Melissa Abel: Thanks so much for having me.
Tanya Dorff: So your study focused on a new sort of emerging patient population that I think we're still grappling with as a prostate cancer community on how to define and obviously how to treat. Which is patients with bone metastases identified on PSMA PET scan, but not on conventional imaging. So somewhere between biochemically recurrent and metastatic. Why don't you tell us a bit about the study design?
Melissa Abel: Yeah. So this study was specifically looking at patients in this very specific group who wouldn't have been considered metastatic before PSMA PET scans existed. They wouldn't have qualified for the metastatic studies historically because they have very, very early evidence of bone disease on PSMA PET that's not large enough to be seen on conventional imaging.
We viewed this as an opportunity to look at early bone targeting therapies in the absence of ADT and some of the more combinatorial therapies that are clearly needed in patients that have metastatic disease on conventional imaging. And so this study is pretty simple. It's just radium-223 monotherapy for the standard of care in terms of the dosing and number of cycles, except that it's given on its own. And we were basically looking to see if there could be a signal with these very small micrometastatic lesions and if there's efficacy there and what the side effect profile looks like, using it in patients with these very early and small amount of bone lesions.
Tanya Dorff: So radium-223 monotherapy, no-
Melissa Abel: No ADT.
Tanya Dorff: ... androgen receptor targeting at all. Did you mandate bone supportive therapies given the history from ERA-223?
Melissa Abel: Yeah, that's a good question. We did not, just because this was ... Because of it being a different stage of disease and not mCRPC. Most of these patients had just one or two very, very tiny bone lesions that were pretty low risk for risk of fracture in general. And they're still hormone-positive and all of that ... Or sorry, hormone-sensitive. And so we did not mandate bone-targeted therapies.
Tanya Dorff: Okay, got it. And so you're saying these are small bone mets, so I assume most of them are asymptomatic-
Melissa Abel: Yes. Oh, yes.
Tanya Dorff: ... but tell me a little bit more about sort of the PSA range and kind of the numbers of bone mets that you were seeing in these patients.
Melissa Abel: Yeah. So I'd have to go back and actually look at what the median number of bone lesions is, but off the top of my head, it was usually probably around two. There were some patients with just one, some patients with three, occasionally more. But for the majority of them, it was probably two or three. One really challenging thing I think with PSMA PET scans with bone lesions is that when they're very, very tiny, is the concern about false positives as well, especially in the ribs. And so I think that it's a complicating thing with this stage of disease as well. But a lot of these patients had one or two lesions in the spine that were clearly likely prostate cancer, but didn't have a lot of disease elsewhere. So no patients that had visceral disease, obviously. Some patients had very small subcentimeter lymph node involvement, and these were largely patients with low PSAs and fairly indolent behaving cancers.
Tanya Dorff: If only a rib met showed up-
Melissa Abel: Yeah.
Tanya Dorff: ... maybe you didn't include that?
Melissa Abel: Those patients were still eligible. So when we started this study, PSMA PET actually wasn't standard of care. So we initially started it with sodium fluoride PETs and then added PSMA PET on very quickly after the trial started. And I think at that point in time, we didn't really understand what we're now kind of ... This sort of emerging data that solitary rib lesions have a high ... There's a high false-positive rate. And so to be a little bit more suspicious in those cases. With this study, anyone that had a bone lesion on PET scan was included. There are no biopsies, these are such tiny lesions, so there wasn't a way to confirm for sure.
Tanya Dorff: So what was your primary endpoint then?
Melissa Abel: Yeah. So our primary endpoint is ... This is the complicated thing about the study. We don't have the primary endpoint data. Our primary endpoint was actually looking at immune ... How the radium-223 impacts the immune system. And we're still, because we just finished our last patient, and so that's data that we'll look at on the backend because we know that radium-223 doesn't always have predictable PSA responses the same way other therapies do. And so it was more challenging to create an endpoint. But we did look at obviously PSA responses and imaging responses as secondary endpoints.
Tanya Dorff: Did you do imaging between the six doses of radium? Because I know some people just give all six doses.
Melissa Abel: Yeah. So we did initially when we designed this study with sodium fluoride, we had one sodium fluoride PET scan after the fourth cycle. And so kind of a little beyond partway through the therapy to see if there was any responses early on. We didn't use that to really dictate therapy if they had a imaging response or didn't. We still continued on with the therapy. And then ... But PSMA PETs, because we added it on after the study was started, we just did beginning and the end.
Tanya Dorff: So how did you talk to patients about why they should go on the study, what you were hoping they would get out of it?
Melissa Abel: Yeah. So I mean, a lot of these patients were very eager to look for androgen-sparing trials. And the way we talked about it with them is that ... And this was also pre-EMBARK with overall survival data with EMBARK. And so what we talked about with a lot of them was with patients with metastatic disease on conventional imaging, we have very clear data with overall survival benefit. With these very early micrometastatic lesions, we have less clear data of what to do here. We didn't doubt that there is prostate cancer there and that other treatment may be appropriate. But a lot of these patients were very eager to look for options that were androgen-sparing. So the way they viewed it as, let's do this study. If it doesn't work, then we'll start therapy after that. Or if things seem to be changing on the scans or there seems to be significant progression. But they were very eager to do something and said, "Okay, there's not a lot of cancer going on. Things are moving fairly slowly, but we see these suspicious bone lesions and we want to do something about them." So that was, I think, the draw for a lot of patients.
Tanya Dorff: So we have to stay tuned for your primary endpoint-
Melissa Abel: Yes.
Tanya Dorff: ... but what results did you show at the endpoint? How did these patients fare in terms of both toxicity and did you see any favorable changes on their scans?
Melissa Abel: Yeah, so we did. We really didn't know what to expect with radium-223 in terms of PSA responses as a monotherapy. We did see PSA responses in a third of patients. These are also patients that had lymph node involvement. So we counseled them that we may not see PSA responses or we may not see them to the extent that we would expect with ARPI or ADT. But we did see a signal and an indicator that this treatment was doing something with prostate in terms of treating their prostate cancer because we did see PSA declines. Interestingly, we did see some PSA declines after therapy ended, so they weren't always during therapy. Which kind of makes sense with the way radiation works and has some delayed effects. So some of these patients a month or two after completing therapy, their PSAs then declined. And we saw a few patients who had really long-term PSA declines following therapy. So at about a third of patients, we also saw imaging changes. We obviously don't have great metrics for how to measure responses with sodium fluoride and with PSMA PET. But we saw cases where the lesions completely resolved. We also saw other cases where they shrunk, the SUV declined. It's hard to know what that means with SUV, but we saw at least a signal and activity of the drug being active in these bone lesions.
Tanya Dorff: So what's your takeaway message for folks looking at your study?
Melissa Abel: We saw very little toxicity. And with radium, obviously there's always a concern when using it in really late-stage mCRPC about bone marrow toxicity. That's a concern that I have when giving it to my patients who've been through a lot of therapies and have a lot of disease in the bones. We saw very rare Grade 2 toxicities, no Grade 3 or 4 toxicities in this study. The Grade 2 toxicities were largely like lymphopenia, leukopenia. We didn't see any Grade 2 anemia or thrombocytopenia, which I think was really encouraging. The majority of our patients had no symptoms. They would come and be like, "Should I have been feeling something? I felt completely normal after therapy." And I think the reason is that they have such a small amount of disease and it's so early that there's less radiation being actually delivered to the bone marrow because there's less of the drug being taken up into these large areas in the pelvis that you sometimes see in later stage disease. So I think in addition with the PEACE-3 data that's coming out makes me more curious about using radium earlier in the disease course when there's lower volumes of disease and hopefully minimizing the toxicity.
Tanya Dorff: And you didn't see any fractures or skeletal events?
Melissa Abel: No. No skeletal events.
Tanya Dorff: Sounds like an intriguing experience, some evidence of clinical efficacy, and then we will await the data on immune activation and using radium in this smaller volume earlier-stage disease. Thanks so much for being here to share that with us today.