Daniel P. Petrylak, MD
Strong evidence suggests that radium-223 dichloride (Xofigo) leads to promising results in patients with bone-metastatic castration-resistant prostate cancer (mCRPC). To build on this success, researchers are exploring the agent in other settings and with other therapies in a number of ongoing studies.
For example, radium-223 is being combined with androgen-deprivation therapy in patients with newly diagnosed mCRPC in an open-label, randomized phase II study (NCT02582749). The trial’s primary endpoint is radiological progression-free survival, with secondary endpoints including treatment-related adverse events, time to first skeletal-related event, and PSA complete response rates, among others.
Additionally, a phase I trial is studying the safety and tolerability of radium-223 in combination with atezolizumab (Tecentriq) in patients with mCRPC following treatment with an androgen-pathway inhibitor (NCT02814669). If the combination cannot be accepted, additional cohorts may be enrolled to evaluate radium-223’s tolerability from delayed treatment with atezolizumab.
While other ongoing trials are examining the radiopharmaceutical in combination with other agents, such as abiraterone acetate (Zytiga) and enzalutamide (Xtandi), radium-223’s synergy and potential with chemotherapeutics remains a question.
In an interview with OncLive, Daniel P. Petrylak, MD, professor of Medicine, Yale Cancer Center, discusses his vision for radium-223 in this patient population and how it integrates with chemotherapy and other agents for treatment of patients with mCRPC.
OncLive: What is the mechanism of action of radium-223?
Petrylak: Radium-223 is an alpha particle that delivers a large amount of energy to a small area. In regard to size, the particle is the size of a bowling ball compared with the size of a golf ball—which would be a beta-emitter. The radius of activity of a beta-emitter is much larger and can clip off normal marrow cells. That is a disadvantage compared with radium-223, which has a much smaller radius.
Over the past few years, how has the field of radiopharmaceuticals evolved?
Previously, the radiopharmaceuticals that were approved were beta-emitters. They didn’t improve survival; they were only for palliative pain. Radium-223 is an alpha-emitter and works a little differently. It does improve survival, compared with the other agents that did not. That is a very big difference between those types of agents.
What do you believe to be the optimal use of radium-223?
Earlier use of radium-223, I think, is better. Unfortunately, we don’t have randomized trials to tell us that. However, certainly, there are studies looking at radium-223 in combination with abiraterone acetate or enzalutamide and it seems that using this earlier approach of targeting the bone, as well as targeting soft tissue, with the other drugs seems like an approach to take.
Do you see more potential of radium-223 earlier in combination with novel agents or upon progression of disease?
I see it in both situations. We have a clinical trial that is looking at radium-223 plus abiraterone or enzalutamide, and that is as a first-line treatment for patients with mCRPC. Hopefully, we will see results that will support the use of the combination in the future.
Do you envision radium-223 potentially being used in the frontline setting?
We are seeing it moved up more and more. Again, with these earlier trials, we will start seeing a greater use of them, if they are found to be positive.
Will chemotherapy evolve over time in this setting, and, if so, will it have any impact on treatment with radium-223?
Well, it has changed already. We know that moving chemotherapy up in an earlier setting shows a big improvement—a survival mean of 10 to 18 months. However, combining it with agents such as radium-223 would be difficult because of issues in dosing. Nevertheless, moving it up earlier does seem to be the trend, at this point.
If a dosing strategy were determined, would such a combination show a proven benefit?
I think it is going to be difficult. The other studies in the past have shown that if you reduce the dose of docetaxel, that actually compromises survival—at least that’s my own opinion. It is going to be very difficult to combine the 2 of them together. There may be some better way to sequence them, such as full doses of both drugs that are administered. It was also shown that, in phase I/II trials, the radium-223 dose was reduced, as well. I am just not comfortable reducing a dose in that situation.
Overall, what are some of the best practices in treating patients with advanced mCRPC?
We have a variety of different drugs approved. The way to look at the disease is to determine whether patients are symptomatic or asymptomatic, or have visceral or nonvisceral disease. Agents such as radium-223 and sipuleucel-T (Provenge) are really not indicated for patients with visceral disease.
The question is, “Would you integrate enzalutamide, abiraterone, and chemotherapy into those particular areas?” That is not as clear-cut as you would think.