Scott Tagawa, MD, MS, FACP: Radium-223 dichloride is an alpha emitter. It was the first ever alpha emitter approved for any type of cancer. That’s as opposed to beta emitters, such as strontium and samarium, which are still approved, but were in use purely for palliation for symptomatic bone metastasis. Radium-223 is an alpha emitter that is 1000-fold more potent than beta emitters. The other main characteristic difference of an alpha vs beta emitter is that the range of the alpha emission activity is very short. It’s traveling over a small number of cells, rather than potentially centimeters, depending on the specific beta emitter.

Radium-223 is a bone-targeted therapy. It specifically binds to hydroxyapatite, so it goes to areas of bone turnover. It’s not directly against cancer, but next to cancer and targeting the stroma. In the development of this drug, we recognized that it was able to target areas of bone turnover, which was interesting in randomized phase 2 trials. That led to a phase 3 trial in patients with symptomatic metastatic CRPC [castration-resistant prostate cancer] to bone, where radium-223 plus best supportive care led to an overall survival advantage over best supportive care alone in patients who had at the time exhausted all the known therapies, including hormonal agents as well as chemotherapy. Although, patients could have enrolled if they weren’t chemotherapy candidates or if chemotherapy wasn’t available.

Radium-223 is a nice drug, in part because it targets bone, and bone remains the dominant site of disease, particularly when we talk about symptomatic metastatic disease. In targeting bone, the great thing is that it targets only bone, more or less. The downside is it targets only bone. For those with extraosseous disease, we don’t think those disease areas are treated as well. That’s why a lot people mention bone predominantly, at least 2 sites of bone metastases on bone scan are an indication without visceral metastasis, and then limited volume of lymph node or soft tissue metastases. We like this drug because bone is an important compartment for patients with prostate cancer.

Because of the targeting, the overall tolerability of this drug is pretty good. Because it’s an alpha emitter, which is quite potent, it’s not surprising that there may be some fatigue associated with it, there may be some pain flares landing in bone, and there may be some anemia or cytopenias with it. It’s probably from either nonspecific circulation or indirect targeting of some marrow as it lands in areas of bone turnover. There’s some excretion through the small bowel. There’s some nonspecific nausea that may happen with circulating radionuclides. We see that with other radionuclides that aren’t necessarily targeting the bowel. But it’s also excretion through the bowel that likely explain some of the nausea that’s present. I wouldn’t say that there are 0 other adverse events that have been reported with this drug, but those are the most common ones. It’s not surprising, based on the way this drug is metabolized and goes into bone, with a bit of excretion in the small bowel.

I use radium-223 reasonably often. The No. 1 reason I don’t use radium-223 as often as I might is because generally speaking, when I see a patient who I think is appropriate for radium-223, I usually also have additional clinical trials, and some of the patients would pick clinical trials. If I didn’t have access to clinical trials, I suspect my use of radium-223 would be higher, because many patients with advanced prostate cancer are good candidates because most would have symptomatic bony disease and not all want chemotherapy or are beyond chemotherapy without additional options.

The nice thing about radium-223 in the ALSYMPCA trial is that there was a clear improvement in overall survival. If one were to look at the forest plots, generally speaking, there was a benefit in terms of overall survival across all the different subsets. That being said, based on the design of the clinical trial plus the mechanism of action of the drug, there isn’t a known improvement in at least radiographic progression-free survival. That was because that imaging wasn’t done routinely as part of the clinical trial, so that wasn’t assessed.

Because this isn’t a drug that directly targets prostate cancer, and it’s also not an AR [androgen receptor]-targeted drug, we don’t see a major PSA [prostate-specific antigen] response rate. Sometimes patients who are symptomatic may get better. There’s a subset where PSA drops, and alkaline phosphatase often drops if it’s elevated to start, but there isn’t a clear response rate to this particular drug compared with some other drugs.

In a way, analogous to sipuleucel-T, if I have a patient on this drug and they’re tolerating it, and they ask me, “Is it working?” I may point toward alkaline phosphatase if that’s relevant. I might point to PSA if it’s relevant. But I do a lot of counseling before, making sure that there isn’t a major expectation for a PSA decline, and I say, “This is a drug that was approved and shown to improve overall survival. If you’re alive to ask me the question, then I’d say it’s working.”

It’s a difficult situation some of the time. I monitor patients, at least patients who have other options, whether they’re investigational or other available noninvestigational options. I monitor with interim imaging. I generally go ahead and do a bone scan at the same time, although that wouldn’t necessarily lead to additional changes. But I do cross-sectional imaging, at least halfway through, to make sure there isn’t significant progression outside of bone. I generally wouldn’t stop a 6-cycle course of radium early just because PSA doesn’t go down or a bone scan shows a few more metastases, which could represent a flare. But if there’s significant extraosseous progression and the patient has additional options, that’s the time where I might make a switch, other than if there’s a toxicity issue.

Transcript edited for clarity.