Alicia Morgans: Hi. I'm excited to be at ASCO 2022 with Dr. Fred Saad, where we're talking about radium and how to support patients who are receiving that treatment. So, one of the things that I always think about when treating patients with radium is that we need to, of course, monitor CBCs, we need to watch their cell counts, but we also need to pay attention to bone health which is important in all patients with mCRPC. But, I think, is of particular relevance and is also supported by treatment in many ways when we're treating with radium. So, can you tell us a little bit about radium and how it works, and how it's really a bone-targeted therapy? Disease-directed therapy?

Fred Saad: Right. So, radium 223 really is focused on bone disease and through its mechanism of osteoblastic inhibition, really targets where the complications are going to come from. From the osteoblastic component of prostate cancer, the cancers around that osteoblastic lesion, so there's indirect cell kill, but it forces us to think that there's the osteoclastic component that we're not really addressing. And so, the combination, if we want to really maximize our effects on bone, radium is the best agent because in terms of reducing complications and prolonging survival, but we also have to have the osteoclastic inhibitor to really maximize that synergistic effect.

And we actually saw it in the very first pivotal study. Patients who got bone supportive agent plus radium are the ones that had the biggest advantage in reduction of bone complications. And then, we did an early access program with radium, and to our amazement, and we published this in Lancet Oncology, the patients who had the combination of radium 223 plus a bone supportive agent in this case, mostly Denosumab, actually had a survival advantage. And so, really trying to maximize the way we manage bone really helps the patient to do better, not only in terms of bone complications but maybe even in terms of survival.

Alicia Morgans: So let's dig into that a little bit. I think this expanded access program was so important to our patients as this drug was really coming to market. And in that study, the combination of radium and a bone health agent was associated, you said, with better disease control, and this was as compared to those patients who had radium but without, of course, this bone health agent. So what are your thoughts there? Are fractures potentially associated with higher rates of mortality in general?

Fred Saad: Yeah. So we published actually a paper several years ago that fractures in patients with prostate cancer, even in breast cancer, had a reduced survival. And so, doing everything we can to reduce the risk of fractures can not only improve quality of life but may actually improve overall survival in our patients. And so, managing those patients as maximally as we can is not only going to improve their quality of life, but hopefully, even maximize their survivals, and probably allow them to have more lines of therapy if we don't expose them to these complications.

Alicia Morgans: And I think that's so important. And one thing that I want to raise and hear your thoughts on are that what we know when we use these bone health agents like we did in the P3 study that was looking at metastatic castration-resistant prostate cancer, patients receiving Enzalutamide with or without radium, when we mandated these patients really needed to get bone supportive treatment, the risk of having a fracture in that study decreased really dramatically. The agents work and keep our patients safe when they're receiving radium or any other treatment for metastatic CRPC.

Fred Saad: Yeah. When you say worked, there was about a reduction of a 90% risk of fracture. It's amazing going from about a 30 to 50% risk with enza alone or enza combination with radium down to under 3%. And so, really, that mandated obligation of bone supportive agents was clearly important because it made a huge difference compared to the ones who started on study that didn't have a bone supportive agent.

Alicia Morgans: Well, thank you so much for sharing your expertise. I know you're a guru in bone health, among many other things. What would your closing thought be to people who are trying to care for their patients as they're using radium as a treatment for metastatic CRPC?

Fred Saad: Well, clearly, radium is part of a very important treatment continuum for our patients, and we have to try to integrate all the options that are applicable to our patients to really make a difference and not lose windows of opportunity that can make a huge difference. Because patients who, unfortunately, get only one line of therapy for mCRPC do much worse than patients who can get multiple lines of therapy, and missing those windows of opportunity is, unfortunately, sometimes a death sentence for our patients. So, in patients who can benefit from radium really need to try to find that soft spot of six months to get the full dose of radium.

Alicia Morgans: Great. So, maximizing cycles of radium using bone supportive agencies are all really important as we're trying to care for our patients and give them every opportunity for disease-directed therapy that can help make them live longer but also feel well too. So, thank you so much for your time and your expertise today.

Fred Saad: Thanks.