Alicia Morgans: Hi, I'm so excited to be here at ASCO 2022, where I have the opportunity to speak with Dr. Tanya Dorff about treatment with radium, and how we really use this drug, given all of the options that we have available to us today, in an effort to ensure that patients have access to as many life longing therapies that make them feel well, of course too, as they possibly can. So when you're thinking about treating your patient with metastatic castration resistant prostate cancer, who is a patient that you might think potentially could be treated with radium? Or how do you think about it in the landscape, especially given that it's changing so rapidly over time?

Tanya Dorff: There are definitely challenges with the changing landscape, but at the end of the day, prostate cancer is so dominated by bone metastases. And I think you just kind of see it in your practice how much that impacts their day to day function, their quality of life. And so, as we're thinking about sequencing our agents, those patients whose bone disease is just very active stand out as patients who you definitely want to make sure you sequence in radium among the other treatments.

Alicia Morgans: Well, thank you. I think that's very, very helpful. And what's interesting to me too is the way that potentially even triplets might move into the metastatic hormone-sensitive setting. So patients might receive an AR targeted agent in combination with docetaxel and ADT, and by the time they get to MCRPC they've had multiple mechanisms already. And radium does provide a different mechanism of action, as long as that disease, of course, is a bone only. Or bone dominant, I should say, because you could have some small pelvic nodes, for example.

Tanya Dorff: Right. That was allowed in the ALSYMPCA trial. And exactly what you're saying, a first line MCRPC patient now technically could be absolutely a candidate for Radium 223 because they will have already been exposed if they've been treated with appropriate intensified upfront therapy with at least an AR targeted agent and possibly also docetaxel. So the question is which patients are defined as symptomatic. So there are not just palliative benefits to radium. Obviously it did delay skeletal related events, especially symptomatic ones. That was a new definition that was used in the ALSYMPCA trial. But also it prolonged overall survival. And so I like to think of it as using it in sequence with other agents to maximize survival for patients.

And we know that if the bone marrow is not robust enough, patients can't get through all six doses, which is the optimum amount in order to maximize the survival benefit. So in some ways using it a little bit earlier and not waiting till someone has so much bone involvement that they are myelosuppressed and severely anemic makes sense. And so I think it really takes asking your patient about symptoms. I think you have to look at someone who's progressing. Maybe there's new disease on the bone scan or maybe they're just starting to do fewer activities compared to what they used to do, even if the bone scan looks similar. So we have to think a little more broadly about who's eligible.

Alicia Morgans: I think that's such an important point. Because symptoms can include things like fatigue, in addition to the classic pain that someone might have. Sometimes even weight loss, change in taste and change in appetite can be symptoms of cancer progression. Again, it's not just progression in bone. One thing that you also mentioned really rings true to me in my practice is that the earlier we use this treatment, the greater the likelihood that we'll actually have the opportunity to get in six cycles, which is so important from my perspective, as we use this drug to try to ensure that patients get everything that they can out of it. And using it earlier, potentially even in a pre chemotherapy space, has been something that's helped me to get through more cycles of treatment. I'm not sure how that works in your clinic, but would love to hear your thoughts.

Tanya Dorff: Yeah. I also think that sometimes you miss a window because there can be late soft tissue progression, which would then make a patient ineligible. So especially after someone's been debulked by their upfront therapy and they're having progression, they have active bone disease, especially if there were lymph nodes at the beginning that are now maximally treated, I think if we don't use radium in that interval we may miss it. And then we just take one option off the list for that patient. So I look at the kinetics of their soft tissue disease, if they had some lymph nodes at the beginning, prostate primary as well. So I want to make sure they're not having a lot of growth in the prostate primary tumor because that can become symptomatic during a bone focused treatment. But we have to be chess players as physicians and really try to think other options will be available even if those lymph nodes start to grow again. But right now we can maximize treatment of the bones and really help this patient gain every survival advantage possible.

Alicia Morgans: I love that idea. Being a chess player, whether you're a patient or whether you're a clinician. I think that's really such an elegant way to put what we do, which is really trying to sequence our treatments in a way that lets us get the most out of the time that we have. So thank you for putting that into perspective. What would your final thought be? Any closing thoughts as we finish up?

Tanya Dorff: Well, I think there are interesting data being presented here at ASCO, from the REASSURE study, looking at alkaline phosphatase as a biomarker. So initially in ALSYMCA it seemed like patients with higher alkaline phosphatase levels were among those who benefited the most. But what was really interesting in this analysis, which is a poster presentation, is that even in the normal alk pho subset, seeing the alk pho decline was predictive of increased overall survival. So I think when people are using Radium 223, PSA doesn't always tell the story of whether the patient's benefiting or not. So as we always do, we have to look at their symptoms. We look at their scans, but also people should be aware to look at the alkaline phosphatase.

Alicia Morgans: That's a great message. And something else for us to keep an eye on as we are trying to help make decisions with ourselves and also for our patients and with our patients about whether or not the treatment is effective. So important. Thank you so much for your time and for going through this with me today,

Tanya Dorff: My pleasure.