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Alicia Morgans: Hi, my name is Alicia Morgans and I'm a GU Medical Oncologist at Dana Farber Cancer Institute in Boston. I'm so excited to have here with me today, a good friend and colleague, Dr. Tia Higano, who is formerly of The University of Washington, a GU Medical Oncologist in Seattle, who does academic work with The University of British Columbia. Thank you so much for being here with me today, Dr. Higano.

Tia Higano: Thank you for inviting me, Alicia.

Alicia Morgans: Wonderful. So, Tia, I know that you really had such a nice presentation at ESMO 2021 on the REASSURE study and some investigations that you did into patients treated with radium. Can you tell us a little bit about what the REASSURE study is and what you reported?

Tia Higano: Sure. Just to remind everybody, the REASSURE trial is a post-marketing Phase IV study to further evaluate the safety of radium-223 in the long-term setting, specifically as it relates to the possibilities of MDS and leukemia. So the part of REASSURE that we reported in the ESMO meeting is basically a subset of that particular group of patients, which is, the entire cohort for that study is now accrued in long-term follow-up. There's a seven-year long-term follow-up, just so everybody knows it is really long-term. But it occurred to us that we had this large body of data and that when you think about the ALSYMPA trial, which was done quite a while ago now, and that was a trial on which the approval for radium-223 was based, that trial mandated symptomatic patients with metastatic CRPC, who either had or received prior docetaxel or who were not eligible to receive docetaxel and now needed something to treat pain.

Well, in that study, again, this was done by a small company initially, ALSYMPCA. In that study, they really only measured outcomes with respect to pain in terms of pain-related quality of life. And I don't want to diminish the importance of that measurement, but there was really nothing that was quantitative about it. And so we realized that since we were looking at pain response in REASSURE as part of the study, we could actually look at that in a little bit more depth with a lot more patients.

So that's what prompted us to look at the patients with pain in the REgistry trial. And I just want to emphasize that not 100% of the patients had pain coming into that trial. It was not a requirement. It was just whenever the clinician decided it was time for radium, and those patients were eligible to be enrolled on REASSURE.

So in REASSURE, in this pain analysis, we only allowed patients to be part of the analysis if they had a pain score of at least two on the BPI short-form questionnaire. That was the primary outcome. We looked at also, of course, overall survival in other subscales of the BPI short form. We looked at really two subgroups within the entire cohort, which was over 1,000 patients. We thought it would be important to look at those patients who were on opioids or needed opioids to control pain and those who were not. So that was one subgroup. The other subgroup was those patients who had less than 20 bone metastases or greater than or equal to 20 bone metastases. So two subgroups within 1,000 patients.

Alicia Morgans: So I love that you broke into those subgroups. And I also just want to emphasize, as you said, that not all of the participants in the REASSURE trial actually had pain. But you were able to focus on pain management and pain control related to treatment by identifying those patients who did have pain reported. And so, of course, that's going to be an important component of this. So what did you find? And I'd love to hear the results in terms of those subgroups that you specifically identified as clinically relevant when it comes to pain management.

Tia Higano: Sure. So if you looked at all 1,027 patients, they really didn't have any distinguishing factors in terms of their characteristics than any other group of patients with metastatic CRPC would have. So they were not unusual in that respect. But what we found was there were almost 400 patients who were not using either opioids or requiring radiation for pain, and then a little over 600 patients who were on those treatments. So that's about the balance in that subgroup.

Interestingly, there were a little over 800 patients who had less than 20 lesions, and the remainder, a little over 200, had 20 or more bone lesions, which is interesting in a way because you would think maybe people might use radium for those with more metastases. But anyway, that's what the breakdown is. So again, 1,027 patients total, more than half of them achieved a clinically meaningful pain response after radium-223 treatment. And again, that had to be at least maintaining or improving by a score of two on the BPI.

The other thing is that the pain responses were prolonged, so they continued even after the full course of radium, which was six doses, so ideally six doses, so into greater than six months.

Of those who were not on opioids, 58% had a pain response. So specifically in that particular group, there was, not unexpectedly, improvement in pain. But again, I think that tells you perhaps when the best time to position radium is in the trajectory of your patient treatments. And then it turns out that, of course, those with fewer bone metastases had a 53% pain response, and those with 20 or more had a 56% response. So about the same, for all intents and purposes.

When we looked at the sub-scores of the BPI-sf forms for pain severity and pain interference, which I know you know those terms well, but I mean, these are clinically significant for patients and those sub-scores actually improved, as you can see on the poster, with each dose of radium. So that was another good sign.

So those are the primary endpoints.  In terms of overall survival, which was sort of a secondary endpoint, that was about 15 months for the entire cohort. But not surprisingly, if you looked at the patients who did not have severe pain, in other words, were not on opioids or radiation, their median survival was 17.6 months compared to only 12.4 months for those who were on opioids and radiation. So, I mean, this isn't a surprising outcome clinically, but it does establish these differences in this population of patients.

So those were the sort of high points of the poster, I think. And certainly, there are limitations to this kind of study. It's single-arm, it's observational, there's a lot of issues. Some doctors may be prescribing opioids for this level of pain and others not. But in terms of real-world operations when it comes to our treating patients as clinicians, I think it really gives us a good handle on the fact that radium can result in meaningful reductions in pain, regardless of the extent of bone metastasis.

So the other thing is, if you look at the other subgroup where they did not require opioids, there was a meaningful pain response, but they also had longer overall survival. So, I mean, that's the other sort of take-home message. And I think the importance of the poster and the data in this poster is that it is really the first trial to demonstrate the quantitative impacts on pain of radium. And I think it compliments what was seen in the ALSYMPCA trial, where they showed a good response in pain-related quality of life.

Alicia Morgans: I agree, and I love that it's in a real-world cohort. So it's patients who received radium through whatever measures, whatever those bars were that they needed to meet in order to get that treatment in their practices. And that I think is really interesting. I also like the idea of your analysis of comparing men with greater versus fewer bone metastases. Because like you said, one may think that it's more important to favor treating those patients with many bone metastases, but it sounds like both groups actually benefited in terms of pain relief similarly. So that's great.

And the other thing that I think is really nice to confirm is that you demonstrated that patients who have higher amounts of pain actually have a poor survival with radium, which in my clinical practice, certainly could be that patients who have the more aggressive and more advanced disease have more pain. We actually know that's true and we know they have a poor prognosis. But if we can catch patients before they get to that point, we may get a bigger bang for our buck in terms of treatment. And that's not proven in this study, and it's not proven in the European registry that was also similarly demonstrating that. But it is a suggestion for clinicians as they are trying to make treatment choices, trying to get to patients earlier before they have that clinical symptomatology, I think can be really important.

Tia Higano: Right. And I think also at this point in time in treating men with metastatic CRPC, many of them have already received some of the drugs that we used to give in metastatic CRPC. So I think there is a great opportunity now for radium to move a little bit more forward in the treatment trajectory than we used to think of it, just because a lot of those drugs have been exhausted or they have not been shown to make a difference in this setting.

Alicia Morgans: I think that's great. And I really do agree with you that this is incredibly important data. And I love that we are able to take a real-world cohort and draw some conclusions from these findings. If you were to summarize these findings for clinicians and for patients who are trying to draw some conclusions and potentially make some changes in their clinical practice, what would your concluding summary be?

Tia Higano: The message would be that radium should come into people's minds earlier as an option to treat metastatic CRPC. And the patient does not have to be terribly symptomatic as we showed here. As a matter of fact, it's better if they are not at that sort of more late-stage symptoms phase. So I think it's time to perhaps change our treatment paradigm and moving radium earlier, and you can feel good about knowing the results of this analysis.

Alicia Morgans: I think that's a great message and I really appreciate you and the team using this data to answer some very, very important questions, especially questions that relate to patient-reported outcomes, which we don't always get from these follow-up safety type studies. So kudos to you and the team for thinking creatively, for using the data, for answering some questions, and for letting us all hear the patients' perspectives on pain control during treatment with radium. Thank you very much for your time and your expertise.

Tia Higano: Yes. Thanks for your interest in this topic.