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Alicia Morgans: Hi, I'm so excited to be here today with Professor Noel Clarke, who's joining me from the Christie Hospital in Manchester in the UK, and who also joined me at APCCC 2024 in Lugano, Switzerland, to talk about bone health. Thank you so much for being here with me today, Noel.

Noel Clarke: Thanks, Alicia. It's a great pleasure.

Alicia Morgans: Wonderful. So Noel, bone health is certainly a passion of yours for many years, a passion of mine also, but it's often misunderstood. I wonder if you can share some of the key topics from your talk so we can try to make sure that everyone's on the same page?

Noel Clarke: Well, thanks Alicia. I took part in the session which was looking at some of the morbidities associated with the treatment of advanced prostate cancer, and one facet of this that we've been looking at is data based on populations, but also cross-correlation of data from the Stampede trial where we have large volume, very granular data, and we've been able to link that to national data through what are called hospital episode statistics. Briefly, if a patient attends a hospital for whatever reason, a code is applied, and if a patient has a fracture or something bone-related, we're able to pick that up, certainly for the vast majority of patients attending in England, and cross-correlate that with what's going on in the trials. We had previously published national data based on about 75,000 patients which showed that the fracture rate in patients with metastatic disease over a five-year period ran at about 40% in those men having ADT as therapy, and it was running at about 6% or so in M0 patients who were treated with ADT.

Now, what we did first of all was, and this is the work of research fellows, Craig Jones, Ashwin Sachdeva and the biomedical imaging group, part of the Stampede team, which is based at the Christie in Manchester, what we did was we looked at FRAX scoring, which is down in the guidelines as being important, and we had our doubts about this. Stampede had collaborated with the Metabolic Bone Unit in Sheffield University, which is an expert team, Janet Brown and Eugene McCloskey who were the academic team leading that. Eugene McCloskey developed FRAX, and we found that the FRAX scoring was completely unreliable, but in patients who had high FRAX risk or intermediate FRAX risk, had the same fracture risk in the Stampede patients and that even low FRAX scoring patients had a significant rate of fracture.

So what we then went on to do was to look at the initial report of Stampede, which is arms A to E, which you may recall had zoledronic acid as part of the treatment. And we compared ADT, a standard of care in hormone-sensitive cases, with ADT plus zoledronic acid and Docetaxel, alone or in combination. What we found was that the data matched pretty much what we had found in the population study which we'd published earlier, but actually using zoledronic acid, which was at a much higher dose than we would normally use for bone preservation, we got a 50% reduction in the rate of fractures in the M1 patients, which is really substantial. What we then went on to do is ask the question, does the initiation of combined treatment with an ARPI add to the fracture risk?

And Craig Jones and Ashwin Sachdeva then undertook a systematic review of all the data from the trials which had been published in this area. And what they found was that there was an increase in the fracture rate in patients having doublet therapy. It was roughly increased by up to 50% in some cases, but what had not been taken into account in those analyses and reports in the trials was the fact that patients on the doublet actually live longer. So when you think about that logically, patients living longer automatically have an augmented fracture risk because they're living longer.

So we looked at this in other aspects of the Stampede trial, arm J, which was the abiraterone arm, and ADT was the standard of care. We looked at the combination of abiraterone and enzalutamide against ADT, and we looked at arm H, which was radiotherapy to the primary site, and in all three circumstances, we were looking to see whether there was an increase in the fracture risk. What we found actually was the opposite of what we'd found in the systematic review; the addition of an ARPI actually reduced the fracture rate in M1 patients, and we think that that's because the patients get a much better anti-cancer response from those combination drugs. And that was the same with abiraterone and with abiraterone and enzalutamide. And finally, looking at the radiotherapy, well, that doesn't seem to make a difference either, so it's possible to irradiate the patient's primary site in metastatic disease and not interfere with bone metabolism.

So putting it all together, really, there's a significant fracture risk in M1 patients that runs at about 40% at five years. There's a risk of between six and ten percent in patients with M0 disease at five years, so that too is significant. The use of a bone-protecting agent—in this circumstance, zoledronic acid—reduced the risk of fracture by half, and there's a clear recommendation that bone protection is fundamentally important in these patients.

I think the one rider I would add, which I did try to add at APCCC, was that the dose of zoledronic acid doesn't need to be the treatment dose. It probably is sufficient once, maybe twice a year as an administration, and if that's not possible, then an orally administered bisphosphonate will be adequate. So it's a very clear message. Look after your bones when you're treating prostate cancer patients with metastatic disease.

Alicia Morgans: Yeah, thank you for summing that all up, and thank you for continuing to do this work. Stampede certainly has a wealth of opportunities for investigation, and I'm really delighted that the bone health of these patients is part of what you've been investigating.

Let's just touch back on one of the key points that you mentioned because from a US audience, from a European audience, the messages around the FRAX score are different, and the guidelines in Europe really suggest that all patients should be considering bone health support when they're receiving androgen deprivation therapy. That recommendation I think is similar with the once annually zoledronic acid or perhaps something, as you said, oral. But in the US, it's actually all around. That guidance is all around the FRAX score, and so we're calculating that and using that online calculator all the time.

And you and I have spoken about this before, that the FRAX score of course, was not developed in a patient population that had metastatic prostate cancer. This was developed in Sheffield using patients who didn't have metastatic cancer to really understand the bone health risk, and it's interesting that we've adopted that in the US. I wonder if we in the US should consider, certainly based on some of the data that you just discussed, that perhaps FRAX is not the way we should go and we should be considering this once-a-year zoledronic acid treatment or whatever treatment is that preventative fragility fracture prevention dose that works in our clinic, rather than using the FRAX score. Although of course, we have to acknowledge the guidelines still recommend FRAX in the US.

Noel Clarke: Yeah, it's a very good point, Alicia, and what we have now done is to recommend that everybody gets a bone-protecting agent irrespective of a FRAX score because it simply isn't reliable. Interestingly, we have an awful lot of scans from the Stampede trial. Our team is working on using different methodologies, and we're actively engaged with the team at Sheffield who developed FRAX to try to rewrite this scoring system to see if we can improve it, but also to look at ways of measuring the physical bone strength on a standard CT scan, which is not currently possible, but we think will be possible. Because that, and another key important element is sarcopenia. What we are also measuring is the loss of muscle mass, which is acute once the patient starts ADT. The muscle mass really starts to come down and it continues to go down the further out a patient gets on treatment.

And we think that this may be influential in the issue of falls related to fractures because naturally, if somebody is weakened by something like sarcopenia, then their predilection to fall and break something is greater. So there's a bit of work to do in this area, and hopefully, we'll be able to report back on that pretty soon.

Alicia Morgans: Absolutely, and I know that there are some companies that have proprietary algorithms for calculating bone density and bone strength scores from CT scans, and I completely agree with you. If we can do away over time with DEXA and actually have this reported out on our CT scan as well as a measure of sarcopenia, I think we'll both have the data that we need when we need it rather than having to get additional tests, and we hopefully will be able to improve on our counseling of patients.

Because right now, at least in US populations, the utilization of things like DEXA scans is far below half of patients who would qualify for that, and this includes even those who are very dedicated to getting these scans. No one is perfect, but if it's automatically happening in CT scans that we are absolutely getting for these patients, we can do better.

So as you think about a final message for clinicians, they're going into the clinic tomorrow morning, what is your message on bone health? I know you've said it before, but just give us one last thought here on bone health.

Noel Clarke: I think... Well, I hope it's clear that if you're going to start ADT, then start something which stops the loss of bone, and the best way to do that is to give an infusion of zoledronic acid probably once a year. You can give an oral bisphosphonate probably once a week, and there are other agents. Denosumab also is possible.

Alicia Morgans: Wonderful. Well, thank you so much. I do look forward to hearing more about your work. I look forward to some of the publications that I know are sure to come, and certainly look forward to hearing more from you at APCCC 2026 when we will meet again, and hopefully, we'll talk some more about bone health. Thank you for your time today.

Noel Clarke: Thanks, Alicia, and thanks to everyone for listening.