The Uromigos Episode 113: Decreased Fracture Rate by Mandating Bone-Protecting Agents in the EORTC 1333/PEACEIII Trial

Silke Gillessen gives a safety update from this EORTC study focusing on fractures.

The randomized phase 3 EORTC-1333-GUCG (NCT02194842) trial compares enzalutamide with a combination of radium 223 and enzalutamide in asymptomatic or mildly symptomatic metastatic castration resistant prostate cancer patients. View the ASCO abstract.

Episode Transcript

Brian:
Welcome, everyone, to another Uromigos ASCO Podcast. We’re joined by Silke Gillessen, our fellow Uromigo … Uromiga, perhaps. And Silke, thanks for joining us. If you could briefly introduce yourself and give us maybe the background of your abstract, then we’ll launch into the data.

Silke Gillessen:
Okay. I’m a Uromiga, and I’m also a medical oncologist, now in Bellinzona in the southern part of Switzerland.

Brian:
Very lucky, too.

Silke Gillessen:
Yes. Beautiful. Lots of sunshine.

Tom:
Silke, do you want to talk a bit about your presentation at ASCO? I mean, I’d be happy to talk [inaudible 00:00:57] as well.

Silke Gillessen:
Okay, let’s go to the ASCO first. Yes, so this is interestingly a safety analysis and even an updated safety analysis of a trial that’s a [Neo-TC 00:01:12] trial and it’s in metastatic CRPC first line combining enzalutamide plus radium versus enzalutamide alone. So, enzalutamide alone as you know is a kind of a standard in that setting. And we tested the combination versus enzalutamide.

The interesting part of it is actually the story, because there was a very similar study from Matthew Smith, which was called ERA223, that was doing the same thing, metastatic CRPC first line, combining abiraterone with radium versus abiraterone plus placebo.

And in November 2017, that trial was on blinded. And because there was in one arm many more fractures and also more deaths. Everyone was, including me thinking, “Yeah, this is probably the mono arm.” But then it turned out it was the combination arm. And I guess, all of us were really a bit surprised about that. And at that time point, we had already started our P III EORTC trial that tested enzalutamide in that combination with radium.

So obviously, we were very kind of threatened by these results that were very unexpected because as you know, radium had an overall survival benefit in mCRPC, and also abiraterone, and also enzalutamide. And they weren’t clear hints that the combination would have overlapping toxicity or anything.

From this ERA trial, we learned some interesting things. First, the fractures were in 75% not at the sites of metastasis. And the other thing was that even if bone protecting agents or actually in all the guidelines for that situation, 60% of the patients in that ERA trial didn’t receive a bone protecting agent. But then if you would look in a post hoc analysis, they looked in the patient who got that bone protecting agent, and they saw that they had a clearly decreased rate of fractures in both arms.

And that’s why our IDMC obviously from our trial was then very interested in fracture rates. And we did this safety analysis to see what happened in our trial. And I think it’s really interesting because also in our trial before we made it mandatory, because when that result came out, we made it mandatory with an urgent safety letter that every bone had to receive a bone protecting agent.

So, we made an amendment, and we changed the trial to that everyone, [inaudible 00:04:21] a bone protecting agent. And I think, it’s pretty impressive, the data, because we look now in the patients that we had before that amendment, and we see that at one year, 37% in the combination arm of the patients had a fracture, but also 16% in the enzalutamide alone arm. And after we changed and we made the BPA mandatory of for the patients who had a BPA, so bone protecting agent, that rate is less than 3%.

So, I guess what we learned from that trial is that you have to give bone protecting agents in this population.

Tom:
So how many patients did you present and what are the other issues in the trial that you identified?

Silke Gillessen:
So, this is really now an analysis where we looked specifically for the fractures. This is now 267 patients randomized. So, we are not finished with the trial. For the trial, it’s event driven trial, we will need about 400 patients. And that’s the data analysis that we have right now from 267 patients.

Brian:
And Silke, what is it about the combination of either abi or Enza and radium that increases fracture risk? Is it known mechanistically?

Silke Gillessen:
No, I think it’s still a surprise. So, what we will do in our trial is that Fred [inaudible 00:05:58], who is a specialist in imaging, a radiologist and Bertrand Tombal, they will really look at the scans. We made it mandatory that we have central scan review. We will look at the scans and try to find out what is the mechanism behind it.

But again, I just want to emphasize that also Enza low, the fracture rate is not that low. And that’s something we’re giving a lot. So, for me, it’s really a bit… That’s the message that we really should give bone protecting agents and these patients.

Brian:
So, all patients, regardless of treatment.

Silke Gillessen:
Exactly.

Tom:
Yeah. So still keep Radium-223 is a drug that’s been around for a while. What is its future? We had a conversation with Mike a few minutes ago about his shaky data that’s being presented [crosstalk 00:06:52] session with lutetium and PMSA. This area seems to be moving very quickly. Is radium going to be thing of the past, by the time your trial reads out? Or is it going to have a separate role? How do you see it fitting in in the future?

Silke Gillessen:
Yeah, that’s a very good question. First of all, I’m not sure what is the availability of lutetium [PS 00:07:15] or actinium-PSMA worldwide. At least in Switzerland, is rather expensive. I know in Australia, it’s pretty cheap. So, it’s obviously something that is very depending on the country you’re living in. I mean, I ask Brian, I guess in the States, it will be very expensive. You don’t know.

For the radium, I have to say there is some elderly patients that have only bone metastasis, very kind of [inaudible 00:07:50] disease. And I guess for them, actually that schedule only coming in every six weeks can be, if you need, if they have pain, for example, because it’s approved for patients with pain, I think, it’s a rather kind of pragmatic option when they already had novel endocrine agent. So, it’s easier than most of the other options we have for really kind of fragile patients.

Tom:
Silke, in that 2017 presentation by Matt Smith, with the original abiraterone and Radium-223 data. I missed that presentation at ASCO. I may have been pulling together the pieces from the night before, after being at Callahan’s Bar, which is a problem I’ve not got this particular year, which allows me to look at your data through sub detail.

Do you think with hindsight that that data actually has dampened the enthusiasm to use Radium-223? And do you think from now people will be more confident with it and use it more? And does that make your data presenting practice changing?

Silke Gillessen:
The one thing that I think is that it has clearly dampened the enthusiasm to include patients in the PEACE III trial. And really clearly, I think, I totally understand [inaudible 00:09:15]. So now I think with that new data when you really see these fractures really go back to a very low baseline and are very similar in the combination arm versus the mono arm.

This hopefully make some new enthusiasm to really include patients in the PEACE III trial. And then we will see if the combination. And you write, are we then going to use it later in mCRPC? But maybe in another situation, then we will know if the combination gives some benefit versus the monotherapy.

Brian:
Silke, you said in the abi post radium trial, most of the fractures were not at metastatic sites. Is that the same in this trial?

Silke Gillessen:
Yeah, that’s again, a very good question. We don’t know yet. So, this is something we are going to look at specifically again, with that analysis we are planning of… The interesting thing is, I don’t know how much prostate cancer of patients you see, but probably on the estimated fractures, because also sometimes the patients don’t tell you if someone has bone meds, you always assume it was at a place of bone med, of a side of a bone med.

But in reality, it’s probably a lot of it is osteoporotic or even traumatic. And this is really something we want to go and look into in-depth.