STOCKHOLM – The investigational agent radium-223 chloride cut the risk of dying during follow-up by 30% among men with symptomatic, castration-resistant prostate cancer and bone metastases, and resulted in less toxicity than did placebo in a phase III, randomized trial.
Results of the preplanned interim analysis were strong enough to prematurely stop the ALSYMPCA (Alpharadin in Symptomatic Prostate Cancer) trial, and caused a stir at the European Multidisciplinary Cancer Congress.
After a maximum follow-up of 3 years, median overall survival was significantly increased from 11.1 months with placebo to 14.0 months with radium-223 chloride (Alpharadin) (hazard ratio, 0.695; P = .00185).
Dr. Chris Parker
The survival benefit was maintained across all subgroups studied, regardless of baseline alkaline phosphatase (ALP) level, current bisphosphonate use, prior docetaxel (Taxotere) use, and Eastern Cooperative Oncology Group performance status, lead author Dr. Chris Parker reported.
"In my opinion, radium-223, which has a completely novel mechanism of action, is likely to become a new standard treatment for this disease," he said.
"This is a very important finding, certainly practice changing, and very likely could become the standard of care ... all over the world," European Cancer Organization (ECCO) president Dr. Michael Baumann of the Technical University of Dresden (Germany) said during a press briefing.
Likewise, Dr. Jean Charles Soria of the Institut de Cancérologie Gustave Roussy in Villejuif, France, and cochair of the congress scientific program said that "this is really practice changing, and pending regulatory approval, I think this is going to be a major player in prostate cancer management."
Current bone-targeting therapies such as denosumab (Xgeva) have been shown to improve symptom control but not survival in patients with castration-resistant prostate cancer (CRPC) and bone metastases. More than 90% of men with metastatic CRPC have evidence of bone metastases, conferring almost a fivefold greater risk of death.
Radium-223 chloride is not approved in the United States or Europe, but was granted fast track designation by the Food and Drug Administration in August 2011. Approval could come by the end of 2012, said Dr. Parker, a consultant clinical oncologist at the Royal Marsden Hospital in Sutton, England.
Radium-223 acts as a calcium mimic, and targets new bone growth in and around bone metastases via heavy alpha particles that have an ultrashort range of less than 100 mcm. It takes only a single alpha particle to kill a cancer cell, and the short penetration results in highly localized tumor-cell killing and minimal collateral damage, Dr. Parker explained.
He suggested that it would be relatively straightforward for hospitals to offer radium-223 because it takes 5 minutes to administer as an injection in the outpatient setting. Storage would be limited because of the drug’s short half-life of 11 days, but the agent would not require special radiation protection because alpha radiation is stopped by a piece of paper.
ALSYMPCA randomized 922 patients to best standard treatment plus six injections every 4 weeks of radium-223 (50 kBq/kg) or to placebo. The patients had symptomatic CRPC, at least two bone metastases, and no known visceral metastases; they had previously received or were unfit for docetaxel. Notably, 40% of patients had more than 20 metastases on bone scintigraphy, and 60% had previously received docetaxel.
Radium-223 significantly prolonged the time to first skeletal-related event from 8.4 months with placebo to 13.6 months (P = .00046; HR, 0.61), Dr. Parker said at the joint congress of the ECCO, the European Society for Medical Oncology (ESMO), and the European Society of Radiotherapy and Oncology (ESTRO).
All other secondary end points were met by radium-223 over placebo, including time to total ALP progression (HR, 0.163; P less than .00001); time to prostate-specific antigen progression (HR, 0.671; P = .00015); total ALP response, defined as a 30% reduction (43% vs. 3%; P less than .001); and total ALP normalization (33% vs. 1%; P less than .001).
Dr. Parker pointed out that "ALSYMPCA is one of a very few phase III trials in which the placebo arm had more toxicity than the active intervention arm."
Hematologic events were slightly increased in patients treated with radium-223, compared with placebo, but were rare, he said. There was also an excess of mild diarrhea and vomiting, but severe GI toxicity was not seen.
The placebo arm had more grade 3 or 4 adverse events than did the radium-223 arm (59% vs. 51%), more serious adverse events (55% and 43%), and more treatment discontinuations (20% vs. 13%). Of note, best standard treatment could include bisphosphonates, palliative radiotherapy, and hormonal therapies.
Pain was not studied as part of this trial, but was shown in a previous phase II study to be improved. Quality of life data will be reported at a later date, he said.