Rashid Sayyid: Hello, everyone, and thank you for joining us today in this UroToday Journal Club recording. I'm Rashid Sayyid, Robotic Urologic Oncology Fellow at the University of Southern California in LA. And I'm glad to be joined today by Zach Klaassen, Associate Professor and Program Director at Wellstar MCG Health in Augusta, Georgia.

And today, we'll be discussing the very exciting recent publication of the EORTC 1333, or more commonly known as the PEACE-3 trial, that looked at the combination of enzalutamide plus radium-223 and metastatic CRPC. This manuscript was recently published in Annals of Oncology, with Dr. Tombal as the first author and Dr. Gillessen as the senior author.

So as we look at the landscape of mCRPC and the approvals that have come through over the last almost three decades now, we see that we have many options for mCRPC patients. But unfortunately, the reality is that the survival outcomes for these patients remain quite poor.

If we look at data from clinical trials, we see that the median overall survival is roughly three years. And that is based on historic data now from the COU-AA 302 trial of abiraterone, the first-line setting before docetaxel, as well as enzalutamide pre-docetaxel in the PREVAIL trial.

One may say that, well, this data is almost or over a decade old now. And so you would expect the more contemporary results to be better. But if we look here, the Kaplan-Meier curve, and a bit of a sneak peek on what's to come later on, we look at the control arm of these three that received enzalutamide, which is an approved first-line agent in the mCRPC setting, we see that the median overall survival is even less than three years.

And so clearly, the current first-line treatments are insufficient. And this becomes or looks even worse when we look at real-world data, where the median overall survival is about two years. And this discrepancy between real-world data and clinical trials has been related to the clinical trials, including healthier patients with a better performance status, better able to tolerate the drugs.

And also they have more access to second and third-line agents, given that they're typically treated in tertiary care centers with access to clinical trials. And so we see here, overall, a pretty gloomy picture for mCRPC patients and really an important cohort of patients to focus on with regards to future research efforts.

And so what is radium-223? Radium-223 is a targeted alpha emitter which selectively binds to areas of increased bone turnover in bone metastases. And it acts as a bone-seeking calcium mimetic, which binds to new bone stroma and then emits high-energy alpha particles over a short range. And so this leads critically to DNA double-strand breaks in the tumor cells, but also to osteoblasts and osteoclasts. And we'll see why this is particularly relevant in the next few slides.

Radium-223 has been studied most famously in the ALSYMPCA trial that looked at radium-223 in the pre-Abi and pre-Enza era. And this ALSYMPCA trial was a phase 3 RCT that included just over 900 patients, patients with symptomatic mCRPC with at least two bone metastases and no visceral metastases. And eligible patients in this trial were randomized 2 to 1 to receive six IV injections of radium-223 versus placebo. And importantly, all patients received additional best standard of care.

And this was a positive trial where radium-223 versus placebo improved overall survival by about 30%, as we see here. But also importantly, in addition to the survival benefits, we saw an improvement in the time to the first symptomatic skeletal event about a 34% reduction.

So overall, this was a clear win for radium-223 in the setting. But unfortunately, despite these promising results, we still see an underutilization of radium-223 in these patients that's typically reserved in the second, third, or even fourth line setting for eligible patients.

And so the next question is why combine enzalutamide and radium-223? What is the rationale here? And to answer this question, I'm going to refer to this excellent slide from Dr. Fizazi at the ESMO in 2024 when he presented the PEACE-3 data for the first time.

And so the rationale here is that we see an overall survival benefit with an ARPI Abi or Enza in this setting. But also, as we just clearly saw, the results of the ALSYMPCA trial, we see a survival benefit with radium-223. So what about combining these two agents that each individually have a survival benefit, particularly when we account for the fact that ADT and radiotherapy have been shown to have synergy in the localized setting? And so this really proved as the foundation, as a rationale for combining these two agents.

And so this leads us to the study design of PEACE-3. And this is often a slide that most people gloss over. But it's important to understand the eligibility criteria because this is how we're able to transfer this information to select patients in our clinical practice, understand who are these patients and how does it fit into our paradigm.

And so this was a phase 3, open-label trial, international across numerous sites across the globe that included patients with mCRPC and bone metastases, namely at least two bone metastases similar to ALSYMPCA. But we'll see later that this also changed over time.

Patients were required to be asymptomatic or mildly symptomatic, and as you would expect, no prior treatment with enzalutamide or radium-223. We said these patients had at least two bone mets, but no visceral metastases were allowed. Nodal metastases, no problem at all.

And docetaxel and abiraterone were allowed in the score. But again, most patients did not receive them. And if they did, they received it in the mHSPC setting. Eligible patients underwent 1 to 1 randomization to radium-223 given intravenously every four weeks for six cycles, plus enzalutamide at the standard dose of 160 daily.

One big important thing that happened during the conducting of this trial is that there was a major study amendment secondary to the results of ERA 223. And what was ERA 223? And how is this even related to PEACE-3 in the first place?

So ERA 223 was a phase 3 trial that looked at the combination of abiraterone and radium-223. So in theory, not too dissimilar to enzalutamide plus radium-223, 800 patients randomized 1 to 1 to either arm.

But in November 2017, the study was unblinded because we had more fractures and more deaths in the radium-223 plus abiraterone group. So not only did these patients die faster, but they also incurred more fractures during the follow-up period.

And this is very nicely reflected here in the median symptomatic skeletal event-free survival as we see here in the placebo group, was longer 26 months versus 22.3. And the fractures, almost 30% in this combination arm versus 11% in the placebo arm. So clearly a very convincing signal here.

And this gets even more convincing when we look at the fact that in this ERA 223 trial, among patients who received bone-protecting agents, there was no difference in the symptomatic skeletal event-free survival. Whereas amongst those patients who did not receive bone protective agents, we see quite clearly here in blue that the patients in the Abi plus radium-223 group were more likely to experience such an event.

So again, really hard results to ignore. And kudos to the steering committee and to the authors for rallying and introducing this amendment into this trial. And so the take-home message based on these results is that bone protective agents are needed when using the combination of an ARPI, such as Abi or Enza, plus radium-223.

And so what were these study amendments? In March 2018, based on the results of ERA 223, the PEACE-3 IDMC issued an urgent safety letter. And a month later, it mandated bone protective agents, either denosumab or zoledronic acid, at least six weeks prior to the first dose of radium-223.

And then the EMA, or the European Medicines Agency, took this a step further, and given this concern, they increased the minimum number of bone metastases required to at least four at the European sites. This didn't affect the other sites, such as the Latin American sites, the Irish or the Canadian sites, but this was another change. For the rest of the sites, it was at least two bone mets required.

Now, when we talk about the study endpoints, the primary endpoint was an rPFS. And the progression here was assessed using conventional imaging, not PET CT, with a bone scan, and a contrast enhanced CT, chest, abdomen, pelvis MR. And this was performed at a standard interval of every 12 weeks.

And then when we look at the key secondary endpoints, these are your run of the mill endpoints that we see typically in these phase 3 trials-- safety, overall survival, time to next treatment, time to pain progression, and then importantly, time to the first symptomatic skeletal event.

This study was powered to detect about a 32% rPFS benefit when adding a radium-223 to Enza, with a hazard ratio obviously of 0.68. And this was powered at 90% with a one-sided type 1 error rate of 2.5%. So very standard sample size calculations. And this required a sample size of 446 patients, which was the study sample size. And importantly, these are event-driven outcomes. And so the number of events is critical here. And 283 events were required.

One important point here and one concern that we typically see with these trials that evaluate many secondary endpoints is that you increase the chances of finding something with a different doesn't truly exist, meaning false positive results become more likely when you use the typical p-value cutoff of 0.05.

And so in an effort to counteract that, what the study investigators did is they studied the secondary endpoints in a semi-hierarchical fashion, meaning that they looked at overall survival first. If overall survival was statistically significant, they moved on to the next two outcomes looked at jointly, time to next therapy and time to pain progression.

And then this was followed by time to symptomatic skeletal event in that order. And as we see with these survival analyses, they use the your usual mix of Kaplan-Meier curves, Cox proportional models, as well as Fine-Gray competing risk analysis for the other secondary outcomes of interest.

And at this point I'll turn it over to Zach. He'll go over the results and discussion and frame these results for our patients and how we can apply them to our practice.

Zachary Klaassen: Rashid, thanks so much for a great intro, not just looking at the trial design and the statistical methods, but also really setting the scene for the context and the history of this trial, which I think is really important as we attempt to go through the results and put this trial into context for mCRPC patients.

So when we look at this table 1 from the trial, we see enzalutamide alone in this column here, enzalutamide plus radium-223 in the column to the right, and then all patients on the far right. Some key just basic baseline demographics to highlight, median age of 70. Roughly three years since diagnosis of prostate cancer. Time from initiation of ADT roughly 1.8 years.

Majority of these patients had minimal pain, roughly half of these patients. When we look at the prior docetaxel, use roughly one third around 30% of patients. But only about 2.5% of patients had prior abiraterone. Not surprisingly, majority of these patients, more than 60%, had Gleason score greater than or equal to 8. Roughly one quarter had N1 disease at randomization. And as mentioned, these patients had to have bone mets over 99%, and 1b stage at randomization.

With regards to the number of bone mets, pretty similar between less than or greater than 10. Maybe slightly more, less than 10. And when we look at the median PSA, we see that in the enzalutamide alone arm, 21.4 versus 24 median PSA in the combination arm.

This is the primary endpoint for PEACE-3, which is radiographic progression-free survival in the intention to treat population. And we can see here enzalutamide alone in red and enzalutamide plus radium-223 in gray. The median rPFS for combination was 19.4 months compared to 16.4 months in the enzalutamide alone arm for hazard ratio, favoring the combination of 0.69, translating to a 31% risk reduction in radiographic progression for the combination arm.

When we look at the subgroup analysis, looking at baseline pain prior to docetaxel administration before and after the bone protective agent safety letter, age, performance status, and number of bone lesions, again, majority of these-- all the point estimates to the left favoring the combination. Several of the confidence interval crossing one, but generally no subgroup standing out for not favoring enzalutamide plus radium-223 in this study.

The key secondary endpoint, as Rashid mentioned, was overall survival. And we see here an improvement in overall survival with the combination arm 42.3 months, enzalutamide 35 months, hazard ratio of 0.69, 95% confidence interval, 0.52 to 0.90.

Other key secondary endpoints were time to next systemic antineoplastic treatment. This also favored the enzalutamide plus radium-223 arm in this cumulative incidence curve, hazard ratio of 0.57 and a statistically significant 95% confidence interval.

When we look at time to pain progression, again, no difference between these arms, hazard ratio of 1.03. And finally, the other secondary endpoint, time to symptomatic skeletal event, no difference between these two arms, hazard ratio of 0.93.

Importantly, let's look at the treatment-emergent adverse events. And so when we look at any adverse events, grade 3 plus 55.8% in the enzalutamide alone arm compared to slightly more in the combination arm, 65.6%. Serious AEs also higher in the combination, 28.4% versus 18.3%.

And when we look at some of the adverse events of note, hypertension about the same in both arms, one third of them having grade 3 plus hypertension. And then when we look down about halfway down the table, fatigue, 1.8%, grade 3 plus for enzalutamide alone, compared to 5.5% in the combination arm.

Importantly, fracture characteristics. So when we look at time to first skeletal fracture, we see that this is higher in the combination arm, hazard ratio of 2.00. This is over the totality of the trial. What I think is important for this context is to look at what happened after the urgent safety letter mandating bone protective agents.

So before BPAs were mandated, we saw 20.3% fracture rate in enzalutamide alone and 53.6% in the combination. So certainly much higher as we saw in the ERA 223 trial. But with the mandating of the BPAs after March 14, 2018, we see this drastically reduced in both and essentially similar rates in both arms, 10.9% enzalutamide alone and down to 14.2% with enzalutamide plus radium-223.

So by way of discussion, we saw that this was a positive trial. Radiographic progression-free survival improved with radium-223 plus enzalutamide as first-line mCRPC treatment. We also see that at the interim analysis with 80% of OS events accrued, PEACE-3 strongly suggests that there is an OS benefit to first-line radium-223 plus enzalutamide.

And when we look at this in the context of what this trial showed and what other trials show, we see basically a net gain of seven months for combination radium-223 plus enzalutamide versus enzalutamide alone. And as Rashid mentioned, the PREVAIL trial looking at enzalutamide in the pre-chemotherapy space also was about 32.4 months.

So we see that the enzalutamide arm in PEACE-3 is performing well, a slightly less than three-month benefit for enzalutamide alone. When we look at the median OS gain for radium-223 versus placebo in ALSYMPCA, 3.6 months. And so this is a strong OS signal. And certainly when we see the final 299 deaths and a subsequent analysis, we'll really see what the true benefit is for this combination of radium-223 plus enzalutamide.

There's several important considerations for this trial as we take it into context. And one of them is the long duration of the trial, more than 8.5 years. It was also hampered by the unblinding of ERA 223 trial early, and then the subsequent regulatory agency imposing new restrictions on radium-223 use. So this is certainly led to a longer trial, difficulty of accrual.

The other thing that's important to note is that only 2.5% of patients received an ARPI in the hormone-sensitive setting. And certainly we know we have several doublets and triplets now for treatment intensification, metastatic hormone-sensitive prostate cancer.

But even in developed countries, many patients still receive ADT alone, which may be upwards of 59% to 71% even in the United States. So there certainly is a lack of treatment intensification that makes this study very relevant at the time of publication in 2025.

So if we take all of this together, the ideal PEACE-3 patient is somebody that had ADT alone prior to mCRPC, or may have been on ADT alone during the non-metastatic CRPC setting and then subsequently progressed to mCRPC, and those with bone only metastases. And I would argue that this is, again, very relevant considering the lack of treatment intensification we still see in many first world and other countries.

So take-home messages-- PEACE-3 showed that adding six cycles of radium-223 to enzalutamide plus a bone protective agent as first line treatment for mCRPC with bone metastases. Increased radiographic progression-free survival.

At the time of the interim analysis of AD OS events, this suggests a survival benefit. But again, we'll see what the confirmed OS benefit is with additional follow-up. And thus, combining enzalutamide and radium-223 with a bone protective agent, really a triple therapy, is a new treatment option for patients with metastatic CRPC.

We thank you very much for your attention. We hope you enjoyed this UroToday Journal Club discussion of the recently published PEACE-3 trial in the Annals of Oncology.