Enrique Gallardo Diaz: Thank you.
Oliver Sartor: So the PEACE-3 trial is familiar to many people, but not all. And I wonder if you might kind of describe broadly the PEACE-3 trial to give a context to what we'll follow.
Enrique Gallardo Diaz: PEACE-3 trial is an academic multicentric trial promoted by EORTC. It compares enzalutamide plus radium-223 versus enzalutamide alone in first-line treatment of metastatic castration-resistant prostate cancer in patients with bone metastases, since radium-223 is a drug directed to bone metastases. The patients are asymptomatic or mildly symptomatic with no visceral disease and a good performance status. So the primary objective was radiographic progression-free survival. whose results were published, communicated at ESMO '24 and published at Annals of Oncology last year. Primary analysis showed positive results with an improvement of radiographic PFS with a hazard ratio of 0.71. And now we present the results of the overall survival. Patients are stratified by country, pain, previous use of docetaxel and abiraterone and use of bone-protecting agents before the use of this BPA was mandatory after the publication of results of the ERA-223 trial with a combination of abiraterone plus radium-223 and a high incidence of fractures to try to avoid these fractures.
Oliver Sartor: Let me ask a little bit of bone protective. What type of bone-protective agents were actually used in the trial? And after an initial phase where there was no mandate, subsequently there was a mandate from the DMC saying bone-protective agents must be used. But help us understand which bone-protective agents were used after the mandate was in place.
Enrique Gallardo Diaz: Either zoledronic acid or denosumab were allowed with a schedule of every four weeks, every month.
Oliver Sartor: I think that's important because we talk about enzalutamide therapy, we talk about radium therapy. There actually is this additional component, which is the bone-protective agents, which if left off, as shown in the initial phase of the study with enzalutamide or in the prior ERA-223 study is very problematic. So the bone health agents are actually part of the regimen, in my opinion. Is that reasonable?
Enrique Gallardo Diaz: Yeah, absolutely.
Oliver Sartor: Okay.
Enrique Gallardo Diaz: But what I would like to say is that not only for the combination of radium-223 plus enzalutamide, but I think most of metastatic castration-resistant prostate cancer with bone metastases should receive a bone-protecting agent. Even in a monotherapy, for example, with enzalutamide or whatever. Looking at the data of PEACE-3 trial, previously to the mandatory use of bone-protecting agents, the incidence of fractures was 53% in the combination arm and 20% in the enzalutamide arm. After, it decreased to 14 and 10. I mean, in the enzalutamide arm also it was a protective effect of BPA. So this is the way I say that probably the BPA should be, I don't know if mandatory, but recommended in most mCRPC patients.
Oliver Sartor: No, thank you for that point, which I think is very important.
Enrique Gallardo Diaz: Yeah.
Oliver Sartor: Now, the oral session included the final overall survival analysis, and I wonder if you might give an update based on the prior data and the current data. So tell me what's new presented here at ASCO GU.
Enrique Gallardo Diaz: In the interim analysis, overall survival was positive with a hazard ratio of 0.71, but we observed a crossing of the curves previous to 18 months. So this was because it was recommended a longer follow-up to prove that these results are strong. So in the final analysis, overall survival benefit was maintained with a hazard ratio of 0.76 and the significant threshold below the prefixed threshold. So it was a positive result. We observe deaths before and after 12 months in order to try to understand this curve crossing. What we saw is that the difference in the beginning of the follow-up in the first 12 months, the difference between combination arm and control arm was only of six additional deaths. It's a small number. But well, in the beginning it was significant. Following the trial, the longer follow-up you get, the better survival you see. So this overall survival benefit was maintained across all the follow-up.
Oliver Sartor: I'm going to do a little bit of a clarification because that early crossover the curves was never statistically significant.
Enrique Gallardo Diaz: No. No, no.
Oliver Sartor: And the confidence intervals always overlapped. So it could have been due to chance. It's a small number of events that having to go one way instead of another. But just to make sure our listeners understand, it was never statistically significant. Now, what about medians? You didn't mention the medians in this setting, but I think they're quite strong.
Enrique Gallardo Diaz: Yeah. Median overall survival were 32.6 months in the control arm and 38.2 in the combination. So the difference was 5.6 months in overall survival. I think it's a very good, very, very important figure.
Oliver Sartor: No, it's a robust finding and a very strong control arm. I mean, enzalutamide is well known to prolong survival and currently an FDA approved agent in all the guidelines in this setting. So I think it's a big win for the radium to show that radium can add value to a strong enzalutamide control arm treatment. So very, very nice. Now what about toxicities? You mentioned earlier about the possibility of fractures in the longer term follow-up with the bone health, with those fractures under reasonable control, other issues, MDS or myelosuppression, other issues that led to concern?
Enrique Gallardo Diaz: Yeah. The combination produces a moderate increase in adverse events. We saw, for example, Grade-3-to-5 drug-related adverse events, which are the most probably relevant in these treatments from 19% in the control arm to 29% in the combination. We saw no drug-related deaths were reported in both arms. Treatment discontinuation rate was really low, 5% for enzalutamide, 3% for radium-223, so it was not very high. And regarding specific adverse events, fatigue fractures, anemia and neutropenia were more frequent in the combination, but the difference in this or even any other adverse event was less than 5% in comparison to the control arm. Regarding fractures, at the end the fracture incidence was 27% in the combination, 14% in the control arm, but most of them were Grade 1-2, no major concerns about it. And the difference in, again, in Grade-3-to-5 fractures was also less than 5% between arms. Regarding hematologic complications, there were three cases of hematologic malignancies in the combination regarding bone health, as you say, besides fractures, we observed 17 cases of osteonecrosis of the jaw, 14 were in the combination and from these five were grade three. Well, it's a concern. We must be conscious about these complications, but probably the incidence is not so high to be a major worry.
Oliver Sartor: Very interesting. Thank you for the updated presentation. Are there any particular future plans, regulatory approval? Will that be submitted or is that something you can speak to?
Enrique Gallardo Diaz: As I know, the combination is reflected at NCCN guidelines with a possibility in certain circumstances. So this is important to be reflected the benefit of the treatment. Regarding regulatory situation, I'm not really informed about in what moment is the process, but I think it should be an option because of the observed benefit. I think that the study, besides the benefit of the combination, strengthen the role of radium-223, because as you said, enzalutamide is a potent agent with a very significant overall survival benefit, and the addition of radium-223 improves it. So even in monotherapy, it should be a possible option for patients. The role of bone-protecting agents, I repeat for every patient with mCRPC, you should consider it. And another important thing in my view is the involvement of patients in the decisions, because when you combine two treatments, it's true that you produce an improvement in overall survival, but you may also increase toxicity. So this could impact in quality of life of patients. And I think the decision taken should be shared between doctors and patients.
Oliver Sartor: No, thank you very much, Enrique. And I'll simply say thank you for presenting really wonderful new data.
Enrique Gallardo Diaz: Thank you.
Oliver Sartor: It's good follow-up and a pleasure to have you on UroToday.
Enrique Gallardo Diaz: Thank you