Bone-Protective Agents and Survival Benefits in PEACE-3 Trial Subgroup Analysis - Fred Saad
March 23, 2025
Fred Saad joins Zachary Klaassen to discuss a subgroup analysis of the PEACE-3 trial, which evaluated enzalutamide with or without radium-223 in metastatic castration-resistant prostate cancer. Dr. Saad highlights how bone-protective agents (BPAs), made mandatory after high fracture rates were observed, significantly impact outcomes. Among 115 pre-mandate patients, those receiving BPAs gained 14 months in radiographic progression-free survival and 17 months in overall survival compared to those without, regardless of treatment arm. There was also a 71.6-month survival in patients receiving the full quadruple therapy (ADT, enzalutamide, radium-223, and BPA). The analysis reveals that BPAs not only reduce fracture rates from 36.5% to 12.5% but may provide additional therapeutic benefit. Dr. Saad attributes clinicians' reluctance to prescribe BPAs to the challenge of recognizing preventative benefits and emphasizes their importance as patients live longer.
Biographies:
Fred Saad, MD, FRCS, FCAHS, Professor, Department of Surgery, Raymond Garneau Chair in Prostate Cancer, Director of Prostate Cancer Research, Director of GU Oncology, Université de Montréal, University of Montreal Hospital Centers (CHUM), Montréal, QC
Zachary Klaassen, MD, MSc, Urologic Oncologist, Assistant Professor Surgery/Urology at the Medical College of Georgia at Augusta University, Wellstar MCG, Georgia Cancer Center, Augusta, GA
Biographies:
Fred Saad, MD, FRCS, FCAHS, Professor, Department of Surgery, Raymond Garneau Chair in Prostate Cancer, Director of Prostate Cancer Research, Director of GU Oncology, Université de Montréal, University of Montreal Hospital Centers (CHUM), Montréal, QC
Zachary Klaassen, MD, MSc, Urologic Oncologist, Assistant Professor Surgery/Urology at the Medical College of Georgia at Augusta University, Wellstar MCG, Georgia Cancer Center, Augusta, GA
Read the Full Video Transcript
Zachary Klaassen: Hi, my name is Zach Klaassen. I'm a urologic oncologist at the Georgia Cancer Center. I am delighted to be joined on UroToday, as always, by Dr. Fred Saad, urologic oncologist at the University of Montreal. Today, we're going to be discussing EAU 2025 data that Dr. Saad presented, looking at a subgroup analysis of the PEACE-3 trial. Fred, thanks very much for joining us.
Fred Saad: It's always a pleasure, Zach.
Zachary Klaassen: So we obviously have heard the high-level results of PEACE-3 previously, and those have been discussed extensively on UroToday, but maybe just set the stage why bone-protecting agents, which the subgroup analysis you presented are an important topic, even going back several years to previous trials.
Fred Saad: Yeah, it's amazing that 20 years after the pivotal publication on the importance of preserving bone health to prevent skeletal related events, we're still discussing the need for bone-protective agents or bone-targeted agents. You know, and now more contemporary data is just confirming what we thought was important 20 years ago—that when you don't treat these patients, especially that they're living longer, they are going to have a high complication rate, including fractures and obviously the spinal cord compressions and the need for palliative radiation. And when you don't treat—ERA 223 was a wonderful study, but it was stopped prematurely because of a very high fracture rate in those that didn't get a bone-protective agent when you're following these patients properly.
Zachary Klaassen: Right. No, exactly. And I think that led to some changes, which we'll talk about in your presentation for the PEACE-3 trial. So maybe just pull up the slides you have. Just highlight the PEACE-3 trial design and some of the data you presented at EAU.
Fred Saad: Just to remind, PEACE-3 was a phase III randomized trial looking at patients with first-line mCRPC that were going to get enzalutamide plus or minus radium-223, the standard every four weeks for six cycles with a primary endpoint in terms of reducing progression of metastasis. So rPFS was the primary endpoint with multiple secondary endpoints, obviously, that includes skeletal symptomatic events and overall survival importantly.
Now, before the urgent safety letter, a bone-protective agent was not mandatory. It was left up to the investigator whether or not they would use a bone-protective agent. And so the first 119 patients were split 50/50 with or without a bone-targeted agent. And then there was an urgent safety letter that was sent out once ERA 223 reported, mandating the use of a bone-protective agent like denosumab or zoledronic acid.
And so just to remind the top-line results, the study was positive. There was a significant statistically and, in my opinion, clinically significant improvement in rPFS with a 31% reduction in the risk of radiographic progression. Overall survival still requires some maturity. But here again, 31% reduction in the risk of death with the addition of radium to enzalutamide alone.
Now, looking at the fracture rates, before the urgent safety letter and after: before the urgent safety letter, 36.5% fracture rate in patients without a bone-targeted agent. And this was up to 53.6% in the enzalutamide and radium arm and 20% in the enzalutamide arm, which is pretty much the standard of care. After mandating bone-protective agent, that went down to 12.5%, 10% in the enzalutamide arm and 14.2% overall. So, a big reduction in the risk of fractures.
Now, the objective of this analysis was to look at before the urgent safety letter, where we have a split of patients with or without a bone-protective agent. So we looked at the 115 patients that received protocol treatment—51% had no bone-protective agent, 49% had a bone-protective agent prior or during the study. And basically, to sum it up, the rPFS was 14 months longer in patients with a bone-protective agent compared to patients without a bone-protective agent. This is a hazard ratio of 0.6, so 40% reduction. And the confidence interval is below 1. So we can't talk about statistical significance, but I think very intriguing and with a confidence interval that is tight.
And when we look at the subgroups, well, whether you had radium or not, the benefit was similar. But when you're looking at the extremes, enzalutamide alone without a bone-protective agent, rPFS was 12.9 months, and then enzalutamide plus radium with a bone-protective agent was up to 28.9 months. So, very big difference in terms of rPFS. And surprisingly, even in terms of overall survival, a 17-month longer overall survival in patients with a bone-protective agent compared to those without. And it's an outstanding 71.6-month survival if you were getting enzalutamide, radium, plus a bone-protective agent in this study, where the follow-up is long, making up for small numbers.
So briefly to conclude, rPFS is significantly improved with the addition of radium to enzalutamide in the overall study. In the cohort that we were able to study, a bone-protective agent improved rPFS by 14 months over not using a bone-protective agent. And this was a similar advantage in both arms. And a bone-protective agent led to a 17-month improvement in overall survival. Again, a similar advantage in both arms of the study, but outstanding results if we consider this quadruple therapy—enzalutamide plus radium plus a bone-protective agent plus the base ADT. So, really quite intriguing in terms of results and suggesting that bone-protective agent in combination with life-prolonging therapeutic options in mCRPC is safe and may provide additional therapeutic benefit. Thanks.
Zachary Klaassen: Fred, just remarkable data. I mean, if you think about not only safer—there's no question, the fracture rate goes way down—but patients are living longer. That's almost a six-year survival with mCRPC. We've never seen this before, right? I mean, I know you mentioned off the top you've been talking for 20 years about BPAs. And I guess my question is quite simple: why is there such a, I don't know, hesitancy or reluctance or just a paucity of ability to prescribe this with these men that truly need it?
Fred Saad: Yeah, I mean, I don't want to make excuses, but I can understand sometimes the hesitancy of doing preventative care, right?
Zachary Klaassen: Sure.
Fred Saad: I mean, we're used to seeing results with what we do. PSA declines. We take out a prostate, the PSA goes down to zero. We give ARPIs, the PSA goes down. We know we're doing something of importance, and that's going to lead to better outcomes. Here, the idea is we're preventing something. And when we don't see it, we don't really know if it was coming. You need large numbers, long follow-ups. And you talk to people: I don't see fractures, I don't see spinal cord compression. But that's not true. They're happening before patients die, and it's just that we don't follow them long enough, and we don't pay the attention that it requires.
Zachary Klaassen: No, absolutely. I know, as you mentioned, not powered to show differences. But when you see that median overall survival as long as it is with that triplet therapy, it really is impressive. Great data, great presentation. Always good having you on UroToday. Anything we didn't cover you want to hit on, maybe a take-home message or two for our listeners?
Fred Saad: Well, I think the take-home message is that these patients are living longer. So we have to think of survivorship. We have to think of maintaining the overall quality of life and their bone integrity. And that leads to better outcomes. And I think the data is supportive of that.
Zachary Klaassen: Absolutely. Fred, always great having you. Thanks so much for presenting your data at EAU 2025 on the PEACE-3 trial.
Fred Saad: Thanks, Zach.
Zachary Klaassen: Hi, my name is Zach Klaassen. I'm a urologic oncologist at the Georgia Cancer Center. I am delighted to be joined on UroToday, as always, by Dr. Fred Saad, urologic oncologist at the University of Montreal. Today, we're going to be discussing EAU 2025 data that Dr. Saad presented, looking at a subgroup analysis of the PEACE-3 trial. Fred, thanks very much for joining us.
Fred Saad: It's always a pleasure, Zach.
Zachary Klaassen: So we obviously have heard the high-level results of PEACE-3 previously, and those have been discussed extensively on UroToday, but maybe just set the stage why bone-protecting agents, which the subgroup analysis you presented are an important topic, even going back several years to previous trials.
Fred Saad: Yeah, it's amazing that 20 years after the pivotal publication on the importance of preserving bone health to prevent skeletal related events, we're still discussing the need for bone-protective agents or bone-targeted agents. You know, and now more contemporary data is just confirming what we thought was important 20 years ago—that when you don't treat these patients, especially that they're living longer, they are going to have a high complication rate, including fractures and obviously the spinal cord compressions and the need for palliative radiation. And when you don't treat—ERA 223 was a wonderful study, but it was stopped prematurely because of a very high fracture rate in those that didn't get a bone-protective agent when you're following these patients properly.
Zachary Klaassen: Right. No, exactly. And I think that led to some changes, which we'll talk about in your presentation for the PEACE-3 trial. So maybe just pull up the slides you have. Just highlight the PEACE-3 trial design and some of the data you presented at EAU.
Fred Saad: Just to remind, PEACE-3 was a phase III randomized trial looking at patients with first-line mCRPC that were going to get enzalutamide plus or minus radium-223, the standard every four weeks for six cycles with a primary endpoint in terms of reducing progression of metastasis. So rPFS was the primary endpoint with multiple secondary endpoints, obviously, that includes skeletal symptomatic events and overall survival importantly.
Now, before the urgent safety letter, a bone-protective agent was not mandatory. It was left up to the investigator whether or not they would use a bone-protective agent. And so the first 119 patients were split 50/50 with or without a bone-targeted agent. And then there was an urgent safety letter that was sent out once ERA 223 reported, mandating the use of a bone-protective agent like denosumab or zoledronic acid.
And so just to remind the top-line results, the study was positive. There was a significant statistically and, in my opinion, clinically significant improvement in rPFS with a 31% reduction in the risk of radiographic progression. Overall survival still requires some maturity. But here again, 31% reduction in the risk of death with the addition of radium to enzalutamide alone.
Now, looking at the fracture rates, before the urgent safety letter and after: before the urgent safety letter, 36.5% fracture rate in patients without a bone-targeted agent. And this was up to 53.6% in the enzalutamide and radium arm and 20% in the enzalutamide arm, which is pretty much the standard of care. After mandating bone-protective agent, that went down to 12.5%, 10% in the enzalutamide arm and 14.2% overall. So, a big reduction in the risk of fractures.
Now, the objective of this analysis was to look at before the urgent safety letter, where we have a split of patients with or without a bone-protective agent. So we looked at the 115 patients that received protocol treatment—51% had no bone-protective agent, 49% had a bone-protective agent prior or during the study. And basically, to sum it up, the rPFS was 14 months longer in patients with a bone-protective agent compared to patients without a bone-protective agent. This is a hazard ratio of 0.6, so 40% reduction. And the confidence interval is below 1. So we can't talk about statistical significance, but I think very intriguing and with a confidence interval that is tight.
And when we look at the subgroups, well, whether you had radium or not, the benefit was similar. But when you're looking at the extremes, enzalutamide alone without a bone-protective agent, rPFS was 12.9 months, and then enzalutamide plus radium with a bone-protective agent was up to 28.9 months. So, very big difference in terms of rPFS. And surprisingly, even in terms of overall survival, a 17-month longer overall survival in patients with a bone-protective agent compared to those without. And it's an outstanding 71.6-month survival if you were getting enzalutamide, radium, plus a bone-protective agent in this study, where the follow-up is long, making up for small numbers.
So briefly to conclude, rPFS is significantly improved with the addition of radium to enzalutamide in the overall study. In the cohort that we were able to study, a bone-protective agent improved rPFS by 14 months over not using a bone-protective agent. And this was a similar advantage in both arms. And a bone-protective agent led to a 17-month improvement in overall survival. Again, a similar advantage in both arms of the study, but outstanding results if we consider this quadruple therapy—enzalutamide plus radium plus a bone-protective agent plus the base ADT. So, really quite intriguing in terms of results and suggesting that bone-protective agent in combination with life-prolonging therapeutic options in mCRPC is safe and may provide additional therapeutic benefit. Thanks.
Zachary Klaassen: Fred, just remarkable data. I mean, if you think about not only safer—there's no question, the fracture rate goes way down—but patients are living longer. That's almost a six-year survival with mCRPC. We've never seen this before, right? I mean, I know you mentioned off the top you've been talking for 20 years about BPAs. And I guess my question is quite simple: why is there such a, I don't know, hesitancy or reluctance or just a paucity of ability to prescribe this with these men that truly need it?
Fred Saad: Yeah, I mean, I don't want to make excuses, but I can understand sometimes the hesitancy of doing preventative care, right?
Zachary Klaassen: Sure.
Fred Saad: I mean, we're used to seeing results with what we do. PSA declines. We take out a prostate, the PSA goes down to zero. We give ARPIs, the PSA goes down. We know we're doing something of importance, and that's going to lead to better outcomes. Here, the idea is we're preventing something. And when we don't see it, we don't really know if it was coming. You need large numbers, long follow-ups. And you talk to people: I don't see fractures, I don't see spinal cord compression. But that's not true. They're happening before patients die, and it's just that we don't follow them long enough, and we don't pay the attention that it requires.
Zachary Klaassen: No, absolutely. I know, as you mentioned, not powered to show differences. But when you see that median overall survival as long as it is with that triplet therapy, it really is impressive. Great data, great presentation. Always good having you on UroToday. Anything we didn't cover you want to hit on, maybe a take-home message or two for our listeners?
Fred Saad: Well, I think the take-home message is that these patients are living longer. So we have to think of survivorship. We have to think of maintaining the overall quality of life and their bone integrity. And that leads to better outcomes. And I think the data is supportive of that.
Zachary Klaassen: Absolutely. Fred, always great having you. Thanks so much for presenting your data at EAU 2025 on the PEACE-3 trial.
Fred Saad: Thanks, Zach.