Is There Still a Role for Radium-223? APCCC 2022 Presentation - Neal Shore

September 14, 2022

At the 2022 Advanced Prostate Cancer Consensus Conference (APCCC) Hybrid Meeting, Neal Shore presents the role of radium-223 in the modern treatment armamentarium in metastatic castration-resistant prostate cancer (mCRPC) patients.


Neal D. Shore, MD, FACS is the Medical Director for the Carolina Urologic Research Center. He practices with Atlantic Urology Clinics in Myrtle Beach, South Carolina

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Johann de Bono: Our next speaker is Dr. Neal Shore, who's going to talk on, Is There Still a Role for Radium-223? Key question.

Neal Shore: Well, thank you very much, and of course, thank you to Silke and Aurelius. I think it's a hundred percent consensus how amazing these two are and how we look forward to coming here every 2 years, especially during a pandemic, so we can't thank you enough. Is There Still a Role for Radium-223? And particularly, I was asked to look at the issues regarding before and after lutetium 617.

Before getting into that, let's think about the treatment options for CRPC, influenced really largely now, by what happens in the mCSPC. We debated that so far, couplet versus triplet therapy. But what's really poignant or rather shocking is that the majority of patients receive, at best, two life prolonging agents when they have CRPC. So a theme to, should you still be thinking about the opportunity for a novel therapy that has level one evidence in the form of radium? The answer, in my mind, is absolutely, yes, to optimize the number of novel mechanisms of action that patients receive, and unfortunately, the data speaks poorly to that. Not to the folks attending this meeting, but to many of our colleagues globally.

And so, ultimately, we were trying to, from a healthcare economic standpoint, you want to reduce emergency department visits, in-patient admissions. This overall lowers healthcare costs to virtually all ecosystems. The four P's we always talk about. Prolonged survival, preserve quality of life, prevent complications of therapies, sequencing, overlapping therapies, and then really do justice to understanding patient's preference values, how risk intolerant or risk-seeking they are. I'll talk about that in terms of what we know about radium.

It's an evolving story, but it's been approved for nearly 10 years now. One of the things that, of course, thanks to the ALSYMPCA trial, the hazard ratio 0.7, survival benefit, its primary endpoint, 3.6 month median and overall survival. I'll show you the breakdown between pre chemotherapy and post chemotherapy in a minute.

Then ERA-223 came along, and what really set it back quite significantly is that it was an unexpected result that combining with abiraterone actually led to an increase in fractures. It was initially a concern regarding earlier deaths, but that ultimately didn't reach statistical significance. Nonetheless, it led to a label restriction in EMA, less so in the US. But of note, the trial was really designed to be a combination type of a trial with the best standard of care, what was described back then as the BSoC. Data have shown, published by Oliver Sartor, that chemotherapy can be given safely following treatment with radium-223. So I think that's important. The PEACE III is a very, very important trial that's ongoing right now, which mirrors the ERA 223, but instead of using abiraterone in combination, it uses enzalutamide. I'm hearing that they're very close to nearly completing accrual.

So what are the clinical factors that support a treatment choice? I've already said, and I think this is incredibly important, is really making sure we optimize the number of novel mechanisms of action. So we have seven novel mechanisms of action now that are FDA approved, leading to 12 life-prolonging agents. That's quite amazing. But then I just earlier showed you data that was published by Dan George and others, that, essentially, patients are only receiving at best 1.7 therapies before they succumb to the disease. So there's a problem right there. These are some of the things that we look at in making that treatment choice. This was published by Hoskin in Lancet Oncology, and it really shows you that, in the interesting aspect of the ALSYMPCA trial, it was almost half pre-chemo half-post chemo, but one sees the hazard ratios for both demonstrating the survival benefit, but it's even more profound for the pre-chemotherapy patients.

Let's talk about the safety data with radium-223. Now it's really important to see 3-year follow-up here and even longer. Look at the grade 3/4. The worst adverse events that really mostly keep us up at night with any therapy, and it's all essentially in low single-digit percentages. And so what we've come to recognize, that radium really changed everything. This is not your samarium, strontium, really highly toxic beta isotopes, but rather the alpha particle and the lower penetration into the bone marrow. And we see a really remarkably well tolerated decay in the enteric pathway, making it particularly well tolerated as well.

Additional data from ALSYMPCA, as well as the REASSURE, which was a global registry of over 1400 patients, many of us participate in this, and really what you see, whether it's before or after chemotherapy, is after real-world data, nearly 1500 patients globally collected parallels the safety tolerability of quite low, very similar to ALSYMPCA. In terms of consideration for sequencing, this is just a slide, I'm sure Maha will do a lot more justice to it and her presentation, but when would you consider radium versus considering docetaxel? You could read through this for purposes of time, but of course, clinical trials are always the key.

Let's talk about lutetium, which is really the thrust of my presentation. And so, can we administer lutetium-PSMA after radium-223? So there was a certain restriction criteria in the VISION trial that had to, you could have received radium, but it had to be at least 6 months before entering into the study. You could not get it in the comparator arm. So, is it safe? Is there additive myelosuppression, particularly looking at beta versus alpha particles? Effects and cytopenia? Is it effective? Is it accessible? I'm going to focus a lot on accessibility and implementation challenges. This is not going to be simple for most sites. Are there going to be supply chain issues in terms of the isotope? What about economic accessibility? I think it's fair to say we're all globalists. We want to make sure that there's full economic and physical accessibility, and even issues regarding radioactivity materials licensure for your nuc med or your radiation oncologist. It varies by country and varies by your nuclear commission regulatory rules. This is quite complex.

Here's the VISION study, brilliantly presented as always by Matthew Smith, but of note, on the left side, you see that this is the biomarker for this will be having access to a PSMA PET. Right now it's a specific proprietary to AAA and Novartis. It's their LOCAMETZ, at least with what they're calling it in the US, or the gallium Illuccix PSMA PET. So there is a limitation there. With radium, you just need a technetium bone scan under a CT scan or MR, so there's less complexity to that.

I borrowed this, this is from Jeremie Calais at UCLA. What can we expect? I showed you earlier radium toxicity. Let's look at the toxicity here. You could read through this, but you have off-target affecting salivary glands, even occasionally renal, and then there can be flare phenomenon that we see well documented than you see with radium. This is another example of the landscape. It's vibrant, it's robust, in trial landscape for the theranostics world, which I think is fantastic. This is our seventh now RLT novel mechanism of action, which I would encourage everyone to be considering.

What about radium if it's administered before lutetium? This was presented at SNMMI by Baumgarten, and essentially looking at 29 patients within 8 weeks of their last cycle of getting lutetium within their last cycle of radium, essentially the same, small numbers, unless a caveat for the next few slides, there are all relatively small numbers, but nonetheless, they're contemporaneous data all presented recently within the last 18 months. And you're looking at the same level of hematotoxicity. Additionally, this was present, this was published by Hojjat Ahmadzadehfar, and he looked at two groups, small numbers again, 20 receiving radium before, 20 not, and then going on to receiving lutetium. And essentially no significant differences between the two groups. So that's reassuring. And again, two different novel mechanisms of action.

Additional work from the WARMTH registry. Again, Hojjat Ahmadzadehfar published separately, demonstrating, again, small numbers, 77 patients, but one can see, regardless really of the number of bone lesions, a survival benefit in patients who received combination therapy, sequential combination therapy. And even within the REASSURE, this also suggests that retreatment or treatment after radium with lutetium is safe and has a survival benefit.

This is important to notice that there are really differences right now, and so it's not about binary, pick one versus the other, it's that you just need to be aware when you're creating your RLT program. The imaging for a radium, as I mentioned earlier, is conventional versus the PSMA gallium PET. That may change over time to other PSMA PETs, whether it's 18 FPyL or rhPSMA or a copper assay, but nonetheless, pre-medication is not required with radium. It is with lutetium 617. There are limitations in terms of precautions and handling that are very, very different between these two agents. More complicated with lutetium 617. The infusion time and the throughput in your clinic clearly would favor the use of a one minute infusion with no premedication, no post-medication, no need for hydration or intravenous saline.

Then the precautions are actually quite significant. In certain countries, this is only administered in inpatient modality. And then there are clearly travel restrictions, as well as handling restrictions and even going home and being with family and caregivers.

I won't go through all of the details here, but if you're going to champion a radioligand therapy program, you'll need someone to really take charge of this. You can go through the lists that I've enumerated here, from planning to implementation to the operationalization. It is not straightforward. It is clearly doable, but nonetheless, it will require energy and it will require a team. Just to note, that in the NCCN guidelines for 2022, radium is level one, category one evidence pre and post chemotherapy in the mCRPC population.

Here's a proposed sequence of radium-223 and prostate cancer. It's a program that I actually had the privilege of working with Nick James on. You can read through this and you can see where you might want to consider, based upon your imaging biomarker, based upon prior therapies, where you would consider the role for each. And we can certainly debate that with the questions that are coming up.

I think the recommendations, and I'm almost done, the penultimate mCRPC goals to administer as many novel life-prolonging therapies as possible. These are just some of the trials that are out there. I'll move faster here, too. PEACE III is very, very important and coming up. Here is the radium-223 studies combination with docetaxel. We are actually starting the PEACE III, I mentioned. Care is an mCSPC trial. We're about to launch a phase III study, an ARPI for mCSPC with or without radium.

In summary, I commented on what's new in the last 2 years, what's the evidence, what are the gray zones, the trials that are addressing these open issues. This is still a limited list here. Most importantly, how are you treating your patients in this situation? Well, for me, my mantra, my go-to is clinical trials as a standard of care, which ASCO endorses. And now I would say radium-223 is more readily accessible administratively, economically, with better tolerability, and generally does not preclude taxane chemotherapies lutetium. Thank you very much.