Radium-223 Improves Survival in Patients with Advanced Prostate Cancer
Results from a phase III trial called ALSYMPCA show that radium-223 dichloride (Xofigo®) improves overall survival in men with advanced prostate cancer that has spread to their bones compared with a placebo.
New England Journal of Medicine (NEJM), July 17, 2013 (See the journal article.)
In most men with metastatic castration-resistant prostate cancer—prostate cancer that no longer responds to hormone therapy—the cancer spreads (metastasizes) to the bones. Bone metastases can cause intense pain, weakness, and bone fractures, greatly impairing quality of life—and in some cases causing death.
Several drugs have been approved by the Food and Drug Administration (FDA) to prevent pain and fractures in patients with bone metastases, but none of these drugs improves the survival of men with prostate cancer.
Radium-223 dichloride (radium-223) is a radioactive isotope that emits low levels of alpha particle radiation. The alpha particle radiation causes double-strand breaks in DNA, killing cells. Radium-223 is a “calcium mimetic” that, like calcium, accumulates preferentially in areas of bone that are undergoing increased turnover, such as areas where bone metastases are forming. Once the drug, which can be given intravenously, reaches bone, it emits very low levels of radiation that travel less than 100 microns, or approximately four one-thousandths of an inch, limiting damage to the surrounding tissues.
The Alpharadin in Symptomatic Prostate Cancer Patients (ALSYMPCA) trial enrolled 921 patients with metastatic, castration-resistant prostate cancer. Men in the trial were randomly assigned to receive either radium-223 (six intravenous injections, one every 4 weeks) plus the best standard of care or a placebo plus the best standard of care.
The trial’s primary endpoint was overall survival. Secondary endpoints included time to the first symptomatic skeletal event—such as a bone fracture, spinal cord compression, or the need for radiation to treat bone-related symptoms—and quality-of-life measures.
In early 2011, when an independent data safety and monitoring committee evaluated interim data from the trial and found that men who were assigned to receive radium-223 had statistically significantly better overall survival than men assigned to receive the placebo, the trial was stopped early and men taking the placebo were allowed to “cross over” and take radium-223. The results published in the NEJM paper reflect patient outcomes before any crossover took place.
The trial was funded by Bayer Healthcare Pharmaceuticals and Algeta, the company that developed and manufactures radium-223.
Median overall survival was 14.9 months for the men assigned to receive radium-223 and 11.3 months for those assigned to the placebo. An overall survival benefit with radium-223 was seen in all subgroups of men analyzed—for example, men benefited whatever the extent of their disease and regardless of whether they had previously received docetaxel or were currently being treated with bisphosphonates.
Men assigned to receive radium-223 also lived longer without having a skeletal-related event than men assigned to receive the placebo (a median of 15.6 months versus 9.8 months). And fewer men in the radium-223 group experienced serious adverse events (47 percent versus 60 percent) or stopped treatment because of adverse events (16 percent versus 21 percent) than in the placebo group.
Compared with men in the placebo group, men assigned to receive radium-223 also reported a better quality of life as measured using a standard assessment tool.
On May 15, 2013, based on interim results from the ALSYMPCA trial, the FDA approved radium-223 for the treatment of men with castration-resistant prostate cancer with bone metastases that are causing symptoms.
The trial investigators, led by Christopher Parker, MD, of the Royal Marsden National Health Service Foundation Trust and Institute of Cancer Research (Sutton, United Kingdom), wrote that the study findings are likely to be “generalizable to routine clinical practice.” They also noted a potential limitation to the study, which is that despite its otherwise broad eligibility the trial did not include “patients with visceral metastases, which may occur in up to 25 percent of patients with castration-resistant prostate cancer.”
In an accompanying editorial, Neha Vapiwala, MD, and Eli Glatstein, MD, of the Department of Radiation Oncology, Perelman School of Medicine at the University of Pennsylvania, noted that there are no “validated methods to quantify the [radiation] dose delivered to the body and to each [metastatic] lesion.”
“This well-executed study shows a clear survival benefit in patients who had received the treatments that were available when the study was conducted, including standard chemotherapy,” said Bhupinder Mann, MBBS, of NCI’s Division of Cancer Treatment and Diagnosis.
Drs. Vapiwala and Glatstein agreed. “The real-world applicability is undeniable; these patients had symptomatic skeletal disease and had received previous or concurrent complementary therapies,” they wrote.
The trial, they added, “imparts some long-awaited momentum to research on the use of alpha emitters and shows an overall survival advantage with a compound that is safe and manageable for both patients and providers. Radium-223 will both complement and contend with existing therapies.”