Alicia Morgans: Hi, I'm excited to join you from ASCO 2022, where I'm able to speak with Dr. Fred Saad about radium and how we think about bone health, which has been a passion of yours for many years. And especially in patients with Metastatic CRPC in the context of radium. I'd love to hear your thoughts. So what should we think about when we're using bone health agents in this setting?

Fred Saad: Yeah, I mean we started to talk about bone health, it's already more than 20 years since the first study was completed showing that we really could make a difference in terms of reducing skeletal complications with bone directed therapy, like zoledronic acid, and then Denosumab, and with all the exciting new drugs that came out after that, because this is even pre Docetaxel. Then we had docetaxel, cabazitaxel, enzalutamide, abiraterone. We started to think, well, we don't need to really worry about the bone because we're treating the cancer with these exciting drugs and we kind of neglected... and then we did studies showing that the combination of bone targeted therapy and abiraterone led to better outcomes.

And now we have radium, which really acts on the osteoblast and really inhibits the osteoblast... that's its function. And if you treat with radium without thinking of the control of the osteo-clast component of your metastases and the issues of bone loss over the years, you can run into trouble where patients might experience fractures that they might not have experienced otherwise, especially with all the therapies that we have that keep them alive for a long time. So the importance of bone health has not disappeared because of all of these new, exciting agents that we have.

Alicia Morgans: Well, I think to that point, radium is a drug that we use in metastatic castration-resistant, prostate cancer. These patients have had, in many cases, years of exposure to androgen deprivation therapy, which you and others have shown really does cause loss of bone mineral density, and puts you at risk for fragility fractures before you even get to a metastatic CRPC state. When we're using radium, we find ourselves in an even more high risk situation. Of course, we've got bone with disease in it. And we also have very thin bones... so really an important piece of incorporating our holistic care of the patient. You know, one thing that I've heard that I think really is not a myth, but something that we should address is that, radium itself is not associated with... as a single agent, I think, any more bone complications than any of our other agents. And I'd love to hear your thoughts on that. What is the risk of any of our agents essentially in this setting? Do we have a sense of that?

Fred Saad:  Yeah. So the agents, like you said, are not really the responsible factor. It's the fact that these patients have been exposed to years of therapy that have made the bones more fragile. And when we further keep them alive with our effective therapies like enzalutamide, abiraterone, these patients are more and more at risk of having these bone complications, including fractures or needing radiation therapy. And one study that really is amazing... where we're co-leading with URTC in Canada, is the PEACE III study. And this was really an opportunity to look at the effects of not treating, or treating, with a bone supportive agent when you're giving a drug like enzalutamide, with or without, radium and what the study showed was that... and there are no efficacy results yet, but it's the only study I'm aware of that had two podiums at ASCO without any efficacy data, is that the fracture rate, if you're following patients properly, without addressing the bone was almost 30% with enzalutamide alone in two years.

So it's amazing the risk that we expose our patients to, if we don't address... and those numbers plummet down to under 3%, if we give a bone supportive agent. It's even worse, if we're giving the combination of enzalutamide and radium where the fracture rate can go up to almost 50% in those patients. And so clearly when we're going to give radium, but basically any drug, we have to think of bone supportive agents like Denosumab or zoledronic acid to address that fragility in the bone that's even worsened by the presence of metastases.

Alicia Morgans: Well, I think what's so interesting about PEACE III is that the ERA 223 data that looked at abiraterone with, or without radium in the metastatic CRPC population, came out and demonstrated that the combination of Abi and radium seemed to have a higher risk of fragility fractures than Abi alone. But again, for the entire study, there was a higher rate of fracture. And this particularly seemed to be a problem in patients not treated with bone health agents.

PEACE III mandated at a certain point, that all patients really should be on these bone health agents. And the numbers that you initially quoted were for patients who... it was the overall population, but a large number of those patients didn't have bone health agents. It was so interesting that in the combination arm and the single agent enzalutamide arm... so, patients treated with radium and enza, and with enza alone, had a severe decrease in fracture rates, a wonderful decrease in fracture rates when we simply use bone health agents. And so we can make a difference in this problem. We can give the standard of care, which is to use bone health agents in patients with metastatic CRPC, up to monthly, to try to prevent these skeletal related events.

Fred Saad: Absolutely. And the study, as you said, started off by giving the option of a bone supportive agent and almost half the patients were not on a bone supportive agent until ERA 223 came out. And then all of a sudden people realized the importance of bone supportive agents, even though you're effectively treating the cancer, that you still have to think of these bone supportive agents that can eventually actually reduce the risk of death, because fractures are related to an increased risk of death. And so you don't want patients that are going to live longer from their prostate cancer to die because they're exposed to fractures. And so we really have to think of the whole person that we're treating and not just the prostate cancer part. There's really a completeness that we have to integrate in our treatment of prostate cancer.

Alicia Morgans: Well, I love this message, really thinking about ensuring that we're treating bone health, because this is something that applies to all patients with metastatic CRPC, especially when we're thinking about patients treated with radium or with any other agent, but as radium is bone targeted, I always think of making sure I have these bone supportive agents on board when I'm starting that treatment. Any final thoughts, as we're thinking about using radium and ensuring that our patients have good bone health?

Fred Saad: Well, I think we summed it up. Any patient with mCRPC, should be considered for bone supportive agents earlier, rather than later. And sometimes I see it being left to the last line of therapy. That's really too little too late. The bones are completely fragile. I mean, a patient that you know is at a high risk of a heart attack, you're going to do preventative therapy before he gets to a second or third heart attack. Why would you wait for a patient at a high risk of bone complications until he actually experiences one or two or three of these complications? So early intervention, intensive intervention. And then the question of how long we treat we can worry about later, but it's the fact of starting treatment early and then maintaining it for at least a couple of years in these patients that might do very well for a long time.

Alicia Morgans: That sounds great. Well, thank you so much for talking me through that... the use of radium and particularly having a focus on bone health in all patients, of course, with mCRPC. I appreciate your expertise.

Fred Saad: It's a pleasure.