Charles Ryan: Back here at ASCO 2019, I’m talking with Oliver Sartor from Tulane University, and we’re going to talk about radium, which has been a topic you’ve been discussing and teaching us about for a long time.

There’s been a few new developments in the world of radium this year that come from the ERA 223 study and combination data. And many are probably aware of this data, but fill us in on what the current state of radium is, and what these studies have shown.

Oliver Sartor: Sure. I’ll start on the ERA 223. Abiraterone works, getting Chuck Ryan, who’s helped to contribute a little bit to that literature. And it turns out that radium works and that is, naturally, in the minds of many, a combination that ought to be explored. And so there was a trial called the ERA 223 trial, where the combination of abiraterone and radium was explored prospectively in a nice large trial. Really, it was a good idea. I don’t think anybody would complain about the rationale of putting the two drugs together. Potential synergy and potentially good outcomes could be had. However, it wasn’t the case.

And so this trial, which used abiraterone and radium beginning at the same time for bone metastatic CRPC Because obviously, you want the bone involvement in order to give the radium. It turns out the trial was closed early, and it was closed early for safety reasons. There was a large increase in the number of fractures and the initial data at the time of the closure by the data monitoring committee actually had survival going the wrong way as well, and that was a bit of a shock. Quite frankly, when I heard the trial was closing early, I was thinking, “Oh terrific, we’ve got a positive trial.” Instead, it was, “Oh my goodness gracious, this trial was negative. It’s negative in a bad way.”

With a little further follow up, it turned out that the survivals curves seemed to come more together. So along with follow-up, there was not a detriment in survival. However, there was a huge increase in fractures. Went back and looked at it, and one of the things that turned out to be key was the administering of bone health agents. This could be things like zoledronic acid or denosumab, and that markedly reduced the risk of fracture. But if you gave the abiraterone and radium together without a bone health agent, it really was quite bad and the fractures were frequent and often in multiple.

Charles Ryan: Several-fold increase

Oliver Sartor: Several-fold increase. It turns out that people had fractures, which may not be a surprise to many, also were not living very long. I mean, fractures are bad for your health. So that was a little bit of a shocker to take this nice concept and come up with a bad outcome, and that really caused a reevaluation of the combination.

But, it was kind of interesting, there was a separate trial called PEACE-3. PEACE-3 used enzalutamide, plus or minus radium, but very similar to the ERA 233 design. And here at ASCO 2019, there’s going to be an oral presentation looking at those outcomes and you know what they found? Fracture rates hugely increased if you are using enzalutamide and radium in combination without bone health agents, and the bone health agents have a very substantial reduction. So it turns out that that trial will continue, but bone health agents are going to be mandated.

So if you are using radium, I’m going to ask you to think about bone health agents and then I’m going to cite a Sartor et al. article in Lancet Oncology, where we looked at the interaction between the bone target agents and radium. Did not find a survival benefit, but there was a very, very, very substantial reduction in what we called the SSEs, the symptomatic skeletal events. Radiation bone fractures come out when you put those two drugs together, there seemed to be some synergy. So, if you’re using radium, use it with bone health agents. That’s the bottom line.

Charles Ryan: I think there’s a lot of lessons from this story. Number one is clinical trials are important even when you’re combining known FDA approved agents, right? That, you know, you and myself and others we said, we can just combine these because why would be not? But we forgot about the third leg of the stool there which was the bone-targeted therapy. The other thing is, and I’ll confess to this, when I saw the radium data initially, I saw okay, survival benefit, SRE benefit, we don’t need the bone-targeted therapies anymore because it has all of the benefits of a bone-targeted therapy and has survival benefit as well. And so I think many thought like I did, that okay now we have a one-stop-shop for bone health. And that’s not the case.

Oliver Sartor: It’s not the case.

Charles Ryan: And, you know, I wish I had … we had seen that coming, but nobody did.

Oliver Sartor: No. Honestly, nobody saw it coming. I was honestly shocked when I saw the initial results. Particularly on the survival. Survival going the wrong way.

Charles Ryan: And if we go back to ALSYMPCA, was there a large penetrance of bone-targeted therapy in the ALSYMPCA population? As well.

Oliver Sartor: It was about 40% if I remember correctly.

Charles Ryan: We didn’t see a difference.

Oliver Sartor: There was no difference in the survival. Remember it was a pre-taxane, post-taxane combo, and now you’re starting to subdivide further into bone-targeted, non bone-target. It was really underpowered, to look for survival.

Charles Ryan: But also you’ve got enzalutamide and abiraterone which are response-inducing therapies, whereas radium by itself is not. Right?

Oliver Sartor: Correct.

Charles Ryan: To a large extent. So you’ve got this biology where the tumor is shrinking in the bone, the bone is trying to heal, and I’m telling your story now, right?

Oliver Sartor: No, but I’m agreeing with you.

Charles Ryan: And as the bone is trying to heal instead of taking up healthy calcium to build the bone, it’s taking up radium 223, which may have a deleterious effect on nascent bone, so to speak. Right?

Oliver Sartor: Absolutely. I think it’s a great hypothesis, and you know, you’ve described early on this flare phenomenon with abiraterone, where you have induced the bone remodeling, where the bone growth becomes exuberant and the cancer growth diminishes, and actually that’s right where radium goes and it could’ve been to what we thought would be synergistic actually just turned out to be damaging the bone.

Charles Ryan: Right. Well, the flare, you know, we really didn’t prove that it was bone growth, but what we proved was that it was technetium uptake.

Oliver Sartor: Yes.

Charles Ryan: Right? So that should’ve been the canary in the coal mine, so to speak, to say, “Okay, if it’s taking up technetium in the setting of response, perhaps it will take up radium.”

Oliver Sartor: Well, it’s the same target, and that’s hydroxyapatite. It’s the inorganic bone matrix, and when you remodel it … yeah, you’re right, bone growth is not the right term. But it’s bone remodeling with the inorganic matrix and those surrounding cells, including the osteoblasts, that are helping to lay down that new bone, that’s where very vulnerable to the actions of something like radium. And I’m afraid that that backfired, the good hypothesis just backfired.

Charles Ryan: So, take-home message for the clinicians out there, radium is still safe, we don’t yet know about the long-term efficacy of combining it with abiraterone and enzalutamide, but if you do and even if you don’t, consider bone-targeted therapy alongside radium, as opposed to doing what I said which is considering them to be the same.

Oliver Sartor: I agree. And I’ll just say, I concur.

Charles Ryan: All right, great. Always a pleasure talking to you.

Oliver Sartor: Thanks, Chuck.