Retreatment With Radium-223 Found Safe in mCRPC

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Luke Nordquist, MD, discusses a study investigating a higher dose of radium-223 dichloride (Xofigo) in patients with metastatic castration-resistant prostate cancer and the ongoing potential of the agent in treating the disease.

Luke Nordquist, MD

While the ALSYMPCA trial led to the FDA approval of radium-223 dichloride (Xofigo), the phase III study left several questions to be answered regarding its use in metastatic castration-resistant prostate cancer (mCRPC), says Luke Nordquist, MD.

One area where uncertainty remains is proper dosing. While this drug is approved at 50 kBq/kg monthly for 6 months in mCRPC, that dose is somewhat arbitrary, according to Nordquist, a urologic medical oncologist and CEO of the Urology Cancer Center and GU Research Network.

“When they initially picked these doses, it was a little bit random. It was not really based on a lot of prior data because this is a novel agent,” says Nordquist. “It was just a starting point. With many other agents, we have found that a higher dose may be better and additional dosing is sometimes better.”

To determine if a higher dose of radium-223 would be safe, an international, multicenter, prospective study examined 44 patients with mCRPC with bone metastases. Radium-223 was found to be well tolerated in this study, with incidence of adverse advents in retreated patients comparable or lower than those seen in the ALSYMPCA trial. No new safety concerns were observed with the higher dose.

OncLive: What were the goals of this study?

At what point after the original 6 doses would retreatment occur?

What were the most significant findings?

In an interview with OncLive, Nordquist, an investigator on the trial, provides more insight on the study and the ongoing potential of radium-223 in mCRPC.Nordquist: There were many questions that remained unanswered after the ALSYMPCA study: should we give radium-223 at a higher dose, should we administer it for longer than 6 treatments, should we give it in combination, and should visceral metastasis be allowed? This study was designed to try and answer one of those questions. We needed to determine if it was safe and whether there is a benefit of going beyond the 6 to 12 doses.The median time was 6 months after the initial treatment of 6 doses in this particular study.There were 44 patients internationally who were accrued to this study. The primary endpoint was safety, but there were exploratory endpoints with radiographic progression and progression-free survival looking at PSA.

What questions remain regarding the use of radium-223?

In terms of safety, there was no marked differences compared with the safety of the ALSYMPCA trial. What was really striking was the hematologic toxicities. When we deal with radioactive pharmaceutical agents, we are very concerned about the effects on the bone marrow. There was not a difference in the hematologic toxicity with the additional 6 doses, and there were no grade 4/5 hematologic toxicities reported.In this study, there was only 1 patient with confirmed radiographic progression during the additional 6 doses. Therefore, when we look at this, we can ask, “Is it tolerated?” Based on the study, I would say that it is.

The second question is, “Is there a therapeutic benefit that?” This is a small study and we have not answered that yet. There are additional ongoing studies looking at it in different combinations, adding the ability to administer it during visceral metastasis, and also at a higher dose.

What combinations are being investigated with radium-223?

Overall, what potential do you see for radium-223?

Are there patients who should not be considered for radium-223?

What are the next steps in this research?

Bayer is sponsoring a 3-arm study in which patients are assigned to the standard 50-kBq/kg dose for 6 doses, a higher dose of 80 kBq/kg for 6 doses, or the 50 kBq/kg dose for 12 doses. This will help provide us additional information of that topic.Just about everything. Abiraterone acetate (Zytiga), enzalutamide (Xtandi), sipuleucel-T (Provenge), and docetaxel are being explored in combination with radium-223. All of these are FDA-approved drugs for mCRPC, and they are all being explored either on clinical trials or even just in clinical practice.Radium-223 holds a lot of potential, and not just in prostate cancer. Biologically, it should work in other types of cancer that also have bone metastases. I know they are looking at breast cancer; in my own practice, I have used it to treat patients with bladder and kidney cancer with bone metastases.You would have to give this drug with caution in patients who have underlining bone marrow suppression from prior treatments or other causes.Knowing that this is safe, we now have to start looking into the therapeutic benefit of retreatment.

Nordquist L, Keizman D, Saba K, et al. Radium-223 re-treatment: experience from an international, multicenter, prospective study in patients with castration-resistant prostate cancer and bone metastases. Presented at: 2016 American Urological Association Annual Meeting; May 6-10, 2016; San Diego, CA. Abstract: MP50-16.

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