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Oliver Sartor: Hi, I am Dr. Oliver Sartor, and on behalf of UroToday, it's really a pleasure for me to be able to welcome Fred Saad. Fred is incredibly well-known in the global community for prostate cancer, has been the leader on many, many trials, including some of the original bone health agents, which we're actually going to be coming back to during this presentation. But today he's going to be talking about some of the very provocative results presented at ESMO 2024 in Barcelona on the PEACE-3 trial of which he was an investigator. So Fred, I would love to hear a little overview about the trial and then we'll talk about it.

Fred Saad: Thanks, Oliver. It's my pleasure to be able to summarize some of the highlights of this important PEACE-3 study. So thanks, Oliver, and thanks to you and to UroToday for allowing me to very briefly summarize some of the highlights of the EORTC PEACE-3 study. So this is an intergroup cooperative group phase three study that included patients with metastatic CRPC who had to have bone metastasis, whether they were asymptomatic or mildly symptomatic and with no known visceral metastatic disease. So under 500 patients were randomized one-to-one to receive enzalutamide plus or minus radium-223 given at the standard dose of every four weeks for six cycles with a primary endpoint—an ambitious primary endpoint of rPFS—to really delay disease progression in terms of metastatic disease with multiple secondary endpoints that are clearly important, including safety and overall survival, and then time to next treatment, etc.

Of importance, when the study started, there was no obligation to use bone-protecting agents, and I won't go into all the details, but clearly to say that in the era when patients did not receive bone-protecting agents coming into the study, we saw a much higher fracture rate, and that was already reported at ASCO a couple of times without any efficacy data. But the importance of bone-protecting agents in combination with these therapies, whether it's enzalutamide alone or radium-223 plus enzalutamide.

The primary endpoint, jumping straight to the important endpoints, is that rPFS was significantly prolonged in patients getting the combination of enzalutamide plus radium-223 with 45% of patients reaching progression in the enzalutamide alone arm versus 36% at the 24-month endpoint. And overall, a 31% reduction in the risk of progression, which was very statistically significant with a p-value of 0.0009.

And other important endpoints obviously are what are we doing to overall survival? And here actually the overall survival, there was a reduction in risk of death again of 31%, hazard ratio of 0.69, again statistically significant with a p-value of 0.0031. And this is extremely important because it supports the importance of our PFS endpoint in this study. We're still waiting for longer-term data in terms of overall survival, but this is extremely encouraging that both our PFS and overall survival seem to be impacted by the addition of early radium-223 in combination with one of the standard of care options of mCRPC, which is enzalutamide. Time to next systemic therapy also delayed with the combination of enzalutamide plus radium-223, again with the hazard ratio of 0.57. Very impressive statistical significance and I would suggest a clinically important endpoint of not needing subsequent therapy as early since we know that after an ARPI, the results with subsequent therapies are not very good.

And so this is very encouraging in patients getting the combination. So I'll conclude there that the combination of enzalutamide plus radium-223 significantly improved our PFS. This improvement was supported by an improved overall survival that still needs to be confirmed with longer follow-up, and there was an improvement in time to next systemic therapy. And in terms of the additional adverse events by the combination, in terms of grade three adverse events, there was a slight increase with the addition of radium-223, going from 19% to 28%. But these were all quite manageable, and I think it is a very safe regimen in patients who can get access to this combination and hopefully will become a therapeutic option and maybe the first therapeutic option in terms of combination therapies that might have a life-prolonging effect in mCRPC. So thank you very much. Look forward to some of the discussions with you, Oliver.

Oliver Sartor: Thank you, Fred. One of the things that I think was really interesting about this study is the contrast with ERA-223. And just as a little bit of a reminder, there was another study with abiraterone plus monotherapy radium that did not meet its primary endpoint. And I wonder if you might just give a little bit of a compare and contrast between that particular trial and this particular trial. And let me hear your perspective on how you think things might've been different now versus then.

Fred Saad: Yeah, so clearly I think we all had a very significant wake-up call with ERA-223, where we saw patients treated in that study that had a very high fracture rate, really quite early. Within 12 to 18 months we were seeing separation of the curves in terms of fractures in the combination arm of abiraterone plus radium-223. But what was striking is even with patients just on abiraterone, the rates of fractures were high. And when we looked at why this might've happened, we realized that many patients were not getting any bone-protective agents even though for years we've been saying for metastatic disease that is CRPC, that has bone metastatic disease, we should use bone supportive agents and a significant proportion were not. And when we looked at patients on bone-targeted therapy and those that were not, we saw that there was a big difference in terms of fracture rates. And this was unknown until the study was closed.

But this data helped PEACE-3 because when that data came out, there was an urgent safety letter to all investigators to ensure that patients are on a bone-targeted therapy. It became an obligation. So with only about 50% getting bone-targeted therapy, this went down to under 3% of patients not getting a bone-targeted therapy. And the results we see today with PEACE-3 might not have been the same if that knowledge wasn't there and that obligation to use a bone-protective agent was not implemented.

Oliver Sartor: Fred, I agree completely. And one of the things I might want to emphasize, but I'd like to get your take on it, when I look at this therapy, we're not talking about really a doublet. We're actually talking about a quadruplet. We're talking about ADT, enzalutamide, a bone health agent, and radium. So there are actually four components to this therapy, and I wonder if you just might comment on that or any perspective on the statement I just made.

Fred Saad: So coming from you, Oliver, I take that with a lot of gratitude because I've always thought that a bone-protective agent is a form of therapy for these patients. It was unfortunately, for good or wrong reasons, ignored a little bit as if it was just an add-on that was expensive and maybe a burden. And now we're realizing exactly what you said, that this is probably adding to the therapeutic efficacy of our therapies. And we saw this early on with the abiraterone study in mCRPC pre-chemotherapy where patients who did get a bone-targeted therapy seemed to be doing better even though they were asymptomatic. And here we're combining therapeutic agents that have different mechanisms of action, all important in our management of these patients. And so I totally agree, I think it is part of optimal care of patients with metastatic CRPC.

I can't say that for hormone-sensitive disease; we still are not sure what dosing and how we should implement it, but clearly in the mCRPC state where these patients are at their highest risk of having these bone complications that include fractures and many other complications, it is an integral part of care.

Oliver Sartor: I'm going to do a little bit of a shout-out to Fred because not everyone may remember, but many years ago there was a phase III with zoledronic acid. It happened to be led by one Fred Saad, and it showed the unequivocal benefit of the bone health agents. And I would agree to some extent it had been ignored over the years, but here I think it really floats to the top of the discussion. We look at ERA-223, we look at the PEACE-3, we look at contrast, we look at reduction in risk after the initial run-in without the bone health agents. And my conclusion is thank you, Fred, for bringing this to our attention many, many years ago. I can't remember what year that was—what year was that in that original—

Fred Saad: 2001, Oliver. That's 2001 that study was completed. And in all fairness, people questioned whether it was as relevant with the addition of all these new therapies. It actually came out before docetaxel reporting. We had a hard—but since then, even the UK group looked at docetaxel plus or minus zoledronic acid and saw an improvement in time to SRE. In your own study with ALSYMPCA looking at radium without a bone-targeted agent, you saw a difference in terms of SRE. So it takes time for us to realize the importance of what we consider supportive care, I think is actually doing more than just supporting; it's actually helping make our therapeutic options more effective.

Oliver Sartor: I'm going to throw out an idea, and I'd like to hear your comment. I think there's the possibility of a special relationship between the bone health agents and radium-223 because of the enhancement of the stroma that occurs when you inhibit the osteoclasts, thereby making the lesion perhaps a little more osteoblastic, enabling radium to bind to that osteoblastic lesion perhaps with a little more avidity. And I just wonder what you might think about that concept.

Fred Saad: I can't do anything else but totally agree. I think they have really complementary mechanisms of action, and used together we really get the best of both. Obviously radium is the life-prolonging agent, but to make the most out of the agents and what causes the morbidity and even adding to the mortality of patients are the bone complications. And so this synergy I think is really, really important. And we published an EAP study that you and I were both involved in, and when we saw radium with or without other agents, we had this impression that wasn't randomized—that's why we needed PEACE-3—but we saw improvements when you added an ARPI. And surprisingly, survival was improved with the combination of radium plus denosumab, which was a surprise to us. So this complementarity is going beyond just helping the bone; I think it really helps control the disease.

Oliver Sartor: Well said, Fred. One of the things that's a little bit interesting here, I look at the survival curves and I think there's a lot of maturity, and you look at the split and it's wide and it gets wider with time. Yet you've mentioned that we need to have more data despite the fact that it was statistically significant. Help the readers understand that conundrum because on the face of it, it looks mature and statistically significant. But I know there's more to the story, but I want to hear it in your words.

Fred Saad: To put it very simplistically, you saw that early on in the study there was a crossing of the curves. So this is something that statisticians don't like and are asking us to make sure that really the effect on overall survival is there. And so this is something that statistically forces us to wait a little bit longer to really confirm this overall survival. If you ask me what my personal impression is, that crossing of the curves is very close to where we were seeing those high fracture rates. And in ERA-223, those high fracture rates were also trending towards worse survival. And so the importance of fractures goes way beyond only quality of life; it might actually impact survival of patients. And once that implementation of a bone supportive agent where we saw almost no fractures anymore, those curves separate, like you say, extremely, extremely well and are very encouraging that we are seeing an overall survival effect.

Oliver Sartor: One of the issues I think that is going to create discussion around this trial is the fact that it started a long time ago, took a long time to mature, and there have been changes in practice, particularly with using the ARPIs earlier into the treatment course we typically use now for metastatic hormone-sensitive disease and what might be called non-metastatic CRPC as well. I just wonder if you might give a little bit of perspective on the changing landscape and how it might apply to these particular results.

Fred Saad: Yeah, and you're totally correct. I mean, we would like to see patients that are mCRPC having already been exposed to an ARPI in the past. And I think in your center and mine, those are rare patients that haven't been exposed to an ARPI prior to becoming mCRPC. But what we see around the world is that there's still a lot of patients that are getting ADT monotherapy in the pre-mCRPC state. So there's still a large population of patients that might benefit from this, but you're correct, we have to think of the future. Now I see this as a different mechanism of action. You and I have had these discussions. ARPI to ARPI I think is not the way to go, but ARPI to ARPI with a different mechanism of action by combining with radium might be something that would be very convincing. We need more data because very few patients came in post-ABI, but I think we're introducing a totally different mechanism of action.

So I think even after an ARPI, this could be a therapeutic option. And we've seen patients in our clinical trials doing extremely well even that are already on enzalutamide and starting to progress with the addition of radium-223. Going from ABI to enza with radium-223 I think would be something very interesting. Obviously the right answer is we need some more data. What happens when we go from an ARPI to this combination? But I do see this having a place in the future.

Oliver Sartor: Fred, we're going to be wrapping up in just a moment, but I wondered if you might have any last brief comments for our audience sort of in wrap-up for additional thoughts.

Fred Saad: Well, I think we're heading in the right direction. I mean, what's so sad is we don't have a single life-prolonging therapeutic option in combination form for mCRPC. We're still mono-therapeutic sequential. So will this be our first life-prolonging combination of mCRPC? It might well be, but it just shows that we're still a little bit behind in what we can do for patients with mCRPC, but this is very encouraging. And coming back to your first observation, in patients with bone metastatic disease, we can do much better with combinations. And I like your thought that it's a quadruple therapy: ADT, supportive agent, radium-223, and enzalutamide really attacking the cancer in multiple forms. So I think it's the way of the future.

Oliver Sartor: Thank you very much, Fred, insightful discussion. Appreciate you spending time with us today on UroToday.

Fred Saad: Thanks, Oliver.