I think all of us are dealing with that. And I saw the abstract with really pertinent data from your STAMPEDE trial, another machine, a fantastic database you have created, you and your colleagues have created in UK, you said 12,000 patients with metastatic prostate cancer. So I'd like to ask you if you could please tell us about this non-prostate cancer-related mortality issues you have encountered with a doublet therapy, ADT plus ARPI in patients with metastatic hormone-sensitive prostate cancer, and then we can talk about the implications of these results.
Noel Clarke: Thank you, Neeraj. Yes, I'd be delighted. And of course, we've known for some time that androgen deprivation therapy has consequences, metabolic consequences for patients, and that's associated with increased cardiovascular risk. And we know that it has effects on musculoskeletal integrity. For example, this has led us to study this in much more detail at population level, and we've been lucky enough to have the STAMPEDE trial, and we have a large coordinated translational science program which enables us to analyze the data from the trial. And in this particular instance, we have something like over 12,000 patients in the trial. We've been able to bring together a centralized imaging repository of about 10,000 or so scans, which we've been able to categorize, quantify, and link to what we call hospital episode statistics. Now, these are records from national databases, which gives an indication of what has happened to a patient, whether it's a heart attack, a stroke, a broken bone, or whatever.
If a patient is admitted to hospital with any of those things or goes to a hospital, then we're able to access that information particularly and link it to the STAMPEDE trial, especially for data in England, which is the largest proportion of the STAMPEDE population. And that's a hugely powerful thing to look at. What we have been able to establish is that in STAMPEDE, which looks at M0 and M1 patients, that there's a substantial risk of a clinical fracture at five years. And in STAMPEDE for M0 patients, that runs at about 16%, and for the metastatic patients, it runs about 30%. And when we looked at this at larger scale in the English NHS where we have something like between 50 and 60,000 cases per year, newly diagnosed prostate cancer, we know that those presenting with M1 disease have a rate of about 40% clinical fractures within five years without bone protection. And we've shown that adding bone protection reduces this. Now, we've taken this further by looking at what we consider as standard scans to see if we can gather information from those scans in a way which is much more sophisticated than just simply reading the scan with a naked eye. And we've been able to measure things such as bone strength, muscle area, visceral and adipose fat, and the amount of fat within the muscle, which is an assessment of the quality of the muscle.
And we've used specialist imaging systems, which can read a standard CT scan and produce all this information within a matter of about 30 to 40 seconds, and then we can compute which are the most important factors, things like calcification in the aorta, things like the amount of fat in the psoas muscle, the amount of adipose tissue in the peritoneal cavity by comparison with the abdominal wall. And that is a way of looking at things, which as urologists and medical clinical oncologists, we've not been as good as we might have been. Looking at a sarcopenic patient, assessing the strength and so on, it gives us an objective measure from a standard CT scan, which most of these patients are having and which can be done very quickly. What we presented at the meeting here at GU ASCO, San Francisco 2026, is a combination study which has put together a compound read from a standard CT scan using a program which reads all this very quickly. We tested four different programs, and this program, which is called OSCA, which is freely available online, it's an American-developed program, will conduct these measures. And once we put that through a ranking system matched to outcome, we found that certain parameters, easily readable from a standard CT scan, will give a good indication about non-cancer mortality, which is fundamentally important.
So what we found was that there were certain parameters which were important. That was aortic calcification, skeletal muscle area, skeletal muscle adipose tissue, and the ratio of the visceral to abdominal fat and bone-mineral density. And we can do all that in single read. And that is then cross-correlated in STAMPEDE with those patients who've had specific treatments, ADT alone, ADT docetaxel, or ADT with an ARPI in the form of abiraterone. And by the time we'd filtered the scans and sorted all our database, we had about roughly 550 in each arm, so substantial numbers. And we then put this through a cluster analysis and found that that divided into three essential components. One where the patients were normal, they had normal fat, they had normal bone-mineral density, and the other parameters were unremarkable. There was then a group that had high skeletal muscle fat and a high skeletal... Sorry, a high visceral to abdominal wall fat ratio, and we categorized those as metabolic. And then we had patients who had a very high index of aortic calcification, something called the Agatston score, and they had low muscle mass. And they categorized very clearly into three separate entities. We were then able to look at those separate entities and cross-correlate those with patients who had ADT, ADT docetaxel, and ADT abiraterone. And we followed them at three years, five years, and 10 years looking at non-cancer mortality. And what was striking was that patients who had normal physiology, so to speak, normal muscle mass, normal bone mass, the main effect was ADT. So ADT increases non-cancer mortality to something in the region of about 15%.
But when we looked at the metabolic group, that's to say those men who had high fat content in their muscles and a high fat content in the abdominal wall, basically, then they were disadvantaged much more significantly. They had roughly double the natural history, non-cardiac mortality death, and the addition of abiraterone in particular made that worse. When we looked at those men who had what we call the vascular profile, high aortic calcification, the kind of thin smoker that one is familiar with in the clinic, and they had roughly double the rate of non-cancer mortality if they were given a combination of ADT and abiraterone. So these are very informative bits of data which are available in the clinic.
Neeraj Agarwal: That's what I found. So first of all, this is fascinating work. I'm basically astounded by the volume of patients and by the amount of data you have available, and this is basically a lesson for rest of the world to... And you said it was a freely available software which can generate a lot of these data from the scans, which have already been done. And you are getting such interesting, such clinically meaningful data from these patients who are being treated with systemic therapy. So I just wanted to give you an overarching message I received in the last few minutes from you, which is just fascinating to me. Going back to your point, Noel, just to simplify it, ADT looks like the biggest player here as far as non-prostate cancer mortality is concerned. And then abiraterone adds to that, and maybe docetaxel is adding to that. What we should be doing or what are the results or any other messages you have for the colleagues?
Noel Clarke: Yeah, I think the first thing to say is it's an easily available, an easily usable tool, which is downloadable, and you can use it on a standard CT scan. So it's available for use tomorrow in your clinic. The second thing is that it will put numbers and an objective number and a risk scale on the patient in front of you, so that if you have somebody who is a little elderly, you think might be a bit frail, or even somebody who looks reasonably normal, but is a little bit overweight, you can apply this methodology to help stratify your treatment. Does the patient need ADT? First question. Maybe the patient doesn't need ADT. If you are going to add in an ARPI, and this data we have is specifically in relation to abiraterone, we'll have to follow through with the other ARPIs, then do you really need to add that? Is it going to be beneficial? It may well alter the cancer trajectory, but the other side of the scales means that you may actually augment their morbidity and mortality in some cases.
I think the third thing I would like to say is that it does help to identify those men who need to be optimized first. We know if one is giving a drug like apalutamide, enzalutamide, we know it's going to make the patient hypertensive. We know as soon as you switch off the ADT, sorry, the testosterone with ADT, that the tendency to become diabetic will be greater. The patient will put on more centripetal fat and so on and so forth. The other thing that it will also measure, which we've not presented today, but was presented in a second poster at this meeting, was the sarcopenia index. So we can measure the baseline muscle to see what effect that has. And it certainly has an effect on prognosis. A patient who looks frail, has a measurable diminution in muscle content, may not benefit at all from doublet therapy. There's more work to be done, and I think it's hopefully going to help stratify and modify and improve the treatments on offer to patients when we see them in the clinic.
Neeraj Agarwal: That's great. That's a very clear message for me, for all of us, that there are easily available tools which can really identify these patients at much higher risk of developing non-prostate, especially cardiovascular-related mortality and morbidity, and keys to how to identify these patients in a timely fashion and how to intervene. And I think that's the next challenge for us as a field, especially as these patients fortunately are living so much longer. Thank you, Noel, for taking the time to join us.
Noel Clarke: Thank you. It has been a pleasure.