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Alicia Morgans: Hi, I'm so excited to be here with Dr. Oliver Sartor, who is a GU medical oncologist and the director of radiopharmaceutical trials in Rochester, Minnesota at the Mayo Clinic. Thank you so much for being here with me today.

Oliver Sartor: Thank you, Alicia. Delighted to be here.

Alicia Morgans: Wonderful. So Oliver, I wanted to talk with you about the REASSURE study, which is a really interesting study. The manuscript has just come out in eClinicalMedicine, which is one of the Lancet Journal series. Can you tell me a little bit about this study?

Oliver Sartor: Sure. Let me start out with a little background, if you don't mind. So radium, I think as most people recognize, was the first alpha emitter that was ever approved in the history of medicine. Now, it turns out that alpha emitters are, in some ways, filled with fear. These are powerful particles to protons, to neutrons. They're destructive, they radiate things, and we're injecting these alpha particles into patients with prostate cancer, of course, trying to benefit them. And we did, of course. We have the ALSYMPCA study showing the overall survival benefit. But what about those long-term side effects? What about giving an alpha emitter to patients and their bone marrows? What if there're fractures? What about the bad things that might happen to them if they're followed over time?

So the REASSURE study was the study that took over 1400 patients and followed them as long as they could be followed. And by the way, some of these patients were followed for years. Although I think as we know, the typical patient who receives radium had a median survival around 15 months. But nevertheless, we followed patients until death or as long as we could, and then looked at the side effects. So that's the basic REASSURE study paradigm, and there we go. That's where we start.

Alicia Morgans: Wonderful. And really, I think one of the things that's most important and really interesting about the REASSURE study is that it is really complimentary to ALSYMPCA, which is of course a clinical trial. This was a registration trial designed to lead to the approval of radium, but the REASSURE trial is a real world study, so using data from patients who are being treated in clinics just like yours and in mine in regular routine clinics. Right?

Oliver Sartor: Absolutely. And by the way, just for a little more background, so after the ALSYMPCA trial went to the approval of radium-223, this was a requirement from the FDA because they were concerned about what would happen for patients who've been exposed to radiopharmaceuticals. What are those long-term outcomes? So they requested that a registry be put in place, and I and others, familiar names like Tia Higano and Neal Shore and myself, were put on this committee to be able to help oversee the REASSURE registry to produce this long-term safety that's required by the FDA in the real-world setting.

Alicia Morgans: Wonderful. So as I understand, in this particular publication, the team followed these patients for a median follow-up of just under a year, just about a year I would say. And as you said, you had almost 1500 patients who were included in this registry. What did you find when you looked at things like adverse events that were the things that were of concern when the drug was approved?

Oliver Sartor: Well, interestingly, we honestly didn't find very much, and that was reassuring. So the REASSURE registry was reassuring, and there's some things that we were really worried about. What about fracture risk? Well, fracture risk was about 5%, and you know as well as I do that patients with far advanced prostate cancer, particularly all of these patients had bone metastatic disease because you can be treated with radium unless you had bone metastatic disease, fracture risk of 5% essentially over their lifetime after the radium treatment, I don't think that's so bad. It's not so scary.

And other issues that were potentially problematic were things like bone marrow. What about thrombocytopenia? I mean, there was some risk of thrombocytopenia with the ALSYMPCA control. Longer-term, it turns out only 4% had significant thrombocytopenia. What about secondary malignancies? Secondary malignancies are scary things, and it turns out that it's about a 1% risk. But nevertheless, this is a bit deceptive because some of the secondary malignancies occurred either weeks or a couple of months after the administration of radium. They're probably not related. I remember lung cancers, bladder cancers, things we wouldn't necessarily expect to be radium related.

So what we did, despite following for adverse events, following for fractures, following for secondary malignancies, follows for bone marrow failure, we actually were reassured to find that the longer-term follow up here really didn't show much that we should be worried about.

Now, let's talk about limitations, okay, because I know exactly what the limitations are. These patients were far advanced prostate cancer patients treated in the real world, but the median survival was less than a year and a half. And if you're going to be having radiation-induced problems, then potentially those side effects may be further delayed. So if we brought radium earlier into the treatment paradigm, treated patients very early, then perhaps we would have more in the way of concern for bone marrow failure, fractures, et cetera.

But we did the best we could. And again, almost 1500 patients, I mean, this is not a tiny little study. This was a prospective registry mandated by the FDA, put together by the company, data collected from multiple real-world sites, feeding all the data on adverse events into the central database. And then, here's the report. And again, it turned out that there wasn't really that much to report, which is in fact good. But the limitation is the follow-up is still relatively short given the life expectancy of the patients. Not that we didn't try, it's just these patients are tough patients.

Alicia Morgans: True. But there were some patients, I think, who were followed for long periods of time. I think I saw reference even to seven years of follow up for some patients, which is also reassuring, I would say, that there were some patients who were followed for that longer time, and there didn't seem to be a safety signal reported that the longer-term follow up seemed to have higher rates of these hematologic or other complications, secondary malignancies that we might be concerned about.

Oliver Sartor: And Alicia, one of the things, you always have to not only understand what the data might say, but also the implications. So as you likely know, there's a lot of discussion about targeted alpha therapy today, and we're not using radium because we can't curate radium, but we're talking about things like actinium and lead. And there is a concern that these alpha emitters may be causing long-term side effects. Well, I don't say this is the definitive study, but guess what? This is the single best study with an alpha emitter and longer-term follow up, and there's not really the type of safety signal that would make us say, "Hey, these other alpha emitters should not be developed."

So this in some ways gives a little bit of safety data potentially applicable to the actinium targeted compounds, the lead-212 targeted compounds, and it may help in a small way sort of move the needle a little bit more on the side of safety, and so it can proceed. Now, you know as well as I do that every drug will stand on its own. You can't necessarily group all the alpha emitters together, but this is the singular best long-term experience on adverse events with an alpha emitter ever reported. And so, that's why I think it's important, and I think it has implications for how we look at alpha therapies moving forward.

Alicia Morgans: Absolutely. And just one final question, this one really around, there were patients within ALSYMPCA that had had prior chemotherapy. There were others who had not had prior chemotherapy. And in REASSURE, similar things happened because the label really said at your discretion around chemotherapy. Were there differences in terms of things like blood transfusions? When patients had prior chemotherapy, was it maybe a little bit more common for them to have blood transfusions? And was this something that you think was limiting or something that you see as a problem in clinic or as something that is probably manageable, just something we need to know about as we're caring for these patients?

Oliver Sartor: Yeah. Well, first of all, it's manageable whether or not, you had chemotherapy before or after or none. So there was no particular alarms that were going off. Now, that could be related to taxane chemotherapy, which is a little bit different than, say, platinum-based chemotherapy or etoposide or adriamycin. It turns out that, as a whole, taxanes are relatively gentle on the marrow as compared to some of the other chemotherapies that we might use, the alkylating agents, platinums, et cetera. So it's good in this setting, and by the way, radium was the first drug that had an approval either before or after docetaxel for metastatic CRPC. And that was always built in, and it was an initial stratified analysis. And it turned out that, whether or not you gave the docetaxel before or not, that there was improvement in overall survival in both of those subsets, which were pre-specified, which is why the FDA, it wasn't a postdoc analysis. But anyway, I think the larger issue is, we just didn't see a lot to be worried about either way.

Alicia Morgans: Wonderful. So I guess you've said these kinds of comments multiple times. But if you had to sum it up, what would your message be from the REASSURE trial, of course, as we said, recently published in eClinicalMedicine as a manuscript?

Oliver Sartor: Sure. I think if I were to sum up in one sentence, it would be, at the largest experience with radium-223 reported today and the largest human experience in long-term after alpha emitter treatment, that the concerns for long-term toxicity in terms of fractures, in terms of bone marrow suppression, in terms of secondary malignancies, were all in fact perhaps less than expected, giving us stronger safety signals than might have been anticipated when we started this important work about nine years ago.

Alicia Morgans: Wonderful. And what an accomplishment, almost 1500 patients, really a task that was undertaken with a lot of dedication. And I commend you and the authors, and certainly we thank the patients who participated in this real-world study. It is certainly a contribution to the field and our understanding of the safety and outcomes for patients treated with alpha emitters. So thank you so much for your time.

Oliver Sartor: Thank you, Alicia. Thanks for having me.