Dan George, MD: Two things you brought up, Chris, and maybe you can comment on this, Chuck and Joe. You know you brought up the unfit patient, and I think that’s a slippery slope, right? We even forgot patient preference here too. The patients that don’t prefer chemotherapy, whether it’s from the hair loss or the neuropathy or other issues, or just work-life balance. So there’s unfit, there’s the unwilling—we’ll say not preferring. Then there are the real-world situations we deal with. There’s another option, radium, that’s out there that has also shown a survival benefit. It’s also a very disparate mechanism from the hormonal access you’ve been pounding on with these patients. Where do you see the CARD study data influencing your thought process on radium?

Joe M. O’Sullivan, MD, FRCPI, FFRRSCI, FRCR: I think it adds a little complexity. They’re saying at the time the radium trials were being developed, there were not many other agents, at least life-prolonging agents, available or in use. I think what’s interesting is it comes down to fitness as well. Where does radium fit in the modern treatment paradigm?

Well, it’s still patients who have bone-dominant metastatic castration-resistant prostate cancer. Most likely they’ve had at least a first-line androgen-targeted agent. Oftentimes, in the European license, it means it really comes in third line, unless they’re ineligible for chemotherapy, or in most parts of the world it’s a choice after the progression on the AR [androgen receptor]—targeted agent. The choice is often between cabazitaxel and radium, and now we have olaparib for those patients who are possibly DNA damaged. Although in fact there are some data showing that the patients with DNA damage repair may benefit more from radium as well, so there are data in the Italian study.

So where does it fit? Well, I think it fits for the patients who are perhaps not as fit for chemotherapy or are bone dominant. I think radium is a good option for these patients, because it probably has the best adverse-effect profile of all the medications used in castration-resistant disease. It has some mild marrow toxicity, which generally recovers. There’s some mild GI [gastrointestinal] toxicity. But in general, most patients receiving it tolerate it well. But you have to choose your patients correctly, and they have to be patients who don’t have visceral disease or at least don’t have a lot of soft-tissue disease, which is progressing and which might cause them a problem. You must also carefully cancel the patients that they won’t see a PSA [prostate-specific antigen] response necessarily.

It can be a downside of the drug, but you can properly counsel patients that the benefit you’re after here is delay in time to symptomatic progression, improved survival, with relatively good toxicity profiles. What’s also good, because we talked a lot about cross-resistance in the hormonal agents, is that it doesn’t seem too cross-resistance between radium. It’s got to be a unique mode of action compared with the other drugs.

There are some negative data on radium when combined at the same time as abiraterone. It’s strongly recommended not to commence radium and abiraterone at the same time. This is based on data from the ERA 223 study. This study also reveals what’s a very important thing, which Bertrand and others have been talking about for many years—the importance of bone health. We know these patients from the time they have ADT [androgen deprivation therapy], and we add in another hormonal agent. Their bone mineral density decreases. There’s no doubt about that.

Dan George, MD: It’s a class effect, and it’s a cross-class effect now. We’re seeing this with each of these, from hormonal therapy to the secondaries, to the chemotherapy and radium, and they all have decremental effects on this. It’s thinking of that, across therapies, not just with 1 therapy.

Joe M. O’Sullivan, MD, FRCPI, FFRRSCI, FRCR: Particularly for patients receiving radium-223, I think it’s very important that they receive a bone-health agent, and Bertrand presented some very nice data at ASCO [the American Society of Clinical Oncology Annual Meeting] this year showing the PEACE III trial, which is a study combining enzalutamide with radium-223, that as in the ERA 223 study, patients receiving the bone-health agent really didn’t experience increased fracture risk of virtual...

Bertrand Tombal, MD, PhD: Indeed, with radium, especially in Europe, we’re still suffering a lot from the ERA 223. It was very funny that we also are running a registry trial, the REASSURE trial, and now more than ever we need to reassure the physician about radium-223. It’s because we unfortunately see that it’s pushed in that niche of patients who are unfit for anything else. I think that’s a problem because we’re probably missing some good opportunity, bone-dominant patient, elevated alkaline phosphatase, symptomatic. They’re usually not in that good shape. That’s really a good rug for these patients, and there are plenty of patients like that.

Dan George, MD: You’ve got to think about it, though. Just like the profile and everything else, if you don’t think about it, talk about it with patients. You’re not going to use it. You’re not going to see those benefits. I think those are excellent points, well taken.

Transcript Edited for Clarity