Alicia Morgans: Hi. I'm thrilled to have here with me today a friend and urologist, Dr. Neal Shore, who is a urologist at the Carolina Urologic Research Center in South Carolina/Myrtle Beach. Wonderful to have you here today.

Neal Shore: Great to be here, thanks.

Alicia Morgans: Wonderful. I wanted to talk to you a little bit about the practical utilization of radium, because as we're thinking about metastatic CRPC, one of the things that I always talk to my patients about is really changing mechanism of action, incorporating all of the options that we have to really give our patients the best shot at controlling the cancer regardless of how we can do it. We've got a lot of tools, let's use all of them for everybody. So who is the patient or when are you thinking about using radium?

Neal Shore: Yeah, so I love the premise of your question which is we know CRPC is a terminal disease unless somebody dies of some other event, cardiovascular or some other illness or a trauma for unfortunate reasons. So I like being able when we see patients progress towards death, is ultimately say, well did they have an opportunity to receive all of the approved agents and were we good stewards about when we offered these agents? And radium's been around now for close to seven years and I still find that many of our colleagues are confusing the optimal timing or the window of opportunity for it. The ALSYMPCA trial, which led to its approval, was almost a little bit more than half had received a drug post-docetaxel and another half about prior to docetaxel.

So it has an approval label regardless of when you would use docetaxel. There's ample evidence that the administration of the course of therapy, six infusions, you really need to get in at least five of the six, ideally six, but really five of the six, to have the survival benefit. I still think many of our colleagues think that radium is given, or Xofigo®, as a palliative drug or for palliative purposes. It's a life-prolonging agent, and that's how I look at it. I don't look at it to be given for palliative purposes. Of course, I'd like to see that happen. That said, I tell my patients most of the time when I'm using it is prior to using docetaxel. Big fan of docetaxel and I tell my patients that you can expect to receive docetaxel and ideally you will probably also receive cabazitaxel and that chemotherapy should not create a wave of fear and concern.

We are much better at dealing with taxane-based side effects, but I really like getting in from my bone-predominant patients who have mCRPC, a course of Xofigo®, radium-223, it's typically before or sometimes during an androgen receptor-targeted therapy. There's been controversy regarding some earlier data and trials like the ERA 223, where we didn't recognize the importance of concomitant use of bone health agents, typically denosumab or zoledronic acid to help prevent associated fractures and skeletal-related events. So at ASCO GU 2020, there are some really nice meta-analyses looking at some of the real-world experience as to how we're using radium prior to docetaxel and how we're using it either with concurrent or a layered use of an androgen receptor-targeted therapy, typically abi or enza. And it's arbitrary, but if you say is that concurrent is giving an abi or enza with a course of radium within 30 days, many would think of that as concurrent and outside of 30 days as a layered phenomenon.

Potentially, part of the reasoning for doing this is letting the bone milieu adjust. There's still a lot we don't understand about the microenvironment of the bone compartment and how the class blast relationship is affected by an AR-targeted therapy and then hitting it with a really potent DNA damaging mechanism effect of radium. So Tia Higano had a poster here and did a large meta analysis and I was fortunate to be part of it and we're hoping to write all this up and really showing that, in the real world, we're seeing a lot of layered, as well as concurrent use. It's almost 50-50. Interestingly, we're not seeing enough regular use of bone health agents and I do think that should be quite standardized now, whether making sure the patients are on either denosumab or zoledronic acid at the same time.

Alicia Morgans: Absolutely. So just to sort of reiterate those issues, ERA 223 included patients who had abiraterone plus or minus radium, and we saw that in the combination arm, there was a higher level of fractures than in the single-agent arm, but we actually saw fractures across the board and a relatively low rate of utilization of bone health agents in mCRPC patients who technically, you know, are really eligible and should be getting up to monthly injections of denosumab or zoledronic acid to reduce the risk of skeletal-related events. When this was analyzed in PEACE III, which was patients receiving with mCRPC, receiving enzalutamide with or without radium, we saw that there was a pretty dramatic reduction in the rate of fractures that had been occurring within the trial, after a notification that all patients absolutely must be on a bone health agent, that rate went down to nearly zero.

So when we use bone health agents in these combination situations, where when you're talking ... You mentioned we have this DNA damaging agent and this AR antagonism or low levels of testosterone, we can change that narrative. We can change the course of these fractures and prevent them. And so all of these patients, we already know all of these patients should be on bone health agents and we need to make sure that that happens. But when we do, the rate of fracture is actually low, whether you're a single-agent radium, probably, although that was not any of the arms in these trials or whether you have a combination, as you're mentioning.

Neal Shore: Yeah. So if I could, you know, we have a really fun and I think a really cool trial that we're doing and you're helping out with it, which I'm so pleased with, with your expertise in neurocognitive assessment. So we're taking patients who have mCRPC and we're randomizing them to their first line of treatment to receive darolutamide versus enzalutamide in bone-predominant and/or with soft tissue, no visceral metastases. We are going to look at a lot of their neurocognitive effects over a 12-week period and then they'll have a second point of randomization to receiving a course of radium or placebo infusion. And so as opposed to PEACE III, which was structured very similar to ERA 223, ERA 223 was concomitant use of abi and radium, PEACE III concomitant use of enza and radium, we're allowing for this 12-week run to see if it makes a difference.

I'm of the mindset that I think it does, but we have to show that. And so like I said, getting the bone compartment adjusted. So I think in other cancer types and metastatic foci, we see combination therapy used much more regularly. We've had a bit of some headwind towards us in prostate cancer, where we tend to be very monolithic in sequencing one drug after another. And we've had a hard time of figuring out how to really ideally do combinations. So I'm excited about it for a whole host of reasons and we'll get some additional answers, hopefully.

Alicia Morgans: Absolutely. So before we wrap up, is there a patient that you think is not a good candidate for radium, because I think it's important for us to recognize that there are good patients and maybe some patients that are not so good and how does your sequencing actually help you to target those patients, while they may still be good candidates, before they may become less good candidates for radium?

Neal Shore: Yeah. Well, you know, I think in the label, if I'm not mistaken, patients with visceral metastases should not be receiving the drugs. It's not been adequately studied there. I think that patients who can't receive at least five of the six infusions, they're given every 28 days, would be a poor candidate who just doesn't have the performance status or an actuarial likelihood for survival. So I think those may not be ideal candidates. And getting back to what you said earlier, I really like the idea of finding that window to get the treatment in, because it's life-prolonging, as are the AR-targeted therapies as are our two approved taxane-based therapies. And then at some point in time, to try to get them into the appropriate trial, ideally based on some biomarker evaluation.

Alicia Morgans: Absolutely. Wonderful. Well, and just to reiterate, yes, absolutely patients with lots of nodal disease or any visceral disease are not going to be candidates for radium, just because radium really doesn't work outside of the bone and we wouldn't want that to limit the patient. But when I talk to patients, I often say, you know, we have an opportunity. You have bone only disease right now. We have an opportunity to use this drug that may not be there in the future. And I'm always thinking about how the disease can change, and we actually never know how that disease will change, whether it will go to lymph nodes, lung, liver. And so when we have the opportunity, I do try to do my best to give the patient, again, every available treatment, including radium.

So, thank you so much for your time, your expertise. This was a really valuable discussion about a treatment that we need to use. Actually, I think a little bit more to give our patients access to all available therapies, as well as the bone health considerations that we need to take in mCRPC, generally, but certainly in the setting of using some of these combinations. So thank you so much.

Neal Shore: Pleasure.