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Alicia Morgans: Hi, I'm so excited to be here with Dr. Neal Shore, who's a urologist and an expert on how we think about optimal sequencing of drugs in metastatic CRPC, and in many other things, of course. But Neal, I'm really excited to talk with you today about this.

Neal Shore: I'm so happy to be here with you.

Alicia Morgans: Wonderful. We have so many options in metastatic CRPC, and we have newer radiopharmaceuticals, radioligand therapies that we're also trying to integrate, but we also have a really pretty impressive group of drugs that we've been working with for the last number of years. How do we think about using some of the tools that we've really optimized, and in a way that makes a lot of sense. As we have these new options, at this point in time, like Lutetium, which is a later line option?

Neal Shore: Yeah. It's such an important observation, and yet, a vexing question. The observation that you make is, look, we've got 12 life-prolonging therapies in advanced prostate cancer, and within those 12 approved by the FDA, seven novel mechanisms of action. And yet, our recent studies have demonstrated that, a typical patient in North America who dies of advanced prostate cancer may see, on average, just two therapies. So I love the basis of the question, because we have to incorporate a really full throated, very expansive multidisciplinary team approach. Unless you're an uber uro-oncologist, or uber medical oncologist, or radiation oncologist, nuc med radiologist, pathologist, it's hard to do. So everybody really needs to say, how do we, the north star approach, which is patient efficacy and safety first. And yet, there are all these great therapies, taxanes, androgen receptor targeted agents, PARP inhibitors, radiopharmaceutical in the form of radium, and now PSM RLTs, and immunotherapies and taxanes.

It's not a one size fits all, as we all know. And it's thinking about tumor burden, it's thinking about patient comorbidities, access. And at the end of the day, and I've been doing this long enough, when I have patients who succumb to the disease, I always look at their charts, and I look at the number of lines of therapy. And I don't know if it's right to say I feel better, but maybe I do feel better, if I know they've been exposed to at least four or five, ideally more, and a clinical trial. Because as ASCO points out, and other associations, a clinical trial is a standard of care, and it's the only way we're going to make advances.

I think, to really do this well, and we had a plenary presentation at AUA 2022 this year, Lenny Gomella, myself, and Mike Cookson, and Alicia, you've been a champion of this for your careers, getting everybody involved. And I think this is so important.

The treatment of advanced prostate cancer has become more complex. You add on genomic profiling, understanding next generation imaging. And so, it really does take a team approach, to optimize patient care, and to figure out the sequencing correctly.

Alicia Morgans: Well, when we're thinking about the team, I just would love to hear, from your perspective, how do you really optimize the team, if you want to give something like radium, for example? How do you pull together the members of the team, to make sure that they're working together? They're not stepping on toes. And really collaborating, when sometimes they're all in the same center, but other times they're at different centers, different hospitals even, trying to do their best to care for the patient.

Neal Shore: Yeah. I really appreciate that. We gave the first FDA approved dose of radium-223 at our clinic, back in 2013. And what saddens me when I look at a lot of market data and surveys is just, even almost 10 years later, how many of our colleagues don't appreciate the fact that radium is a life prolonging agent. Yeah, you can get palliation from it, but it's not really to be given for palliation, it's to be given for life prolongation.

There was a setback with the ERA 223 trial, combining it with abiraterone. I think we all very anxiously await the PEACE III trial, which combines radium-223 with enzalutamide. Now, one of the important issues there is that, historically, and really truthfully, radium doesn't typically lower the PSA. PSA is very important for many of our colleagues, as well as for patients.

There is a nice window for mCRPC patients when they progress on abi or enza, prior to chemotherapy, to get their radium. But I think, a lot of times, patients and clinicians are missing that window. I like that window. And I think that's an ideal time. You could still give radium after taxane therapy. Of course, performance status is oftentimes diminished at that point. You can still give radium, frankly today, before or after a PSMA-RLT, such as Lutetium-617, the recent approval based upon the VISION trial. I think, a lot of our colleagues are thinking it's binary. I either give it, or I don't. That's just not the case. There is ample data from Germany, from the US, to be able to safely give radium-223 prior to taxane, after taxane, and frankly, prior to Lutetium-617, and even afterward.

 We all know that radium-223 is, there's not going to be a supply chain issue. It is given very safely and quickly. There's no pre-medication, post-medication. It's a 60 second infusion. The restrictions for the patient, post administration, are much less restrictive, compared to receiving Lutetium-617, and so, these are real advantages.

Lutetium-617 just got approval in the US by FDA, just a couple of months ago. And so, there's going to take some time. There are some issues regarding the licensure for who's going to be giving it, whether it's a nuclear medicine radiologist, or a radiation oncologist, regarding what's called the radio activities materials license, or the RAM. That's not really the case for radium-223. So it's a really important, and I think all of our colleagues, medical oncologists, urologists alike, recognize that we want to optimize the number of life prolonging therapies, and radium-223 clearly, still has a very important role in the sequencing.

Alicia Morgans: I think that's so important. So couple things that I want to sort of just build on there, and ask your thoughts. First, I tend to give radium sometimes before taxane, actually. It's not uncommon for me to give it before a taxane. Because when I have that shared decision with patients, many patients will still try to use chemotherapies later in their treatment algorithm, or their treatment sequence. And radium, of course, does not have hair loss, or some of the issues that kind of come with chemotherapy, including things like neuropathy. And so, they do tend to, in some cases, say, "I prefer this." And I also have a lower likelihood maybe, of having some of the cytopenias, for most patients, than I could have with the chemotherapy.

Additionally, I like that I can get six cycles in for most patients, when I do it in that earlier setting. And there has been data to suggest, that if you can get all of the cycles of radium into the patient, then that patient has a better prognosis, overall. So always trying to aim for the biggest bang for our buck, is something that I think I try to do.

But I'm curious, sometimes patients in that setting, don't have the classic bone pain symptoms that people think of when they think, "Oh, radium is something that I can use mostly in symptomatic patients." And it is for symptomatic patients, but in my clinic at least, I interpret that symptoms come in many flavors, and it's not only bone pain that drives my use of the drug. And you mentioned, you're really giving it for a survival benefit. You're not necessarily doing it for palliative reasons. Although of course, none of these therapies are curative. What are your thoughts?

Neal Shore: Yeah. You raised a great point, regarding this kind of notion around, the subjective notion of symptomatology. I think it was in 2019 at APCCC, we actually asked this question to the expert panel. And the panelist said, I think we had consensus on it, that symptomatology for a patient who had bone dominant disease, who was mCRPC, it didn't matter the level of their symptomatology, but that radium was appropriate drug to give. Now, in the PI for radium, because of the way ALSYMPCA was designed, the use of the word, symptomatic, was incorporated into that label. And we've done some work on this in various marketing, not really marketing, questionnaires data, and looking with patients and caregivers. It's so subjective. And even in ALSYMPCA, 50% of the patients who had symptomatic bone disease were on non-narcotics, and about 50% were on narcotics.

 When someone requires a narcotic, or an NSAID, it's very variable. It varies by age. It varies by ethnicity and racial subgroups. It's really kind of fascinating. Educational status. And so, I find that, the notion around symptomatology, it's very subjective. The bottom line is, if you've got bone dominant disease, radium's a great drug, because it's a calcium emetic. It goes right to where the hydroxy mineralocorticoid phenomenon is occurring, and it causes these double stranded DNA breaks.

And as you said earlier, the safety profile is very good. It's decayed in the intestinal pathway. You see at most, very low grade diarrhea. I've never, I can't even recall, having to start a IV hydration, let alone a hospitalization for someone receiving a course of radium. So that's really important, A, for someone who is very active and fit, who doesn't want to take on a taxane. And on the other end of the spectrum, it's very good for somebody who's maybe, post-taxane and wants to take on a therapy and do something, and not go to palliation or hospice care, but is worried about adverse events.

Alicia Morgans: So thank you so much for walking us through that. Really, radium is a drug that we can use for disease control purposes. It has some improvement in bone pain as an added benefit, from my perspective. But the survival benefit is something that we really can't argue with. And it seems to be effective in patients, especially when we can get all of the cycles in, as with many of our agents. The earlier we give them, the longer we give them, the more benefit they can provide.

So I really appreciate you talking us through this complex landscape, and thinking through some of the nuances around the multidisciplinary administration of radium-223. Which is a drug we've had for a while, but remains a very relevant drug in our treatment sequencing.

Thank you for your time, Dr. Shore.

Neal Shore: Pleasure. Thank you.