Oliver Sartor, MD
With the recent approval of a first-in-class radioactive isotope as a treatment for prostate cancer, urologists have a new weapon in their rapidly growing arsenal of therapies designed to fight this disease.
The intravenously administered treatment, radium-223 dichloride (Xofigo), is generating excitement among urologists and oncologists, and not just because it is the first alpha-emitting radiopharmaceutical ever approved by the FDA for use in humans. During the phase III ALSYMPCA trial that led to its May 15 approval, the drug prolonged survival and increased time to bone progression in patients with castration-resistant prostate cancer (CRPC), symptomatic bone metastases, and no known metastatic disease.
Now, practitioners will need to explore how the drug is going to best fit into their practices.
According to Oliver Sartor, MD, medical director, Tulane Cancer Center, and professor of Cancer Research in the Departments of Medicine and Urology at Tulane University School of Medicine in New Orleans, Louisiana, an important basic guideline is that radium-223 is not a replacement for older therapies for prostate cancer, but instead complements many existing treatments extremely well. While Sartor, who helped design and run the ALSYMPCA trial, doesn’t recommend using the drug with other radiopharmaceuticals, or with chemotherapy until more research is conducted, he noted that the field beyond that is fairly open.
“I don’t use radium-223 in and of itself—I am always using it with another therapy, typically hormonal therapies,” said Sartor, who was the trial’s North American principal investigator. “In keeping with the design of the trial, patients can get best supportive care, manipulate their hormones, or take bisphosphonates if they want while radium is administered. So the nice thing about this drug is that it works well with other treatments. Today, many of these patients are managed with new hormone therapies like abiraterone and enzalutamide, and administering those in combination with radium, quite frankly, is a smart thing to do.”
Furthermore, oncologists who had early access to radium-223 during and after the trial agree that the drug is easy to administer and boasts a good safety profile.
Mechanism of Action
Nicholas J. Vogelzang, MD, a medical oncologist at Comprehensive Cancer Centers of Nevada (CCCN) and a clinical researcher at US Oncology in Texas, was a bit startled when he heard data in 2007 about radium-223 in prostate cancer.
“I saw the first report of the drug being effective and was intrigued, because who would have thought that a radium associated with atom bombs and radioactive fallout would be useful for treating cancer?” recalled Vogelzang, who participated in the ALSYMPCA trial in its final months, when CCCN joined as an expanded access site. “When I was growing up, we had to hide under our tables for atom bomb testing, and one of the things we were told to do was to take a shower if we were exposed to nuclear fallout. A shower washes off the alpha particles, which are in the dust and will burn the skin.”
When it’s directed toward an appropriate target within the body, though, radium-223 has proven quite safe, Vogelzang said.
While gamma particles penetrate tissue the most deeply and beta particles have a more limited penetration, alpha particles— which are the largest—are the most superficial in their reach, Vogelzang explained. At the same time, they’re powerful, he said, meaning they can pack a punch without hitting far beyond their target.
“It’s really very safe, but when it does hit something it’s like a bowling ball hitting a piece of glass: The glass shatters,” Vogelzang said. “The DNA is damaged very easily by these big alpha particles. You can give it in the vein, and it doesn’t burn the vein. Even if you inject it under the skin it doesn’t really burn the skin very much, but it localizes to where bones are being made. That’s important, because where bones are being made is where the cancer sits.”
Consisting of two protons and two neutrons, an alpha particle is able to kill cancer in and around bone because it is a calcium mimetic, going where calcium does—preferentially targeting sites of osteoblastic metastasis where there’s a lot of bone turnover, rather than normal bone or marrow, Sartor explained.