Importance of Bone Protection in Prostate Cancer Treatment "Presentation" - Noel Clarke

November 15, 2024

At the 2024 Advanced Prostate Cancer Consensus Conference (APCCC), Noel Clarke presents findings from the STAMPEDE trial regarding fracture risk and bone protection in prostate cancer patients. The presentation demonstrates that zoledronic acid reduces fracture incidence by about 50% in metastatic disease, and treatment intensification with abiraterone shows substantial fracture risk reduction, while highlighting varying impacts across different patient groups and emphasizing the importance of bone protection strategies.

Biographies:

Noel Clarke, MBBS, FRCS, ChM, Professor of Urological Oncology, Director, GU Research Group Paterson Institute and MCRC Pan-Manchester Biobank, Salford Royal Hospital & The Christie NHS Foundation Trust, Manchester, UK

Read the Full Video Transcript

Noel Clarke: It's my privilege to talk on behalf of the STAMPEDE team and the team in Manchester doing some of the analysis of the translational work coming out of our groups, co-aligned. We know that bone protection is important, but I don’t think we’ve realized how big a problem it is.

If you look at this data, which is from data collected in England in the National Prostate Cancer Audit, if you look at the consort diagram, you can see the numbers there, about 79,000 patients analyzed. And these are clinical fractures—these are patients presenting to hospital with a fracture. You can see in the green line on the graph just how prevalent that problem is when you get out to five years, about 40%.

So can we predict that? Well, FRAX scoring, which was developed at Sheffield University, we’ve been working closely with the STAMPEDE team. This is work from Craig Jones, one of our research fellows. And you can see that FRAX doesn’t really work for prostate cancer.

If you look at the three lines here on the graph, this is high risk, intermediate risk, and low risk. Even the low risk, about 50% are having a problem. And so FRAX, which was not designed for the prostate cancer population, really isn’t fit for purpose. And we need rather better indicators.

I’m going to show you some data relating to fracture-related hospitalizations in high-risk, localized, and de novo mHSPC analyzed within STAMPEDE. And again, I’ve put the consort diagram here. This is the work of Craig Jones, Ashwin Sachdeva, and co. in the big group, the bioimaging group, as part of the STAMPEDE translational program. And here we’ve looked at arms A to E, looking at standard of care, zoledronic acid, docetaxel, and the combination.

This is new data, which we have currently got in submission. And what you can see, in these curves, at the M0s and the M1s, is that in M1 disease the use of zoledronic acid substantially reduced the incidence of fracture by roughly about 50%.

It did come down a bit in the M0 group, which has a different natural history, of course—a much longer natural history—but it didn’t reach statistical significance. And when you put that together and look at this collectively for docetaxel, zoledronic acid, docetaxel and zoledronic acid in M0s and M1s, you can see that in M1s there is a substantial difference.

Now, this is with a treatment dose of zoledronic acid, not a prevention dose. So one has to be careful in extrapolating this data. But nonetheless, it shows that there’s a significant benefit to bone protection in that particular group. I think we’ll have to wait a bit longer for the M0 group.

We put together a meta-analysis looking at the combinations with AAPIs and the risk of fractures and falls in advanced metastatic disease. And this has just been published. Most of the work was carried out by Craig Jones, Peter Doughty Magni, statistician at the MRC, and Ash Sachdeva on the group of patients, which you can see in the consort diagram.

And focus on A, which is any grade fracture, and to the right on B, grade 3 fractures. And what you can see is that in this meta-analysis, which was of all the published trials, there seems to be an increase in the rate of fractures, and particularly so if you combine an APA with ADT.

We’ve gone on to start looking at this in the STAMPEDE fracture program, looking at fracture-related hospitalizations in de novo advanced or metastatic hormone-sensitive prostate cancer. And this really is within STAMPEDE. What we have is hospital episode statistics data. For each hospital attendance, there is a code.

And if we put the code for a fracture—whatever that code is—we can map what happens as a patient comes into hospital five years, 10 years down the line. It’s a very powerful tool to look at population-based data related to clinical trials. And it’s pretty accurate.

Now, this is the STAMPEDE abiraterone comparison trial. You all know this, so I won’t go through the detail. But what you can see is how we filtered down that within the team. And look at the bottom of the consort diagram.

So standard of care ADT 738, standard of care plus abiraterone 715—so substantial numbers looking at outcomes. And this is mainly from England, where we can get the HES data very accurately. And 99% of the eligible trial patients were linked successfully through the HES program.

What we found was that in the M0 patients, 26% had had a fracture by five years, and about 30% of the M1s. You can see the distribution here. And you can see what happens when you’re looking at ADT as monotherapy or ADT and abiraterone. In M0, there doesn’t appear to be a difference. But obviously, the natural history is different. But when you’re looking at the combination of standard of care AAP, then that fracture rate is substantially increased.

And you can see in the metastatic and non-metastatic the degree of change when you’re looking at this population of patients. So the conclusion here is that in M0s, there was no significant difference in the fracture risk seen with the addition of an ARPI in the form of abiraterone. But in M1, there was a substantial reduction in the risk. And that’s largely, we think, because the abiraterone makes patients live a lot longer.

Again, when we looked at the AAP–enzalutamide comparison in STAMPEDE, here’s the trial, which you all know. These are the numbers down at the bottom—800 roughly in each arm, standard of care ADT plus the combination AAP and enzalutamide. And again, good consistency from the trial patients with the hospital episode statistics.

And here’s what you get from that combination. So patients with at least one fracture-related event—that’s hospitalization—M0’s 15%, and M1’s 38%. And when you look at the split in those groups, again, you can see there seems to be a protective effect, actually, of adding the [AAP], which was not really what we expected. And the figures are there for you to see.

So conclusion from that—M0, no significant difference in fracture risk seen with the addition of combination [AAP] therapy. But in M1s, it significantly reduced the risk of fracture-related events, which is not something you get from a meta-analysis of the trials published. So it’s important to recognize that.

Now, the final comparison we did in this series of analyses was to look to see whether radiotherapy to the primary site made a difference. And the standard of care, as you know from ARM H, was ADT plus or minus radiotherapy to the primary in metastatic disease, factored for volume.

Once again, look at the data for the numbers at the bottom. Standard of care, 870 patients, and standard of care plus RT, 854—so quite substantial numbers. And again, good correlation with hospital episode statistics. And this is what we got: that patients with at least one fracture-related event in M1, about 37%, which really matched the population.

And although there is a small reduction in the graphical representation—in red, you see the radiotherapy patients—actually, there was no significant difference. So radiotherapy to the primary site in low-volume metastatic disease primarily presenting doesn’t seem to affect the outcome in relation to fracture. When we look at all that together, you can see that there’s a lot to the left of the line, which gives an illustration of the benefit of adding an [AAP] to this group of patients. It doesn’t increase the fracture rate. In fact, it reduces it. And radiotherapy doesn’t seem to make a difference.

So in summary, a five-year cumulative incidence of fracture-related hospitalizations—and these are clinical fractures—was high in M0, 15%, and high in M1, 38%. And that’s just with treatment with ADT. And one could reduce that by the addition of bone protection in the form of zoledronic acid by about 50% in the M1 group of patients. Treatment intensification with abiraterone, with or without enzalutamide, reduces the risk of fracture substantially in metastatic hormone-sensitive prostate cancer patients. And there’s no evidence of effect of a fracture risk in relation to prostatic radiotherapy.

I’d like to thank all the people who’ve been involved in this project and are still involved with it. As you can see, it’s a big effort. And most of the effort has been put in by the people highlighted in red in the Manchester group, in the MRC, but also throughout the STAMPEDE translational program. Thank you.