Raoul S. Concepcion, MD, FACS: Let’s move on and discuss, specifically, the role of bone-targeted therapy in patients with prostate cancer. Historically, in terms of urologists, we have looked at bone health, and urologists have been very active in this for over the past 7 or 8 years. We know that there are 2 areas of bone health that come into play. First of all, when patients get started on androgen deprivation therapy, primarily for biochemical recurrence after definitive treatment, it sort of sets off this whole cascade of events, which includes pseudo-metabolic syndrome and an increased risk of osteoporosis—something that we recognize and call cancer treatment induced bone loss or CTIBL.
We also know, unfortunately, that when patients do go metastatic with prostate cancer, about 80% to 90% of the time one of the early places that they go, for a lot of different reasons, is the bone. And there are a lot of data. I know at your institution, Mike, they’re doing a lot of looking at some of the factors as to why prostate cancer has this predilection for bone. Can you give us, the audience, any thoughts on that?
Michael A. Carducci, MD, FACP: I think it just continues to feed into the hypothesis. A lot of different candidate cytokines, and even how denosumab came about in terms of the role of RANK -ligand—the osteoclast-osteoblast interactions. But now, looking at bone marrow cells and what they’re secreting to and affecting, that milieu continues to really be an active area of investigation. And yet, how you target that—we have made a lot of progress with drugs that reduce some of the benefits and reduce some of the effects that you talked about, such as osteopenia and osteoporosis. And many of our active drugs that are antitumor agents are also those that reduce skeletal-related events. We have a much wider range of options to reduce skeletal-related events.
Raoul S. Concepcion, MD, FACS: Glen, as a radiation oncologist, you know it’s interesting. We’ve used spot welding for patients with isolated lesions who are symptomatic, we’ve used beta and gamma meters that were mostly palliative, and now we also have an alpha emitting radiopharmaceutical, radium-223, that has a really nice profile. Can you comment a little about your experience with radium-223 and differentiate it, if you will, to some of the previously used betas and the gammas that were palliative in nature?
Glen Gejerman, MD, DABR: When I bring up radiopharmaceuticals at a tumor board, older physicians, particularly who had a lot of experience with strontium-89 or samarium-153, just want to run out the door because there was tremendous toxicity and it has to do with physics. The beta particles will affect the surrounding tissue, which is bone marrow. The radium-223 is an alpha meter. These are huge. Alpha particles are enormous. They have a very high linear energy transfer, called LET. You’re depositing the energy to very small amounts of tissue, probably within 8 to 10 cell diameters.
It’s a calcium-emetic, so it gets taken where there’s a lot of bone remodeling—where you see the metastatic disease. The ALSYMPCA trial, which was a very large trial with more than 900 patients, showed that there was an improvement in overall survival. There was a delay of skeletal-related events. They defined that as an event requiring external beam radiotherapy, spinal cord compression, or orthopedic surgery, if it had to intervene. That was a very important study because we can use that drug vis-à-vis the conversation we’ve had about layering. It seems to be very safe, so you can deliver it for patients. The ALSYMPCA trial required patients who either have had chemotherapy with docetaxel, or were not eligible and refused. The patients that got docetaxel did very well in terms of myelosuppression. There are studies that show you can give chemotherapy after the use of radium-223, and there are a lot of emerging data now using it along with some of the other drugs like enzalutamide. It seems to have a very safe toxicity profile.
Utilizing it early on is really critical. We know that more than 90%of patients who have resistant disease have metastatic disease. Maybe we don’t see it because typical imaging, like bone scans and CAT scans, are somewhat limited. Using more sophisticated studies like 18F sodium fluoride PET, you will often find it. I think the 11C choline PET/CT is a very nice study. The problem with the C-11 is that it’s such a short half-life that, if you don’t live right near cyclotrons, you’re going to have issues. Patients are often scheduled, and it has to be canceled because of a time delay. I think with newer PET/CT imaging, we’re going to find disease earlier on, and I think it’s quite appropriate once patients have symptoms that this drug be considered.
Raoul S. Concepcion, MD, FACS: That’s an important point because, it’s like you said, the indication is approved for patients with metastatic castration-resistant prostate cancer with boney metastases. They can have no visceral metastases, but they could have limited nodal disease.
Neal, if memory serves me, didn’t you give the first commercial dose of radium-223 in the United States? Can you give us some background on how you are looking at these patients? As we’ve talked about it, it’s where to fit these therapies in. And sometimes, just like with sipuleucel-T or radium-223, you’ve got certain windows. If you miss that window of opportunity, it’s gone. So, from a minimally symptomatic standpoint, what are you teasing out from your patients beyond just paying the use of analgesics?
Neal D. Shore, MD, FACS: Glen did a great job summarizing the ALSYMPCA trial, and your question about symptomatology is really important. There’s a lot of subjectivity with this notion of symptomatology. In the ALSYMPCA trial, there was a really wide spectrum of patients who were symptomatic. And they could have been on Tylenol, acetaminophen, a fentanyl patch, morphine, or could just have been taking a COX-2 inhibitor, an anti-inflammatory. It was almost a 50/50 breakdown in the patient population. The bottom line is, they had to have 2 or more bone lesions, and about 85% of the patients had more than 6 bone lesions.
When I gave the first dose, in probably the first 90% of patients I gave the dose to, they were all post-chemotherapy. They had nothing. They’d received everything else. Now, in the last 2 or 2.5 years, 90% of my patients are all getting it prior to chemotherapy. Why do I do that? I give chemotherapy, and I’m a big believer in taxane-based therapies, but we use these words very well tolerated. Well, radium-223 is extremely well tolerated. It is a 45 to 60 second injection. There’s no premedication. There’s no postmedication. And, the adverse event profile is exactly what you saw in the ALSYMPCA trial—low, single digits, and some mild diarrhea. You can get some myelosuppression—again, low, single digits. This doesn’t preclude giving chemotherapy, later, for all practical purposes. The window that you talk about is 6 months, because you want to give a minimum of 5 to 6 doses to get a full course. The data suggest that for anything less than that, you’re not getting the survival benefit. And make no mistake, unlike with strontium-89 and samarium-153, this is not a drug you give for palliation. This is a drug you give for survival prolongation.
As Evan was saying, you want to give a survival-prolongating drug. You want to prevent complications, and you want to preserve quality of life. Radium-223 does all 3. What I like about it, and what we’ve done at my clinic and at my shop, is that we’ve done 2 phase II studies where we’ve layered treatment. The first one layered radium-223 and abiraterone. At a minimum, a third of the patients had been on abiraterone for 90 days and had shown no progression; in the other two-thirds of our patients, approximately 40 patients, we started concomitantly.
We have that paper. It’s submitted for publication, now. I presented the data at the Genitourinary Cancers Symposium and at the American Urological Association Annual Meeting, showing tolerability and no adverse events. My point is, radium-223 is truly a drug that was designed—if you listen to Dr. Chris Parker, the first author on the New England Journal of Medicine article—to be combined with other therapies. I’d like the listening audience to take 2 messages away from this discussion: this is a drug that is not to be given for palliation of symptomatology, although you’ll see that—it’s for survival prolongation, and it really lends itself well to combination or layering. The great limiting step is going to be accessibility and affordability.
Raoul S. Concepcion, MD, FACS: It’s important to understand that this is a drug that should not be viewed by our peers and colleagues as a palliative agent. It’s a drug that has a defined survival benefit, as Glen said, with the ALSYMPCA trial. We also know that in order to get that survival benefit, you should complete the 6 doses. It’s an injection that is given every 4 weeks for 6 months, and there is clearly benefit with 5 or 6 injections. I think your point is well taken, Neal. We know that this is a bone-targeted therapy. We are not doing anything, in terms of this particular agent by itself, to target the androgen receptor access. And, again, I think that’s a really good point—it probably should be designed to be used in combination.
Transcript Edited for Clarity