Alicia Morgans: Hi, I'm thrilled to be at ASCO 2022 where I have the opportunity to speak with Dr. Fred Saad about Radium-223. Thank you so much for being here with me.

Fred Saad: Always a pleasure.

Alicia Morgans: Wonderful. So I wanted to talk with you about radium. This is a treatment that we've had for some time now, really, I think have developed an understanding and a familiarity with this treatment. But importantly, I think we really still need to think about this treatment among all other treatments and identify where it best fits for our patients.

So I'd love to hear from your perspective as a urologist, when do you think about using radium and how do you think about this definition of a minimally symptomatic patient or a maximally symptomatic patient when you're making those treatment decisions?

Fred Saad: Yeah, those are great questions because we have to remember what are our objectives when we give radium, right? We want to be able to control the disease that's in the bone, which is, for most patients, the only place that there is disease, and we want to have a patient who's in a well enough state to be able to get the six cycles because we've shown repeatedly that if you get the six cycles, you do a lot better than if you get four or less. And so they have to be in a state where they're going to be well enough to get all six cycles to really benefit in terms of the survival advantage and in terms of the tumor kill and the bone control.

And so the study used patients that were symptomatic. The problem is how do you define symptomatic? And for some people, symptomatic is on morphine. And that's really when you're on morphine, on high doses of morphine, you've gone through one or two lines of therapy, even worse if it's three lines. You don't even have six months to live. It's not going to be useful. It's, unfortunately, too late to even consider radium.

So when I think of symptomatic, symptomatic, for me, is anybody who has any slight pain and doesn't have to be even on any painkillers. If they're complaining of any symptoms at all, for me, that's a symptomatic patient, especially if they've been exposed to novel hormonal therapy and even more, if they've already been exposed to docetaxel.

Alicia Morgans:Well, thank you for that because like you said, the label just says symptomatic, and that's why I kind of drew this distinction, mildly symptomatic, maximally symptomatic, because by the time a patient is maximally symptomatic, of course, we can use radium, but we probably should have used it earlier because the prognosis of that individual is pretty poor at that time.

So at this point, the label does not say we have to have chemotherapy prior to this treatment, which I think is important to mention. But when you do identify that patient, where do you put it in terms of chemotherapy? Do you usually put it after? Do you put it before? How were you making that choice?

Fred Saad: So, historically it was reserved after chemotherapy because the study looked at patients that were either chemo-ineligible or post-chemotherapy. But I think we've evolved since then because at the time that pivotal study was done, we didn't have drugs like abiraterone or enzalutamide or other novel hormonals that are given even earlier. And so patients who are failing these therapies are pretty much in the same state as if they failed first-line docetaxel, in terms of how much time they have left to live and the speed at which it progresses, so clearly, depending on the patient.

There are some patients where I think they should go to early chemotherapy, very rapid progressors that are... especially if they're more symptomatic, I would tend to go to chemotherapy quickly. In patients who are failing abiraterone, enzalutamide, [inaudible 00:03:35], and they're progressing and you see it, the PSA, you see the progression in the bones, that might be the soft spot, where a lot of patients would be able to get all six cycles and where we actually see even the clinical benefit where patients say, "That slight pain I was having? It disappeared, and I feel better." And you see alkaline phosphatase go down, which is really a signal that the drug is doing what it's supposed to do, and those are the patients that are going to get the best survival advantage from the drug.

Alicia Morgans: Well, I wonder from your perspective, as triplet therapy may become more common giving ADT, docetaxel, and either darolutamide or perhaps abiraterone acetate in that first-line, metastatic hormone-sensitive setting, where do you see radium fitting in then?

Fred Saad: Well, that's the scenario where it would be immediately after because those patients have already, basically, failed two lines of therapy. Even if they got it in the hormone-sensitive state, when they progress in our mCRPC, they are mCRPC having already failed exposure to docetaxel and a novel hormonal therapy, so I would say that soft spot is shrinking and it needs to get in. If you're going to consider it, needs to get in pretty much at that state, and you don't need to wait for severe symptoms. You just need to ask questions.

Patients might not spontaneously complain of symptoms unless it's severe, and so we have to be proactive, and you're the expert on survivorship and quality of life, and if we don't ask questions, patients won't tell us that they've got these slight pains that are starting to show up and basically, almost any patient who has failed a novel hormonal plus or minus chemotherapy has symptoms. I've rarely seen patients that are totally asymptomatic that are progressing.

Alicia Morgans: I think that's such a good point because patients can be really, really functional and just be functioning through their symptoms, and unless you ask, they won't tell you about their fatigue or the joint pain that's starting to get worse in their hips or changes in their appetite, things are not tasting right. These are all associated with progression of cancer. And even those taste changes and things where they're losing their appetite, that's all related to effects of cancer due to some cytokines in the brain stem and these kinds of things. And certainly, these are symptoms that we can treat with disease-directed therapies that can better control the cancer.

Fred Saad: Yeah. And they're slowly installing themselves, so you get used to living with it.

Alicia Morgans: Yes.

Fred Saad: And you only realize you had symptoms when you actually address them with treatment. And then they say, "Finally, that arthritis I thought I had wasn't really arthritis because the drug is making me feel better."

Alicia Morgans: Absolutely. Well, I really appreciate you talking us through. What would your final message be to clinicians who are trying to figure out when to best integrate radium?

Fred Saad: Yeah. So, radium is one of our treatment options and I've been saying it for many years, like many of us, that really, what has led to the significant advantages in overall survival and changes over the years is the fact that we're able to go from one treatment to another. And the more lines of therapy patients are able to get, the better they do, the longer they live, and the better their quality of life.

And so finding that spot for radium, if we think it's going to be useful in a bone-only disease setting is really important for patients. It gives us an extra line of therapy.

Alicia Morgans: And as you said, getting in every line that we possibly can is so important that we give patients every opportunity to have disease control and to feel better as they go through this process.

So thank you for your time and for your expertise.

Fred Saad: Thanks.