Alicia Morgans: Hi. My name is Alicia Morgans and I am a GU medical oncologist and Associate Professor of Medicine at Northwestern University. I'm so excited to have here with me today a friend and colleague, Dr. Oliver Sartor, who is a Laborde Professor of Cancer Research and the Medical Director of the Tulane Cancer Center in New Orleans, Louisiana. Thank you so much for being here with me today, Dr. Sartor.

Oliver Sartor: Thank you, Alicia. A pleasure.

Alicia Morgans: Wonderful. I wanted to talk with you a little bit about some work that you have presented at GU ASCO 2021. Really focusing first on an abstract that you have on real-world outcomes of patients who received either sequential, antigen receptor-directed therapies, or radium-223. Can you tell us a little bit about that, please?

Oliver Sartor: Sure. So, first of all, let me give you a little context. What to do after the failure of abiraterone-enzalutamide for metastatic CRPC is a bit controversial, and there are a wide variety of choices available. You can move onto chemotherapy, you can move them onto second-line hormones, you can move them on to radium, you could go into a clinical trial, and I think all of those are potentially appropriate. And, we shouldn't forget that in the right genomic context, we also have the PARP inhibitors, both rucaparib and olaparib.

So, what we wanted to do here was look specifically at radium. We chose real-world evidence, and this is through the Flatiron database, and we looked at individuals who had already progressed on the frontline abi or enza, and then they were treated with either a second-line hormone or radium, and we just wanted to have a feel for what happened to these individuals. There are not a lot of parameters that we can effectively follow. We can look at some SSE data, we can look at some distribution of metastases, we can look at some overall survival, and we did those types of things.

Alicia Morgans: Great. And so, really, what did you find with that work? And again, let's just emphasize it's a real-world data set, so these are patients who are actually receiving these therapies in the real-world. They're not randomized to one treatment or the other, they're getting them because of whatever clinical features their physicians see in them that would make them want to put these patients on one treatment or the other. What did you find?

Oliver Sartor: Well, first of all, and this is not at all surprising, that the individuals treated with radium were more likely to have bone-only metastases, so they were enriched in bony metastasis, whereas those who might be treated with the second-line hormones did not all have bony metastasis. And what we found is that the survival was really quite similar between the two groups, suggesting, but not necessarily in any definitive way, that no matter what you choose, you might be able to come out and survive the same, at least in this real-world setting.

Now, what was maybe a little bit surprising is that the survival itself was only about a year. So, it turns out that if you look at the clinical trials, you might come to a little bit of a different conclusion about surviving after the second-line hormones were started. But in this setting, it was only about a year of survival, and it was similar between the radium and the second-line hormones.

We weren't really able to track adverse events in any significant way, but it does appear that radium was safe in this setting, which is probably not a surprise. We were able to attract the SSEs, and the SSEs turned out to be similar between the two groups. I think there might've been a fear about potentially more radium fractures, but it really didn't show up in this database. And we can't really make any strong conclusions other than the survival appears to be about the same and it was safe to choose radium instead.

Alicia Morgans: Do you know anything in the data that you had about whether the patients actually went on to receive chemotherapy or other therapies after they received either AR-targeted treatment or radium?

Oliver Sartor: Yeah, excellent point. We were able to track additional therapies that occurred after the radium or second-line hormones, and they were similar. A lot of people using chemotherapy, even a little bit of third-line hormonal use. But the bottom line is the breakdown, whether chemotherapy or non-chemotherapy in the post-radium and post-second-line hormone, was basically the same, suggesting that you are not necessarily compromised in the ability to give chemotherapy post-radium. We've actually already published on that, so that wasn't necessarily a new finding. We had published out of the ALSYMPCA trial what happens to people post-radium, and the administration chemotherapy was deemed to be safe in the post-radium setting and is in additional corroboration.

Alicia Morgans: It's really interesting, and I think that the fact that we as clinicians are choosing therapies that provide these similar benefits over time is also something for us to recognize and understand, because we may choose patients to go onto that second-line AR-targeted therapy because they had such a nice response in the first place. We may choose patients who have more pain or more poor prognostic signals, but a higher burden of disease to maybe go on to radium. But it's important and good to see at least that we don't see any harm in either group, and that we are able, hopefully, to support these patients with similar SSEs and no clear other adverse events that are coming out in this type of a dataset. Are there other conclusions that you take and that you would use in your clinical practice?

Oliver Sartor: One more, and that is that the alternative treatments available in the post-radium and post-second-line hormone appear to be similar. So, safety is not only measured in the adverse events, but also in the choice of subsequent therapy, and I think it basically it turns out to be fine. Radium is definitely able to prolong survival, but those original studies were done in the absence of abi and enza being approved, so a lot of that radium data doesn't really address the use of second-line hormones.

I would like to go ahead and say that there was a trial called the ERA 223 trial, which combined the abiraterone with the radium and found out a high SSE rate. And I will say that if you're going to be using combination therapy, it really is imperative to use the bone health agents, whether that be zoledronic acid or denosumab, I think is up to you, but at the same time, emphasizing that bone health agents should probably be used in combination with radium, particularly in combination with radium and another hormone.

Alicia Morgans: I really appreciate you saying that. That is definitely something that I have wanted to make sure people are aware of. When people did use a bone health agent, like they did in PEACE III, for example, they were able to take the number of complications in bone, actually, from a reasonably high rate, as we saw with some combination of radium plus abiraterone, and PEACE III was radium plus enzalutamide, they took it all the way down to zero. So, if we pay attention to bone health and use those agents, particularly in the setting of combinations of these AR-targeted agents and radium, we can take it down to a level that's importantly, very, very low.

Oliver Sartor: Yeah. And I'm glad you brought up the PEACE III. Bertrand Tombal presented that at ASCO and it was very, very striking. The cumulative instance was probably running in the 40% rate for the radium combined with the enzalutamide, and it went down to zero when you added in the bone health agents, which is typically zoledronic acid or denosumab, so really a striking finding and one that should be emphasized in the real world.

Alicia Morgans: Absolutely. Well, thank you so much for doing this work. I think real-world evidence is a way for us to really think about the difference between efficacy in a clinical trial and effectiveness in the patients that we actually see in our clinics each day. I really appreciate you taking the time to go through all of the work and to explain it to us. We appreciate it.

Oliver Sartor: Thank you, Alicia. My pleasure.