Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: What do you think is the rationale for starting radium-223 before symptoms? Because the current label will say “symptomatic prostate cancer.” Do you think there’s a rationale for using before symptoms?

Nicholas James, MD: The lesson from the STAMPEDE trial in particular, as well as the LATITUDE and CHAARTED studies—and the other trials like it—is that early use of effective therapies is generally better than late use of the same therapy. It’s a reasonable thing to test for in a trial. In the ALSYMPCA trial—this dates from a time when there was only one drug available and only half the patients in ALSYMPCA actually had that—docetaxel [Docefrez] was used in a very clever trial design. They didn’t partition it as the abiraterone in the ENZA trials did into the pre- or postdocetaxel space. It was stratified by whether or not the patients had docetaxel. That trial very clearly showed not palliative benefits but survival benefits and reductions in symptomatic skeletal events [SSE], both of which are clinically meaningful and clinically valuable things.

One way of looking at the ALSYMPCA trial is, in at least half the patients, it was their first-line therapy, which produced survival advantages to see level-1 evidence. The radium produces a survival advantage in the first-line setting. Obviously, where you run into problems is where you’ve got other competing first-line settings. The symptomatic requirements in ALSYMPCA, which is a bit of a slippery thing, is defining who’s got symptoms.

People often don’t realize they’ve got symptoms until you make them better. You know, the backache and stuff that what they thought was old age was actually their bone metastases.

Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: Exactly.

Nicholas James, MD: It’s hard to know how to interpret all of these data.

Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: The symptoms requirement was, largely, to try to get an earlier result for the ALSYMPCA trial, but in clinical reality most of these patients have some form of symptoms.

Nicholas James, MD: We put a lot of patients in the ALSYMPCA trial and for most of them didn’t have much in the way of symptoms. They went in in one sense because they’d had a single fraction of radiotherapy. You only have to have 1 metastasis that was symptomatic enough to justify a single shot of 8 gray, and they were in. They didn’t necessarily have to have large disease burden. Other centers obviously would have had different guidelines. What you end up with depends on local practice.

Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: There’s quite a spectrum of symptoms in the trial. There’s some patients who were on opiate analgesia regularly, and then those who had previous external beam radiation.

Nicholas James, MD: But early on ALSYMPCA predominated and the trial almost failed because there were simply too many of those and nobody was living long enough to get the radium.

Noel Clarke, MBBS, FRCS, ChM: ALSYMPCA was a bit of a dirty trial, wasn’t it? It was practical—it addressed an issue. Half of the patients had docetaxel upfront and half of them hadn’t. Their prostate-specific antigens [PSAs] were dichotomized. They didn’t really have detailed scanning.

There was an interesting subanalysis of this trial for those who were using bisphosphonate and those who weren’t: 50% were and 50% weren’t. Interestingly, when you looked to the skeletal event rate, and particularly the fractures, that bone preservation effect was completely lost in patients who weren’t receiving bisphosphonates, which I think plays into what we’ve seen and are going to discuss in the ERA 223 trial.

Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: Yes.

Nicholas James, MD: Absolutely.

Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: This brings me nicely to ERA 223. Data being presented this week here at the European Society of Medical Oncology 2018 Annual Meeting, of the randomized trial, had patients with castrate-resistant prostate cancer [CRPC] randomized to receive abiraterone or abiraterone plus radium-223. There was also a placebo-controlled trial. Nicholas, would you like to summarize this trial?

Nicholas James, MD: The rationale behind the trial was that we knew the abiraterone reduced symptomatic skeletal events and that radium reduced symptomatic skeletal events. There seemed to be every reason to think you could safely co-administer these 2 drugs, with nonoverlapping toxicity profiles. The primary outcome measure for the trial was time to SSE, the hypothesis being that 2 things that reduced it would reduce it even more, and you’d see a benefit.

What happens was that the trial was stopped early by the Data Monitoring Committee because there was an excess of SSEs in the abiraterone radium arm. This in turn translated into a slight excess of deaths as well, which were, obviously, 2 very good reasons to stop the trial. Additionally, the number of extra fractures was large. When the first press release came out, you’re thinking, “Well, how on earth have 2 effective therapies caused patients to die quicker? The answer is that they don’t make you die quicker of prostate cancer. If you look at the cancer-rated outcomes, there’s no difference between the 2 arms, but that comparison is underpowered because the trial was stopped early, of course. What you see is a big excess of early fractures in patients who are not on bone protections. You also see quite a substantial number of early fractures in men just on abiraterone, let alone on the control arm and experimental arm. That rate of fractures was substantially reduced in the men in the trial who had either denosumab or zoledronate [Reclast]. I have to say that in my practice, every time we give them radium, we give them a shot of zoledronate.

Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: Likewise.

Nicholas James, MD: We haven’t seen fracture problems in my practice. Interestingly, it’s a famous London hospital where they have a pretty empty bisphosphonate view. Talking to their radiologist, they see a lot of fractures.

Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: I’ve had the same conversations.

Nicholas James, MD: I’d be interested to see whether they change their practice now.

Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: I think they have.

Transcript Edited for Clarity