Pedro C. Barata, MD, MSc: Let’s go back to the patient you described. We have a patient with high-volume disease who was treated, per CHAARTED or STAMPEDE, with up-front ADT [androgen deprivation therapy] plus 6 cycles of docetaxel, and now he’s progressing. There are a lot of factors that matter, right? I want to know, how is it progressing? Is it just test results, or is it test results and more disease visible on the scans? Is he now developing more visceral disease, or is it bone disease only? Is the patient symptomatic or not?

Neal Shore, MD, FACS: Let’s say he presented with significant bone disease. He had 6 lesions. He got 6 cycles of ADT and docetaxel. He had no soft tissue and no visceral metastases, and his PSA [prostate-specific antigen] is now rising. His other laboratory test results are normal. He has 2 new bone lesions, and he’s mildly symptomatic. He’s receiving NSAIDs [nonsteroidal anti-inflammatory drugs].

Pedro C. Barata, MD, MSc: You are describing the ideal candidate for radium 223, if there’s a place for it. Just a reminder, on ALSYMPCA—that’s the best level 1 data we have—roughly half received it predocetaxel, and around half received it post docetaxel. We looked at symptomatic patients, and around 40% or so didn’t receive opioids with no pain to mild pain. The remaining patients had moderate to intense pain with varying opioid use. We also know more important data from radium 223.

One factor is if we want to use radium 223, we really want to commit the patient to 5 or 6 cycles because we know they perform better. The fit patients, ECOG Performance Status 0 to 1, are those who perform better. We exclude patients who have nodal involvement with a lymph node larger than 3 cm or visceral disease. The more recent data that we have that are important show that adding radium 223 to abiraterone has a negative safety signal, so we want to stay away from that.

PREVAIL had 12% of patients with visceral disease, and COU-AA-302 had 0%. But we all know it works for patients with disease outside their bones. Saying that, I do have a bias. For a patient who’s progressing with laboratory numbers only—serologically progressive and symptomatic—I think it’s a great opportunity, especially if he’s African American, to offer sipuleucel-T, Provenge, and think about radium 223.

I oftentimes offer it after the first AR [androgen receptor]—directed therapy. Would it be wrong to consider a patient with some symptoms and bone-only disease—who we expect will be able to receive 5 or 6 cycles—for radium 223? I have to say, it’s pretty straightforward. It’s a very reasonable thought process. But when I try to identify the best timing for radium 223, I also like to consider the PEACE III data where—Neal, you’re involved in leading those efforts—so far we have not seen safety concerns. On top of that, there might be added benefit.

The reason why we have used a lot of combinations with AR-targeted therapy is because, as we know, radium 223 is approved based on survival. But it does not impact the PSA behavior or PSA kinetics, nor does it impact time to disease on scans. A lot of us get concerned because we’re giving a treatment to our patient for, let’s say, half a year, and we can see PSA continue to rise and we might see more disease on the scans. For a lot of us and for a lot of physicians in the community, that creates a lot of pressure; for patients too, because they don’t want to see PSA rising. They don’t want to see more disease on the scan. That’s my bias, and we all have our biases. But I would argue that for the most part, I tend to start patients on the AR-directed therapy first. And right now, in the CRPC [castration-resistant prostate cancer] setting, it’s going to be abiraterone or enzalutamide, and I think sipuleucel-T makes sense.

The reason I brought up the point about African Americans is because we have real-world data showing a signal for survival favoring African Americans. There is a huge difference in survival favoring African Americans compared with Caucasians. My practice is in Louisiana, where there is a larger African American population than other places in this country. Those are the factors I take into consideration when I try to determine the best treatment. I have to say, sometimes there’s more than 1 best treatment for the patient.

Nancy Ann Dawson, MD: I want to comment on the ALSYMPCA data. There was a survival benefit; that’s why radium 223 got approved. But the arms were not just radium 223. They included radium 223 plus best supportive therapy or best standard care. At the time the study was conducted, the choices included ketoconazole, Emcyt, prednisone, and some other oral therapy.

Enzalutamide, apalutamide, and abiraterone were not approved. They weren’t available. It’s very reasonable to consider, as you said, enzalutamide plus radium 223 and starting them at the same time. You then have benefit in terms of PSA reduction. You’re giving a second-line androgen-targeted therapy that’s going to be beneficial. There’s absolutely no reason not to put those 2 together. You mentioned the data on abiraterone and radium 223 and how there were some problems with more radiological events and worse survival—the reason why we tend to stay away from it—but there’s absolutely no reason not to go with the enzalutamide—radium 223 combination at that point in time. If you want, sandwich in some sipuleucel-T before you use both of those.

Neal Shore, MD, FACS: Those are great points. So much of it is what’s going on in the bone microcompartment. In ERA 223, everything was given concomitantly. We’ve done some phase II studies—Neeraj Agarwal has also done this in some of his work—and looked at layering. We’ve just recently presented a large meta-analysis. We presented a poster at ASCO GU [American Society of Clinical Oncology Genitourinary Cancers Symposium] on real-world use. A lot of therapy isn’t started concomitantly. There’s a layering, and layering is defined by starting the abiraterone or the enzalutamide 30 days or more before the radium 223. Is there something happening that’s allowing for the bone flare that you may see with those drugs? Maybe there’s some homeostasis that’s happening such that when you use a powerful drug like radium 223 with an apoptotic effect, it’s better tolerated in terms of risk of fractures. William, what are your thoughts? You are doing some great work on these combinations as well.

William Oh, MD: As summarized by Pedro before, there are a few important things to point out. AR-targeted therapies, most people would agree, are the standard of care for the vast majority of these patients: abiraterone or enzalutamide. It’s the preponderance of evidence, the quality of the evidence, and for most of our patients, the tolerability of the drug, and the way in which it’s working. Those are what I would generally use.

I do think there’s a role for sipuleucel-T in some of these patients. The data regarding African Americans that come from Oliver Sartor and Pedro are very interesting. There are some patients who may be very bone predominant, where you might really think about starting with radium 223. But most of the data would suggest that the patient you described, Neal, is a classic one. As Alicia mentioned earlier, mechanism of action is very important. This is a patient for whom I would go from chemotherapy in the early CRPC setting to AR-targeted therapy.

The only point I would add about layering in combinations in the absence of high-quality level 1 evidence is that with ERA 223 and with PEACE III, the most important thing I learned is not to forget about osteoporotic fractures. Matthew Smith, Celestia Higano, and others have been talking about this for years. I’m pretty good at managing it, but not as good as I thought I was. We’re all focused on cancer, cancer, cancer. But what happens is this adjunctive therapy—osteoporosis or osteopenia—is leading to some real morbidity in these patients. I think we all have seen it.

The patient is in remission, his PSA is 0 ng/mL, but then he calls and says, “I have severe pain,” and he goes to the emergency department. When you see it, it’s actually quite disturbing. I came back from that ASCO GU meeting last year, where Bertrand Tombal talked about these 3. Just as a reminder, if you’re on any of these combinations—on radium 223 plus any AR-targeted therapy—or even if you’re on AR-targeted therapy alone, there’s a much higher rate of osteoporotic fractures than we appreciated, up to a third. If you’re just on AR-targeted therapy, it’s still up to 5% to 10%.

We started to make sure that our patients are getting a bone density test, if they’re not already on a bone-protecting agent. I think that’s the most important lesson. If you’re going to use a combination, it’s not to do more harm than good. In the meantime, I do think there are many options for the patient you described. They’re all reasonable and can all be argued for, but in my practice, most of my patients are getting abiraterone—more so now because it’s generic, so their co-pays are a little smaller—unless they have a contraindication. Or they receive enzalutamide if they haven’t already received it.

Neal Shore, MD, FACS: You make a great point about the bone-health agents and the androgen receptor—targeted therapy. You’re spot-on about that. It’s absolutely essential to make sure they’re receiving either zoledronic acid or denosumab when they’re receiving these combination therapies when they have significant bone disease. I still find that with some of my patients, I have to hold back because they have really bad dental hygiene. It’s a challenge, and you want to avoid this ONJ [osteonecrosis of the jaw] issue. But you’re absolutely right: that has to be standardized in everybody’s thought process.

Transcript Edited for Clarity