really hope that the work that we've presented as part of this paper makes us consider baseline cardiovascular risks and what we can perhaps do about that to minimize them with simple interventions. And when things are more challenging, clearly guidelines would recommend that we should seek input from a cardiologist or a cardio-oncologist.

Alicia Morgans: Absolutely. Omar, back to the analysis and less sort of thinking about real world and practice and data. I wonder, could you share, every study has its limitations, what are the limitations in this particular analysis?

Omar El-Taji: I think, I guess the first limitation was that, as a systematic review and meta-analysis, we didn't have access to individual patient data. And for that reason, we didn't have time-to-event data. So these patients are now living longer, and do we know whether the increase in their survival is related to the fact that they may end up experiencing a cardiovascular event? But that really does need a kind of individual patient meta-analysis, and we hope that that can be done in the future.

Alicia Morgans: Certainly, and that does make sense, and every meta-analysis, or most, will have a similar limitation in that. But prospective studies hopefully in the future may be able to sort it out, though still may be limited by what Ashwin was talking about earlier, that we have succeeded in reducing the event rates for our patients, at least when it comes to single agent ADT. And still these may be hard questions to answer prospectively.

So Ashwin, where do we go from here? What are the next steps, new directions for you and your team, whether it comes to the investigations of cardiovascular risk or other complications? Because you really have been adding to the literature over the last number of years thinking about bone health and now cardiovascular risk. There are many things that can afflict patients with prostate cancer. Where do you go from here?

Ashwin Sachdeva: Yeah, absolutely. And what is a real hurdle in clinical practice is that when a patient presents and we're discussing different treatment options and the risks and benefits of each of them, we are really limited by the amount of time that we have to spend with the patient, and anything we can do to help risk assess them in an easier manner might allow us to really start to consider which patients might need these additional interventions to mitigate those risks.

So one of the things we're doing is to use standard imaging data. So patients normally have a staging CT either as part of a contrast CT or a PSMA PET-CT scan more recently, and we are hoping to see if features within the scan itself can help us predict which patients might be at increased risk of toxicities. The other thing which we're quite keen to do is address the competing risk of perhaps in the controlled arms of these studies where patients are unfortunately not living for the same duration as those who were treated with an ARSI. We would like to adjust for that potential bias in using individual patient data analysis. And that'll give us a clearer picture of whether ARSIs are truly contributing to this increased risk of toxicities, such as the cardiovascular toxicities that we highlight in this paper.

Alicia Morgans: Fantastic. Well, we certainly look forward to hearing those analyses coming forward as they will absolutely contribute to the decision-making that we make each day with our patients and certainly help them and their families, keep them as well as possible. Omar, you get the last word. What should the take-home message be from this analysis?

Omar El-Taji: I think we've identified that there's an increased cardiovascular risk and we need to make people aware that there's an increased cardiovascular risk. What we can then do is when patients do come into the clinic, we can risk stratify them. We can make them aware that even if they have a low risk, there are ways to mitigate their risk down the line.

So one thing that I will always remember is there's an ABCDE approach. So awareness is most important, make sure their blood pressure is well controlled, smoking cessation if they do smoke, ensure that their blood sugars are well controlled and if they are diabetic, but that needs to be seen by their general practitioner and it needs to be well controlled, and E, exercise, make sure that these patients are exercising, because not only would it reduce their cardiovascular risk, but it has a whole load of other benefits with regards to prostate cancer and general health.

Alicia Morgans: Well, I have always been behind that ABCDE approach. So love that you are interested in that too. Whatever approach we take in the clinic, it needs to be a systematic one and it needs to address those reversible risk factors and certainly acknowledge and make sure patients understand that cardiovascular risk comes with everything we do, particularly when it comes to hormonal therapies. So thank you both so much for your time and your expertise. I look forward to talking to you in the future as more work comes to light. Thank you.

Ashwin Sachdeva: Thank you.

Omar El-Taji: Thank you.