Oliver A. Sartor, MD
As with other new therapies that have been approved in recent years for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC), researchers are not entirely certain about how best to fit radium Ra 223 dichloride (Xofigo) into the emerging paradigm, according to Oliver A. Sartor, MD.
Yet, after nearly a year of clinical use, the optimal setting for radium 223 appears to be in combination with new hormonal therapies as a treatment for patients with mCRPC who have a significant burden of bone-metastatic disease, even though they might not be considered symptomatic, Sartor said.
Sartor, who was the principal North American investigator for the clinical trial that led to the FDA approval for radium 223 last year, shared those insights about the drug during a presentation at the 7th Annual Interdisciplinary Prostate Cancer Congress™, which Physicians’ Education Resources, LLC (PER®) hosted March 15 in New York City. He is the Laborde Professor for Cancer Research and the medical director at Tulane Cancer Center in New Orleans, Louisiana.
An alpha-emitting radiopharmaceutical that targets osteoblastic bone metastases, radium 223 gained the FDA’s approval in May 2013 after demonstrating a 30% improvement in median overall survival (OS) compared with placebo in the pivotal ALSYMPCA trial.1
The next step in the drug’s clinical development is a large phase III trial that will evaluate whether radium 223 plus abiraterone (Zytiga) with prednisone or prednisolone is more effective than placebo plus that regimen in chemotherapy-naïve patients with bone-predominant mCRPC who are asymptomatic or mildly symptomatic.2
Examining the “Symptomatic” Label
The question of whether patients should be symptomatic to be considered candidates for the drug has arisen because of the FDA label indication. The drug was approved as treatment for patients with CRPC, symptomatic bone metastases, and no known visceral metastatic disease.3
However, Sartor said categorizing a patient as symptomatic is a “subjective assessment” with a wide variation among patients, even in ALYSMPCA.
“Symptomatic is a little bit of a tricky nomenclature here because you could be taking one acetaminophen a day and that was symptomatic,” Sartor said, referring to the ALSYMPCA criteria. “Or, you could have radiation in the previous 12 weeks and have no pain at all, but that was still symptomatic. Exactly what was symptomatic was not clearly defined, although there were a number of patients on opioids.”
In an interview, Sartor said he does not use the presence of pain as the determining factor when he weighs the radium 223 option. “I am thinking more about the burden of bone disease as opposed to whether or not the patient says ‘I have an ache in my back,’ ” he said. “Obviously, if a patient is on opioids and they have very significant pain, there is really no question that that’s a symptomatic patient. But there is a bit of a gray line in there.”
In addition to the extent of bony disease, Sartor said he also considers “how the ratio of tissue disease is distributed.” Since patients who receive radium 223 experience some myelosuppression, white blood cell and platelet counts also should be evaluated, Sartor said.
In summary, Sartor said during his presentation, “I am using radium 223 with the new hormones, and in those with a significant bony metastatic disease. That is what I am doing today in the clinic and it appears to be safe.”
As far as moving radium 223 forward in the treatment timeline is concerned, Sartor said no role for the drug has been established thus far in nonmetastatic or hormone-sensitive disease. He said large clinical trials would be needed to either prove or disprove those settings.
Key Clinical Trial Results
Sartor said certain unique characteristics of prostate cancer make radiation-emitting agents a rational approach to treatment. He noted that the bone/soft tissue ratios for metastases are high compared with other solid tumors, that prostate cancer is “exceptionally osteoblastic,” and that bone metastases “are frequently the only radiographically detected site of metastases” in patients with advanced disease.
In all, the FDA has approved three radiation-emitting particles for the treatment of prostate cancer. The agency approved two beta particles, strontium 89 and samarium 153, for pain reduction in 1993 and 1997, respectively. As an alpha particle, radium 223 emits a stronger, more targeted energy dosage than a beta particle, while inducing more lethal double-strand DNA breaks, Sartor noted.