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Rashid Sayyid: Hello, everyone, and thank you for joining us today in this special recording. I'm Rashid Sayyid, a robotic urologic oncology fellow at the Department of Urology at the University of Southern California. I'm joined today by Zach Klaassen, program director and associate professor at the Department of Urology at Wellstar MCG Health. Today, we'll be highlighting the role and the potential of radium-223 in 2024 and beyond, and specifically we'll be addressing how this drug appears to be resurrecting in the treatment of mCRPC patients and how it's disrupting the current treatment paradigm.

What is radium-223, first of all? It's a targeted alpha emitter, and so it selectively binds to areas of increased bone turnover in bone metastases. In that way, it acts as a bone-seeking calcium mimetic, and so it binds to new bone stroma. Once it does that, it emits high-energy alpha particles of short range, and this leads to a double-stranded DNA break, which in turn leads to a potent and localized cytotoxic effect in the target areas, as demonstrated in the schematic to the right.

The major trial that's looked at radium-223 in the mCRPC setting is the ALSYMPCA trial, which was published in 2013 in the New England Journal of Medicine. This was a phase III trial that included 921 patients with confirmed symptomatic CRPC and who had symptomatic bone metastases and, importantly, had no visceral metastases. These patients were recruited in the post-docetaxel or unfit-for-docetaxel or refused-docetaxel setting, and they were randomized 2:1 to either radium-223 plus best standard of care versus placebo. It's important to highlight, again, that all patients received additional best standard of care treatment.

This trial was a success and it met its endpoint of overall survival with a hazard ratio of 0.7 and overall a 3.5-month median overall survival improvement. But beyond overall survival, there are also real benefits for these patients, namely the time to first symptomatic skeletal event, where we see a hazard ratio of 0.66 and a lengthening of the median time to first symptomatic event from 10 months to almost 16 months, so nearly a 60% improvement.

Furthermore, radium-223 significantly improved time to increase in total alkaline phosphatase levels with a hazard ratio of 0.17 and as well increase in PSA level with a hazard ratio of 0.64. Importantly, patients in the radium-223 arm had a lower frequency of grade 3 to 4 adverse events of 56% versus 62%. Based on these overwhelming results, the FDA approved radium-223 specifically for patients with symptomatic bone-only metastatic CRPC.

But despite this approval in 2013, and it's now been over 11 years, there's really been an underutilization of radium-223, and this has really been corroborated in many studies that have shown that radium-223, despite being approved in the first-line setting for eligible patients, is still utilized as a later agent and one of the last regimens patients receive. There are many reasons that have been proposed to explain this poor utilization. Number one, we've seen a drastic change in the mCRPC treatment landscape. When we look at the treatment options that were available when patients were accrued to the ALSYMPCA trial between 2008 and '11, there were very few agents approved, whereas now if we look at the agents, we have androgen receptor pathway inhibitors, we have the taxanes, which were already approved during that time, but we also have PARP inhibitors, we have the rise of lutetium and many, many, many other agents. So really this has further pushed radium-223 into the back of the treating physician's mind.

Next, it's important to note that radium-223 targets activated bone stroma lesions and not soft tissue tumors as we saw in the ALSYMPCA trial. But can we better select for patients who are likely to improve or benefit with radium-223, i.e., can we better detect those patients with bone stroma lesions and better exclude those who have soft tissue tumors that probably won't benefit as much from radium-223? And really the prime imaging tool that's being used nowadays is the PSMA-PET, be it with gallium or PYLARIFY. They had looked at recently in a study published in 2017 that looked at patients who were selected for radium-223 treatment using bone and CT scan only versus those who were selected for using a PSMA-PET scan in addition to the bone scan. And as we see on the right here, patients who were selected using the PSMA-PET as well as bone were more likely to derive a PSA reduction benefit. As such, this is quite a clear signal that perhaps the improved sensitivity and better exclusion of patients with soft tissue tumors really is a key here to better optimizing treatment selection and really maximizing the benefit of radium-223 for eligible patients.

Recently we've seen a resurrection of radium-223, where at ESMO, most recently in Barcelona, we saw the results of PEACE-3 being presented, which was a randomized phase III trial that looked at the combination of radium-223 plus enzalutamide versus enzalutamide alone in patients with asymptomatic or mildly symptomatic bone metastatic mCRPC. At this point, I'll turn it over to Zach, who will go over the trial design, results, as well as the implications of this trial for the treatment of our mCRPC patients.

Zachary Klaassen: Thanks so much, Rashid. That's a great introduction and leading into PEACE-3, which really was one of the highlights of advanced prostate cancer at ESMO 2024 presented by Silke Gillessen. When we look at the PEACE-3 trial design, there are several important points. This was, again, mCRPC patients with bone metastases, and we'll talk about this a little bit further, but this was asymptomatic or mildly symptomatic. As Rashid just mentioned in ALSYMPCA, these were all symptomatic patients with bone metastases. As expected in a phase III trial, excellent performance status. No prior treatment with enzalutamide or radium-223 for enrollment in this trial, no known visceral metastases, and patients that were continuing with ADT. This was a 1:1 randomization, 446 patients, to radium-223 IV every four weeks for six cycles plus enzalutamide versus enzalutamide alone. The primary endpoint for this trial was radiographic progression-free survival, and you can see the key secondary endpoints here, notably overall survival.

Of note, the use of bone-protecting agents was made mandatory, and this was based on the ERA 223 trial of radium-223 plus abiraterone, which showed an increased fracture rate among the patients receiving combination therapy, which subsequently decreased with bone-protective agents. And so this was mandated after the first 119 patients were enrolled in the PEACE-3 trial.

This is the table one baseline characteristics. As you can see here, 12 countries enrolled from 2015 to 2023, median follow-up of 42 months. The median age for both groups was 70. The PSA for each group was roughly 25. We can see that roughly one-third of patients received prior docetaxel, and only 2 to 3 patients had received prior abiraterone in previous disease states for prostate cancer. Roughly 50/50 in terms of bone lesions less than or greater than 10, and we can see that extraskeletal disease at baseline was about one-third of these patients.

This is the primary endpoint, radiographic progression-free survival. There was an absolute increase of three months for radiographic progression-free survival favoring the enzalutamide plus radium-223 arm versus enzalutamide alone. The hazard ratio here was 0.69, 95% confidence interval of 0.54 to 0.87. When we look at the pre-specified subgroups, generally all of these subgroups favored the radium-223 plus enzalutamide combination. This is to the right of the hazard ratio. Some of these smaller subgroups in terms of number of patients, the point estimate was still to the left favoring enzalutamide plus radium-223, but the 95% confidence interval did cross 1.

Overall survival is interesting in this trial. This is a couple of important points here. This was 80% of overall survival events, so there's still some follow-up to get to the 100% of the OS events. We see in the Kaplan-Meier curve at the beginning, enzalutamide looked to have improved survival, these curves crossed at about 18 months, and then clearly split, favoring enzalutamide plus radium-223. We see about a seven-month improvement with enzalutamide plus radium-223 versus enzalutamide alone. The hazard ratio here is 0.69. The p-value is 0.031, which was less than 0.034, the level of significance that was set for the interim analysis. However, due to non-proportional hazards, plus the lack of unequivocal significance of restricted mean survival time, the statisticians and the trial design suggested that we continue to follow overall survival further and continue to the final overall survival analysis of all 100% of OS events.

In terms of time to next systemic therapy, there was improvement and statistical improvement for enzalutamide plus radium-223. What we see here is that at 24 months, 51% of patients in the enzalutamide alone arm had a next treatment option compared to 30%, and this was a statistically significant hazard ratio of 0.57.

In terms of skeletal events, this was essentially exactly the same between these two treatment arms, 18% at 24 months. What's important to note here is that, again, once the mandate for bone-protective agents was mandated in this trial, this went to over 80% of patients receiving BPAs in both of these treatment arms. Again, no difference between these two arms for skeletal events, hazard ratio of 0.93.

When we look at safety, we see several important points here. About one-third of patients had hypertension. There was a numerically increased incidence of bone fractures or fractures in the enzalutamide plus radium-223 arm, 5.1% compared to 1.3% in enzalutamide alone, which is significantly less than what we saw in ERA 223 with radium-223 plus abiraterone.

So there are several important points and implications of PEACE-3 and how we may select these patients. This is a potential new first-line therapy for metastatic CRPC. The first is the point about asymptomatic or mildly symptomatic bone-only metastases. And so as Rashid mentioned in ALSYMPCA, published over a decade ago which led to the approval of radium-223 in the mCRPC setting, these patients had symptomatic bone metastases. In PEACE-3, they could have asymptomatic or mildly symptomatic bone metastases. So the take-home from this point is that although patients with visceral metastasis would be excluded from radium-223 plus enzalutamide, the less stringent bone pain criteria in PEACE-3 may increase the use of combination therapy for these patients.

The second point is related to ADT monotherapy in prior disease spaces, and this would include non-metastatic and metastatic hormone-sensitive prostate cancer. And so, as mentioned in the trial design, an exclusion criteria for PEACE-3 was a prior ARPI. ADT plus ARPI, as we know, is often used as treatment intensification for both non-metastatic and metastatic hormone-sensitive prostate cancer, but there have been many studies, and I've highlighted one of these here, that show that there's a global lack of treatment intensification. So this was a study that looked at several jurisdictions—France, Germany, Italy, Spain, the UK, Japan, and the United States. And we can see here in green, ADT alone in the mHSPC space was quite prevalent. Even in the United States, 1 in 2 patients will not receive treatment intensification, and globally, almost 50% of patients will not receive treatment intensification.

And so the take-home here is if you look at this trial in terms of not having an ARPI in an earlier setting, this is actually quite common. Although 50% of them will not, we still have half of these patients that would be candidates for radium-223 plus enzalutamide as first-line therapy because they have not received treatment intensification in the mHSPC setting.

The third point is what do we do with abiraterone in mHSPC? Obviously, this has been approved based on the LATITUDE and STAMPEDE trials, nearly eight, nine years ago that they were published and approved by the FDA. It's commonly used still. It's actually been generic for the last couple of years, and this may be an opportunity for decreasing cost of therapy. What's interesting, though, is in PEACE-3, only 2 to 3% of patients received abiraterone in the mHSPC setting. And so the take-home message here is that we really don't know what the impact of abiraterone plus ADT in the mHSPC setting is and whether this can be followed by radium-223 plus enzalutamide in first-line mCRPC.

The fourth point is the utilization of bone-protective agents. As I mentioned, the ERA 223 trial, there was an increased fracture rate for radium-223 plus abiraterone in those patients without bone-protective agents. Because of that, at the time of that trial, which was subsequently also accruing to PEACE-3, after 119 patients were enrolled, the use of bone-protective agents was mandated. After this mandate, this utilization of BPAs increased from 42.6% in PEACE-3 to 82-84%. And as I mentioned, the ESMO fracture rate that was reported at the time of the presentation was only 5.1%. So clearly we see that mandating BPAs in the PEACE-3 trial led to decreased fracture rates—still numerically higher than enzalutamide alone, but much lower than what was seen in the ERA 223 trial. So one of the main take-home messages from this trial and from this presentation is that all mCRPC patients receiving radium-223 plus enzalutamide should also be receiving a bone-protective agent.

Finally, what do we do with additional lines of treatment after radium-223 plus enzalutamide? Obviously we want these patients to have durable oncological response with good quality of life, but certainly some of these patients will progress.

And so I think this is a good opportunity to discuss the RALU study which looked at what happens when we treat patients with radium-223 and then subsequently treat them with lutetium PSMA-617. Certainly there's other options we can use in patients that fail radium-223 plus enzalutamide such as cabazitaxel, PARP inhibitors, but specifically looking at RALU, this was a study of 49 patients with bone-predominant mCRPC who subsequently received lutetium PSMA. The median time between radium and lutetium was 9.3 months. We see grade 3 to 4 treatment-emergent adverse events were 41%. Majority of these were anemia, decreased platelet count, and neutropenia.

What's interesting here is when we look at the overall survival from the first injection of radium-223, this was 31.4 months, and the median overall survival from the first injection of lutetium was 12.6 months. And so the take-home message here, and this is important in the current landscape of advanced prostate cancer, is that lutetium PSMA-617 does appear to be safe after treatment with radium-223.

In conclusion, PEACE-3 presented at ESMO 2024 shows that there's support for the combination of radium-223 plus enzalutamide plus a bone-protective agent as a new first-line mCRPC treatment option for patients who have not previously received an ARPI. But it's important, following regulatory approval, that we figure out which patients are appropriate for this treatment regimen in the first-line setting. We will see additional data from phase III trials emerging with radium-223 in the mCRPC setting. This includes the DORA trial of docetaxel plus radium-223, as well as the RADIANT trial of radium-223 post an ARPI and post docetaxel.

We thank you very much for your attention. We hope you enjoyed this UroToday discussion looking at radium-223 in the setting of mCRPC based on the PEACE-3 trial that was presented at ESMO 2024.