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Neal Shore: Hi, I'm Neal Shore, the Medical Director at Carolina Urologic Research Center in Myrtle Beach, South Carolina and I'm here today with a very good friend and colleague, Phil Koo, who is the Chief of Diagnostic Imaging of Banner MD Anderson. It's great to have you here Phil. As you and I were talking about a few minutes ago, so much has happened in the world of CRPC and advanced prostate cancer, but two of the areas that you're incredibly expert in is in radiopharmaceuticals, specifically your experience with radium-223, and also in next-generation imaging and how we think about being better diagnosticians and managers of advanced prostate cancer and certainly other cancers, but I was just curious, radium, now since it's approvable and available for over five years now. What have been some of the learnings that you've had? Because you work with medical oncologists and urologists who work with you to order radium-223 for their patients. What have you seen and how has that evolved?

Phillip Koo: Thank you, Neal. I think, probably the two biggest lessons we've learned are the fact that radiopharmaceuticals can lead to an improvement in overall survival and that they're safe. So, if we look back at when radium-223 was first introduced, I think there was a lot of skepticism for a variety of reasons. One, I think there was very large legacy with regards to radiopharmaceuticals that they are harmful and if we look back to the strontiums and the samariums, it was very true that you would see this marrow suppression, and you would see the blood counts drop and it was scary. It was oftentimes touch and go and that's always a fear because then your treatment options down the road are limited.

So, I think that was one big hurdle that we had to overcome and then when you started talking about alpha particles, when you talk about the linear energy transfer associated with these particles, I think there was an even greater fear that this would damage the bone marrow even more. I think as people got used to it and now what we're seeing is the fact that it is very safe, and we often think with every advantage there comes a disadvantage, but in this case with an alpha particle, it was stronger, and it traveled a shorter distance, so you really had less side effects, and I think it took a lot of people a little bit of time and just experience to start believing it.

So, I think at this point in 2019, it's safe to say that I think we've shaken off the baggage of the old radiopharmaceutical errors with strontium. Huge, huge advancement from my opinion because this is just setting the stage for a growing field of therapeutic radiopharmaceuticals, and I think we're learning a lot. We're learning that hey, if we work together and we just incorporate this into the armamentarium of all the other treatments that we have, I think, it can lead to greater improvement in patient outcomes and that's what I think we're embracing, and we're realizing. I think this is not going to be the end-all-be-all, but it's going to give us another tool and I think that's what we're looking for, especially as we try to potentially cure this disease.

Neal Shore: Yeah, I think your points are so well taken. When the drug was first launched, there was this legacy notion, or the stigma around other radiopharmaceuticals like strontium and samarium as you said that had a lot of toxicity. I've been giving radium now for over five years and have done now several trials, and I had the reflection that I've had patients who've said, I can't take anymore androgen deprivation therapy, or I cannot take another dose of abiraterone or enzalutamide because of fatigue effects or patients who couldn't get through a reasonable course or docetaxel or cabazitaxel. I honestly haven't had a patient who said I can't take anymore radium because of the administration or the safety profile toxicity of the drug. I mean, I've had patients who I might have too late, and they might have progressed in their disease, which was shame on me, but not because of the tolerability and I think it's 180 degree difference of how we thought about the drug when it first launched.

Phillip Koo: I completely agree. For me, as the person who administers the drug, it's been such a wonderful experience. Patients come in, we draw labs a day before, two days before, we review them, we get them settled, it's a one minute injection, they don't notice anything, they're gone. So, they're in and out our department in maybe 20, 30 minutes and then when they go home, after the first or second doses, that's what might see maybe a little bit of a bone pain flair, maybe a little diarrhea, some nausea, but from our own anecdotal experience, from doses three to six, it's kind of smooth sailing. So, when they come back every visit, they're usually happy when they compare with all the other therapies they've received in the past, it's sort of a walk in the park for them, which is great, and we do see those improvements in quality of life. Subjectively, when we talk to these patients, they do feel better, they have more energy, they're sleeping better. Again, not everyone experiences improvement in bone pain, but those that do, I think it's a very nice added benefit to this therapy.

Neal Shore: So, really appreciate your insights because you've been a pioneer in these therapies for a long time in the radiopharmaceuticals, what are your thoughts these days when you have a patient come in, they're on radium-223, regarding the use of bone health agents?

Phillip Koo: You know, from my perspective as a radiologist and a nuclear medicine physician, that's not usually part of our scope of practice, but what we're learning is the fact that it needs to be. As the people who are giving this drug, we need to work very closely with a urologist and medical oncologist to make sure we're doing everything to make sure this treatment is effective, and the patients are kept as safe as possible during this therapy and it's very clear that bone health is an area that we need to do better. There are a lot of discussions about how you can make that happen, and I think the idea of these bone health clinics is amazing.

It's something I think we should all take home with and make that a reality, whether it resides in your advanced prostate clinic or a multidisciplinary clinic, it just needs to exist somewhere because we're hitting these patients with so many therapies, they're living a lot longer, they're getting steroids, again just multitudes of things that are weakening their bones, which is actually a success story if you think about it because we have been able to keep our patients alive and healthier longer. And I think people are going about their activities of daily living to a higher degree but with that comes a greater responsibility on our end to make sure we protect those bones.

Neal Shore: Yeah. I think it's a great point and being comfortable, adding on radium when they're already receiving a bisphosphonates for example, zoledronic acid or denosumab, it's there to really strengthen bone formation while we're giving it this powerful DNA stranding apoptotic effect break of what we see with radium is slowing down prostate cancer cell progression in the bone, and I'm excited about some ongoing trials that we're going to see combining therapies with radium, and I think what we've learned from some recent studies, for example with the ERA-223 but with others, is the importance of the timing. Can you talk about the timing?

Phillip Koo: Absolutely. So, when we wrote RADAR-2, I think it was very clear when we introduced this idea of layering that patients would be on these novel hormonal agents and then when the PSA started to rise while they were on these agents, then you would sort of layer on other therapies like radium-223. The idea of starting two therapies simultaneously, I think, comes with a lot of challenges, and I think we know when you start someone on abiraterone, you see sort of this flare response, at least on a bone scan. So, you could imagine the pharmacokinetics and just how the drug works, if you gave it concomitantly with radium-223, would just be different.

So I think, this is something that I think we need to pay attention to because there's a very distinct difference between combination at the same time versus layering and physiologically I think there are differences between those two types of approaches and for radium-223, I think it makes it more sense to have patients who are on something, and we'll learn more from PEACE-3, the trial that I'll hopefully reporting on next year or two where, all right these patients will be on enzalutamide for a longer time and then you add on radium and see what type of effect because theoretically it makes a lot of sense. The mechanisms of action of these hormonal agents versus radium-223 are so different. Radium-223 does not hit the soft tissue lesions, so it makes sense to be able to target both sides of disease simultaneously.

Neal Shore: Yeah. I fully agree with you and being able to combine and, as you say, a novel hormonal agent that can get to soft tissue, viscera, whereas radium is really primarily on the bone, the PEACE-3 trial, which is, as you say, is predominately bone and one CRPC, enza-radium versus enza and then that's the PEACE-3. We're actually about to start a trial called ESCALATE where they'll have a nice 12-week lead in with enza, then add in the radium versus just staying with the enza. So, what's interesting there is the bone's ability to adapt before you hit it with the power of a targeted alpha therapy.

Phillip Koo: It's wonderful that you aren't abandoning the idea of these types of combination therapies that are layered appropriately because just because we had this one signal from ERA-223 doesn't mean that that whole space is fraught with problems because it's not. I think we have a lot of data from the post-hoc analyses from the EAP trial, from your own trial, I think it was ERADICATE, that have shown us that you know what? These combination therapies probably do work and help improve outcomes.

Neal Shore: Well, Phil, thank you very much.

Phillip Koo: Great, thank you.