On May 15, 2013, the U.S. Food and Drug Administration approved radium Ra 223 dichloride (Xofigo) for the treatment of patients with castration-resistant prostate cancer, symptomatic bone metastases, and no known visceral metastatic disease. Radium-223 dichloride is an alpha-particle–emitting radiotherapeutic drug that mimics calcium and forms complexes with hydroxyapatite at areas of increased bone turnover, such as bone metastases.
The approval was based on a double-blind, randomized, placebo-controlled trial in patients with metastatic castration-resistant prostate cancer with symptomatic bone metastases and no known visceral metastatic disease. Patients were allocated 2:1 to radium-223 dichloride at 50 kBq/kg (1.35 microcurie/kg) intravenously every 4 weeks for six cycles plus best standard of care (n = 541) or to matching placebo plus best standard of care (n = 268). Best standard of care included local radiotherapy, corticosteroids, antiandrogens, estrogens, estramustine, or ketoconazole. All patients were to continue androgen deprivation therapy. The median age was 71 years, 94% were Caucasian, 86% had an ECOG performance status of 0-1, and 58% had received prior docetaxel. Fifty-four percent of patients used opiate and 44% used nonopiate pain medications. Overall survival was the primary endpoint.
At the prespecified interim analysis, a statistically significant improvement in overall survival was demonstrated (HR = 0.70, 95% CI = 0.55–0.88; P = .00185). The median overall survival was 14.0 and 11.2 months in the radium-223 dichloride and placebo arms, respectively. The improvement in overall survival was supported by a delay in time to first symptomatic skeletal event favoring the radium-223 arm.
The most common (≥ 10%) adverse reactions in patients receiving radium-223 dichloride were nausea, diarrhea, vomiting, and peripheral edema. The most common hematologic laboratory abnormalities were anemia, lymphocytopenia, leukopenia, thrombocytopenia, and neutropenia. Two percent of patients on the radium-223 arm experienced bone marrow failure or ongoing pancytopenia. No patients on the placebo arm experienced bone marrow failure or pancytopenia.
The recommended dose and schedule for radium-223 is 50 kBq/kg (1.35 microcuries/kg) administered by slow intravenous injection over 1 minute every 4 weeks for 6 doses. ■