PEACE III: Implications for Radium-223 and Treatment Sequencing in CRPC

A roundtable discussion, moderated by Pedro Barata, MD, of University Hospitals, highlighted the evolving treatment landscape of advanced prostate cancer, including hormone-sensitive prostate cancer (HSPC) and castration-resistant prostate cancer (CRPC). The panelists analyze expanding treatment intensity, the utilization of androgen deprivation therapy (ADT) and androgen receptor pathway inhibitors (ARPIs), and integrating patient-reported outcomes (PROs) in care. Dr. Barata was joined by Andrew Armstrong, MD, MSc, of Duke University School of Medicine; Cora Sternberg, MD, of Weill Cornell Medicine; and Evan Yu, MD, of UW Medicine.

In the fifth segment of our roundtable series, the treatment of patients with CRPC is discussed, including the use of radium-223 and the use of treatment sequencing.

View the next segment of this roundtable series: Future Directions in mCRPC: Novel Therapies and the Role of Radium, Radioligand Treatments

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Dr. Barata:
So let’s move on to CRPC. And there’s a lot of segue. We can go in different ways. We talked about bones, so maybe that’s a good opportunity, a good excuse. Big news from ESMO, the PEACE III trial. A cooperative group-run trial in Europe, URTC. Around what, 450, something like that. 446 patients, I believe, randomized to enzalutamide or ENZA plus Radium.

So Dr. Armstrong, let me start with you. These patients had less than 1% exposed to prior abiraterone, I believe, ARPI. So 99%. Basically, it’s a population that was ARPI naive at the time were randomized one-to-one to enzalutamide, or enzalutamide plus Radium. Your leverage on prior phase II data suggesting a benefit of the addition of Radium-223 plus ENZA.

And I still recall it’s much even younger of actually folks were doing a lot of that combo and folks stopped doing that combo where we saw data from the ERA 223 precisely what Dr. Yu: alluded to, which the big concern regarding the fractures, bone-related events, which basically trigger to stop using Radium because of their risk and regarding to bone health.

So my question to you is can you summarize for us quickly the highlights from that trial and then we will talk a little bit about the implications for our practice today, but also in regards to the bone health.

Dr. Armstrong:
Sure. So PEACE III was designed eight years ago when ARPIs were the standard of care in the first line mCRPC setting based on COUGAR-302 and PREVAIL. And so it was conducted during that era and so it’s still relDr. Yu:t to that patient population where around the world maybe 50% of patients are not getting an ARPI early. So it’s still relDr. Yu:t to them.

And then they had to have four more bone metastases where Radium may be useful and is a bone-targeted therapy. They learned from the ERA 223 study, instead of closing down, they learned from it, they instituted mandatory bone anti-resorption prophylaxis. So they saw a very high fracture rate that was nearly 50% in the combination of ENZA plus Radium go down to less than 5%.

And so by the end, they did have a higher fracture rate, but it was under 5%. So I think they saved the study. And then, preventing fractures allows you to see the efficacy of Radium long-term by maybe having some synergy with Enzalutamide. ENZA is an AR blocker. AR is important in DNA repair, Radium is inducing DNA repair. We always think of this as a radiosensitization and now you can actually see it. You never had the chance to see it in ERA 223 because it stopped early because of fractures. And these were fractures not really in the tumor site, but due to insufficiency. Radium and abiraterone and prednisone were really inducing osteoporotic insufficiency fractures.

But when you block that, you now have greater efficacy. So it’s very exciting. I don’t see these patients anymore, so in my practice it might make me consider using ENSA after ABI with Radium. But that landscape’s rapidly changing to include PSMA Lutetium in the near future. You have docetaxel, you have genetic testing now with olaparib in a post-ARPI setting. So there’s a vast menu post-ARPI now, which PEACE III really doesn’t apply to.

Dr. Barata:
Got it. Before I get there, Cora, when we saw the data, I’m curious to hear your thoughts. When I saw the data, we saw about a three month difference favoring the combination of Radium ENZA, but then we see a delta of more than seven months overall survival favoring the combination.

The way I read that was, that disconnect perhaps, to me was almost a line. What we’ve seen in the ALSYMPCA trial designed a center of care +/- radium-223 pre and post chemotherapy is almost 50/50, right? Where we actually see a survival advantage without really seeing a difference in radiographic PFS or PSA by the way, which means there’s something about Radium-223. It’s making patients live longer without necessarily impacting the time to more mets in the scans or even PSA. So does that make sense to you or do you have a different explanation for that? What were your thoughts when you saw the data?

Dr. Sternberg:
When I saw the data, putting them together made sense because ALSYMPCA improved the overall survival. Enzalutamide has improved overall survival. But I think that they didn’t improve the time to pain progression and there was something else that they didn’t improve – the subsequent therapy was about the same. There were many things that were not improved in that study. So I think people will use it, particularly those people who are just giving ADT and are not using an RP in the beginning. And what we need to figure out is what is the right sequencing of that? What comes after that, if they’re going to use that?

If they’re going to use that as a first line for metastatic CRPC because their countries or their insurance or whatever won’t, or they don’t have the access to other agents or other drugs. I don’t know that I’m going to use it so much. I used a lot of Radium when I lived in Italy a long time ago and I’m not using it anymore at all. But I’m not so encouraged to use it now because I’m not seeing those patients really.

Dr. Barata:
Fantastic. Thank you for that. I was thinking about that and I’m curious whether or not there might be some regional differences because patients get to us with mCRPC in one of two ways. Either they were diagnosed with metastatic hormone sensitive disease and we treat them, it sounds like we are all doing the same thing. We are offering treatment intensification, we expose them to ARPI, they progress and they get to mCRPC. But they can also get to mCRPC after being on hormone for non-metastatic hormone sensitive disease, also known as biochemical recurrence, right?

Meaning they’re being seen by urology colleagues. They treat the number, meaning they treat the rising PSA without mets. They keep on hormones often, continuously, and then they end up developing metastatic disease when you get a PET scan and they come to us. Dr. Yu:, are you seeing that population? Because if you are and because it always takes time to get an uptake pre EMBARK, maybe we’ll still have a population suitable for PEACE III like. Is that what you’re seeing in Seattle or not really?

Dr. Yu:
We have those patients what I call M0CRPC. We have some. I would say the challenge is, is that most of them are on an antigen receptor antagonist like Enzalutamide, apalutamide or darolutamide. So as it applies to the discussion on PEACE III, if they’re on apalutamide or darolutamide, I’m not apt to go to Enzalutamide when they progress with radiographic progression.

Dr. Barata:
Let me rephrase. I was referring to the patients are that getting hormones for biochemical recurrence. Just hormones, no EMBARK. Just ADT. They stay on it. And then at some point they start having rising PSA, usually urology managing those patients. They scan them, they see some mets and they send them to us.

Maybe you’re not seeing as much of those patients. Is any of you seeing… I do see quite a bit, actually. It is true that I have a good referral or UH has a good referral system with the community urology and so we actually end up getting calls, et cetera. What do I do now? I now see disease in the scans. This patients been on hormones or they’re about to start them on ENZA and then send them to us. It sounds like-

Dr. Yu:
Not too often.

Dr. Barata:
… Doesn’t sound as often as the other scenarios?

Dr. Yu:
It’s not part of the Seattle tech culture. So usually they’ve come to our attention earlier.

Dr. Barata:
Got it. So probably some differences there.

Dr. Armstrong:
I think globally that’s a common scenario.

Dr. Barata:
Right. So there might be a role I guess because what we’ve seen with the use of Radium-223, it appears that the urology community in the United States do use it quite a bit. And the guidelines outside US, including Europe, have led folks to not use it much. Right? Because hey had some restrictions about it and there was a reference to that, changing the guidelines in Europe because they were mandating a treatment in between the ARPI and Radium. So we’ll see how that pans out.

But what I’m really interested to hear from you guys is sequencing. So maybe Dr. Armstrong, I’ll start with you. So you were stating that, well, I don’t know if this is applicable to patients exposed previously to ARPI. We are all medical oncologists and we actually, the data suggests, that we tend to use more abiraterone than our colleagues from urology to tend to use more an antiandrogen. So let’s take the scenario of a more medical oncology typical case, which is, you have a patient on abiraterone, the patient’s progressing. First question for you, do you ever consider a second ARPI, an antiandrogen? Yes, always? Yes, never? Or no, never? Or sometimes? And if you have some times, walk us through who could be a potential patient for that.

Dr. Armstrong:
Yeah, that’s a complex question, but I would say it depends. It depends on the patient’s characteristics, their biomarkers, their genomics and their preferences, their pace of disease. This is related to Dr. Agarwal’s contact O2 study where everybody got a second ARPI or an experimental drug. But I think most of us would not offer a second ARPI to a patient in pain, a patient who has visceral, like liver metastases. A patient who’s developing symptoms and has a really rapid progression. Those patients probably need docetaxel. Those patients may benefit from Radium and ENZA, perhaps. If they have bone-only disease and are symptomatic, that wouldn’t be unreasonable, if they are not a candidate for docetaxel. Maybe in the near future, PSMA Lutetium, which has a very good progression free survival, good response rate.

The second ARPI type patient would be a slow progressor, node-only disease. They don’t want docetaxel. They’re not ready for it. They have minimal symptoms, no visceral crisis. And I think those patients, it’s reasonable to talk to them. Obviously they’re not going to be accounted for Radium likely either, unless they have high-volume bone mets. But I might talk to them about that, giving them ENZA plus Radium.

I think Silke mentioned it very nicely that you basically don’t have to have symptoms to have a survival benefit from Radium. And I think that’s kind of an exciting advance. As long as you’re using bone health, maintaining calcium D, exercise and using a bone protective agent, I think there’s that chance that you may be benefiting. But her study does not speak to that scenario. But in the real world, it wouldn’t be wrong to take a post ABI patient and give them ENZA, which has only a one third response rate and add Radium to advocate for your patient living longer. I’ve been doing that for years, but only in selected patients.

Dr. Barata:
Got it.

Dr. Sternberg:
What we know from studies like the PLATO study and patients after ABI, there could be a 30% response rate to ENZA. And this is done primarily, I would say, in very elderly patients that really don’t want chemo and don’t want anything else. I mean, patients there in their late eighties who come to New York and they want something. But patients who are on ENZA first, I don’t think ABI works at all from all the different studies that we’ve seen. So I think that there is maybe a 30% chance of ENZA working.