Expert Says Radium-223 Emerged as “Surprise” Solution to Improving OS in mCRPC

E. David Crawford, MD

Radium-223 dichloride (Xofigo) opened an entirely new chapter in the treatment landscape of castration-resistant prostate cancer with bone metastases (mCRPC), says E. David Crawford, MD, professor of Radiation Oncology, Department of Surgery, at the University of Colorado Denver.

“Radium-223 is sort of a surprise drug, at least to me,” says Crawford. “We have had radioisotopes around for a long period of time, including phosphorus-32, samarium-153 (Quadramet), strontium-89 (Metastron), and others. But, they all had a lot of baggage with them, in terms of side effects.

Now, we have a new one—radium-223—which is not associated with the side effects that we were seeing with the other ones, but it is associated with an improvement in survival rate. It’s a game changer.”

In the ALSYMPCA trial, radium-223 had a median overall survival of 14 months versus 11.2 months with placebo (HR, 0.70; P = .00185) in patients with mCRPC.

Based on these results, radium-223 was FDA approved in 2013 for patients with CRPC, symptomatic bone metastases, and no known visceral metastatic disease. However, there is potential to use the drug in earlier settings, in less symptomatic patients, and in combination with other agents, says Crawford.

OncLive: What do you think is the optimal use of radium-223?

How does the mechanism of action of radium-223 compare with other radioisotopes?

In an interview with OncLive, he discusses the history of the agent and how it could be used in the future.Crawford: Radium-223 should be given to patients early. It should be given to people with bone-metastatic disease and to those who are minimally symptomatic, not just people who have advanced disease. The trials have shown that the survival rate is better when it is given early, too. Radium-223 is easy to give and it is well tolerated. We’ve seen really dramatic results with minimal bone pain. Progression has been significantly delayed.There are alpha- and beta-emitting radiation agents, and this is an alpha-emitting particle. It is a large particle, so it delivers a big punch. The good thing is that it doesn’t deeply penetrate, so you are not impacting the bone marrow as much as you would with a beta particle that is smaller and goes into the bone marrow, and causes problems with white and red blood cells.

Do you see potential to move the use of radium-223 into an earlier setting?

It delivers a double-stranded DNA break, whereas beta particles do not always do that. It has a more effective kill, but one that is associated with fewer side effects. That being said, there has never been a trial of radium-223 versus a beta-emitting particle and there probably never will be.The bucket this drug is approved in is metastatic castration-resistant disease. That is not for newly diagnosed. It is approved for pre- or post-chemotherapy. Does it make sense to move it up? Yes. There are trials ongoing.

How has the field of radiopharmaceuticals evolved?

They are also investigating whether radium-223 can be given with chemotherapy, or if more than 6 doses can be given. There is a lot of exciting stuff being investigated. I think we will see it being utilized outside of advanced disease. People think that because radiopharmaceuticals have a lot of baggage, they are only suitable for advanced disease. However, this drug is not.It has changed a lot. We started out with phosphorus 20 years ago. That was effective, but it was also effective in wiping bone marrow out and causing death. Then, the next generation was beta-emitting particles. They had an effect, but they did not have any effect on survival. It is possible that they were not studied the right way, but they did have bone marrow side effects.

Radium-223 started out as a drug for post-chemotherapy treatment or for people who were not candidates for chemotherapy. Almost half of the people on the pivotal trial ended up receiving it before chemotherapy, so now we know that it is better tolerated beforehand.