Daniel J. George, MD: It really dovetails into this next topic I want to talk about, and that concerns sequencing and some of the other novel agents that we haven't necessarily studied in the context of trials like CARD, but follow that same paradigm, meaning it's mechanistic switch.
We're not going from one hormonal agent to another, but from one modality to another, and that would be radiopharmaceuticals. In particular for today, that's radium-223. That may be something different in the future, but for today, radium-223 is a unique class of agent, in terms of being an alpha particle and being a targeted therapy toward bone. In thinking about it mechanistically, it's not tied genetically to any phenotype. It can kill indiscriminately, regardless of RB [retinoblastoma] status, TP53 status, or others. In thinking about radium-223, where do you sequence that now in the context of your chemotherapies and of your hormonal therapies? Where do you see that falling optimally? Chuck, do you have any thoughts on that?
Charles Ryan, MD: You brought up a really interesting point, which has come up a couple of times now. Our field is dividing our therapies into the precision therapies and the imprecision therapies, and both have value. Killing indiscriminately is the way you put it, and that's a good thing, right? That’s one of the key ways we need to think about things. When do we need a targeted therapy? Early. We want AR [androgen receptor] therapy, or PARP inhibitors if it’s a BRCA, etc. Whether we like it or not, more than occasionally, our patients get into a situation where they have disseminated disease, and we don't know what the biology is. This is where radium-223 fits in.
I'm typically using it in the symptomatic patient with obviously predominant bony disease but no visceral disease, or patients who have no option for chemotherapy available to them. It's typically being done with a palliative or survival intent, and it's very well-tolerated. That's one of the areas where it has its greatest value. As we continue the conversation about imprecision therapy, we may see a growth in other radiopharmaceuticals and whether there is a marriage of targeted therapy, imprecision therapy, and targeted radiopharmaceuticals, which is another area. For now, radium-223 is considered a standard option for patients with bony disease who have pain, typically, and bony predominant disease.
Daniel J. George, MD: Tanya, do you think this follows the same paradigm as the other drugs? That is, when we use it later in high-volume, heavily pretreated patients—like where it was studied in ALSYMPCA—we see some benefit, but if we move it earlier in the disease where the disease burden is less, we might see proportionally greater clinical benefit?
Tanya Dorff, MD: Yes, that's a good point. There were toxicity analyses looking at giving radium-223 before or after chemotherapy, because you always want to be playing chess with your patients and making sure that you're not closing doors. I’m wondering what my next 3 moves are and not just about this next move for this patient today. Once a patient has anemia, which can happen as the disease burden gets greater, they don't tolerate the radium-223. They may not finish the 6-dose course, and of course you want to get in a full course if you can, so there's a lot of interest in moving it earlier.
There are a number of studies, including 1 at City of Hope Comprehensive Cancer Center that we're running in bone metastatic castrate-sensitive disease, to see whether adding it early will be beneficial. We obviously don't know the answer yet, and right now it's only approved in castrate-resistant disease. That's where we're using it clinically. At ASCO there was also the question, not just of when to use it, but whether to add it to abiraterone or enzalutamide. Neal Shore, MD, FACS, presented a study using the Flatiron Health database of concurrent versus layered trying to answer that question of whether the increased skeletal events that were seen in the ERA 223 trial with abiraterone and radium-223 would hold true if you layered.
The findings were a bit complex in that layered enzalutamide with radium-223 was associated with more fractures, and concurrent abiraterone and radium-223 was associated with more fractures. The bottom line from that presentation was, if you add the bone support agent and are giving them a bisphosphonate or denosumab, you will mitigate that risk. It's not standard right now to use them together, but certainly if you're going to do it, they've got to be on bone support whether you're layering or using them concurrently.
Daniel J. George, MD: I think that's really great, and we’ve learned that from some of these studies the hard way. We didn't necessarily anticipate that this would be a significant limiting factor to the clinical benefits of combinations. It would make a lot of sense from our localized disease setting that hormone strategies and radiation strategies should play well together, and I think in the bone is where we see these complications in particular, not in other organ sites or other issues.
It's relatively well-tolerated except for this, and mitigating it with bone-strengthening agents is key. To your chess analogy, I really like that. Thinking ahead and using bone-strengthening agents early when you're starting treatment with drugs like abiraterone and enzalutamide in the castrate-resistant setting is an important aspect to this. Then, you've had some lead time to build up and strengthen those bones, and maybe prevent some of that. Not all the fractures are pathologic.
In fact, many of them may be more osteoporotic, so it’s important to recognize that strengthening bone broadly is critical, even if the bone metastases they show aren't necessarily weight-bearing. There are a lot of really important lessons learned from this, and yet it's still an agent we use. It's been beneficial in many of our patients. Ben, what’s the urology perspective regarding radium-223? Where do you guys see this in the continuum, and how does that sequence in regard to your referrals to medical oncology?
Benjamin H. Lowentritt, MD, FACS: I think the critical question with all the discussions we've been having about somatic testing, consideration for chemotherapy, consideration for a PARP inhibitor, and consideration for radium-223 are all going to be occurring largely in the same timeframe. A patient’s failing their first oral therapy. Eventually, we'll be at a different place, but for the next several years, we're going to see those patients who have been on the oral therapies since diagnosis with metastatic disease and now are progressing. They're already at that point, whereas before, we had more options up front.
The way that I have been talking to people about radium-223 is that we were always looking for trials. Many of those trials were PARP inhibitors, so we're a bit beyond that now, but I would say we're going to be looking for the defects to treat for PARP inhibitors. For me, radium-223 is right thereafter for the bone-dominant patient. I think this is a situation where, with the clinical presentation of multiple bone metastases, we need to follow them differently. We need to prepare them differently. Frankly, as they show any signs of progression and some symptomatology, we really need to look at getting them on radium-223, because it is a treatment in which we have found that if we delay, we miss.
They don't get 6 treatments, they don't get to 5; they don't get the benefit. I think we have to be aggressive in looking for these, and it's interesting to hear Chuck describe it as imprecise treatment when it's frankly one of the more targeted treatments that we've had for a long time because it only predominantly goes where the cancer is. It's one that we look very aggressively for, and I put chemotherapy right with it, because Tanya made a good point about the symptom relief from chemotherapy. I think that's essential.
I think there were interesting data at ASCO this year about sequencing chemotherapy after radium-223, showing it’s fairly safe from a hematologic standpoint. Finding that sweet spot for radium-223 takes effort, but is well worth it for the patient. We're actively looking for the patient that can get radium-223 and working hard to get them on it, but it does take some effort. This is a subset of patients that are not all your patients. This is another one of those subsets you're really looking for.
Charles Ryan, MD: I would add that the imprecise comment was meant to say that it's a targeted therapy in a way, but it's not tied to 1 specific angle.
Transcript Edited for Clarity
Benjamin H. Lowentritt, MD, FACS: I understood it completely. I think it was totally accurate, but it is interesting that I still think it's one of the more focused therapies that we have.