Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: What about—you did allude to it briefly—combining radium-223 with abiraterone, enzalutamide, or denosumab? There are some provocative, maybe hypothesis-generating, data from the early-access program. Have you any comment on that, potentially suggesting a synergy there?

Chris Parker, MD, FRCR, MRCP: Yes. First of all, we know it’s perfectly safe to administer radium in combination with abiraterone or enzalutamide. There are no concerns about the safety of those combinations. And, as you say, the observational data show that men who have received radium with one of the AR-targeted drugs seem to live longer than those who received radium without. Of course, that’s pretty weak evidence. And so, I’m going to be very interested in the data that come out, hopefully next year, from the ERA 223 trial, and subsequently from an EORTC trial of enzalutamide with radium. The ERA 223 trial is looking at abiraterone versus abiraterone plus radium, so starting radium at the same time as starting abiraterone. I’m hopeful that will support what I believe is the right thing to do. What’s your take? When do you start radium in relation to abiraterone or enzalutamide?

Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: Like most people, I think probably abiraterone or enzalutamide tend to come first-line in the initial development of castration-resistant disease as opposed to chemotherapy, for example. But in my practice, certainly, we try to get radium in as early as possible. I don’t really worry about having it before chemotherapy. I think there’s good evidence, and I also know from my practice that giving chemotherapy post radium is a perfectly safe thing to do. There’s no particularly extra toxicity. I particularly like the idea of keeping the patients well. This is how I practice, and I think one of the things I like most about radium-223 is the very good safety profile. So, if the patient is well, the treatment is not going to make them unwell. I rarely see patients becoming severely toxic in any way from radium-223, as opposed to many of the other therapies, which can adversely affect quality of life due to toxicity. So, I think it’s an attractive therapy early on, not to mention the fact that you’re potentially getting in before visceral disease develops. You’re hopefully getting in the survival benefit. But very importantly, the patient should remain well and hopefully prolong the time to progression.

Chris Parker, MD, FRCR, MRCP: I’m attracted to the idea of using radium and starting at the same time as starting abiraterone or enzalutamide. I’ve got reservations about adding in radium in patients who are already on abiraterone and enzalutamide and who are progressing biochemically. My worry is that if you take patients who have responded well to abiraterone or enzalutamide, their bone scans have gotten pretty quiet. And then, if they start to have biochemical failure, their bone scans are probably still pretty quiet. And so, maybe that’s not the time to get the most out of your radium treatment.

Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: We should do a bone scan, see what it looks like, and decide based on that. If the bone scan has gone quiet, then maybe radium isn’t for the best. I’m interested in comments from our colleagues.

Bertrand Tombal, MD, PhD: If you look at the trial you did, what has changed is that pain is occurring much later than before. I think that to me, when I see STAMPEDE and LATITUDE, one of the benefits—whether docetaxel or abiraterone—is that patients may live a little bit longer, but we’re compressing the hopeful phase. The problem of prostate cancer is not dying of prostate cancer. We have to die anyway. No, the problem is that very poor phase that is going to happen before patients die. And we had this discussion with denosumab. We had this discussion with the patient: “What would you choose between dying one day without any symptoms—but you don’t die later than you were going to die—or prolonging life in poor condition?” Most choose the first one, except if they’re waiting for something like their daughter is getting married, they’re going to have a kid, or something like this. It’s very important that we compress as much as we can, and we do that quite well. But the problem is if you rely on pain to give radium. Don’t, because pain comes very late, and I consider it a failure to leave a patient in pain going on.

We’re coming too late if they get it in the sixth cycle. Because, as you know, the company has run that post approval safety study that is called REASSURE, and I’m surprised that there’s still a high proportion of patients who receive less than 5 cycles. When you look at the concomitant toxicity, the toxicity doesn’t explain the fact that patients don’t receive 5 or 6 cycles. One of the problems with radium is that if you give it in an exponential phase of progression—something you see when you’ve giving abiraterone/enzalutamide/docetaxel—you don’t have the time. On top of that, the drug is a drug of invisible benefit, meaning that you don’t have something you can feel to say that it’s working. No, either you trust radium is increasing overall survival or you don’t. But if you don’t, and if you are a bit radium agnostic, then PSA levels start rising.

That’s why, to me, the secret of radium is finding that stage of the disease where the patient is progressing in a bone-dominant phenotype and you’ve got a certain amount of time in front of you. You can’t give it too late after abiraterone or enzalutamide. I really think today, in the management of the patient, the most important question is not what we start with, but how we manage patients after the first line. And, to me, they should not be an ADT patient, but a patient who is on ADT and has received 1 line of AR. That’s where I still see many of my colleagues waiting too long, adding abiraterone after enzalutamide or enzalutamide after abiraterone, and that’s where you end up in that exponential phase. What you need is not a drug; it’s a miracle, because a drug doesn’t work anymore. That’s the secret of radium: finding the stage where otherwise you give 1 or 2 cycles and then it’s wasting money. That’s why you have to give it early.

Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: I agree that it’s a big problem if they’re not getting the full 5 cycles, because it’s usually about patient selection in my experience.

Transcript Edited for Clarity