Radium-223 prolonged overall survival by nearly 4 months in men with castration-resistant prostate cancer that had metastasized to bone and reduced the risk of death by 30% in an international phase III clinical trial reported online July 17 in the New England Journal of Medicine.
Compared with placebo, the treatment also improved quality of life and significantly prolonged the time to the first symptomatic skeletal event, the time to an increase in PSA level, and the time to an increase in total alkaline phosphatase level. Further, radium-223 provided these benefits while consistently inducing a lower rate of adverse events than did placebo, said Dr. Christopher Parker of Royal Marsden Hospital, Sutton (U.K.), and his associates in the ALSYMPCA (Alpharadin in Symptomatic Prostate Cancer Patients) randomized trial (NCT00699751).
Dr. Christopher Parker
The industry-sponsored trial was terminated early when an interim analysis by an independent monitoring committee showed a clear benefit of the treatment over placebo. Dr. Parker and his colleagues reported the results of their updated analysis involving 63% of the patients who received all 6 monthly injections of radium-223 and 47% who received all 6 monthly injections of placebo during the 3-year treatment period.
The study subjects were 921 men at 136 study centers in 19 countries who had progressive castration-resistant prostate cancer with two or more symptomatic bone metastases and no visceral metastases. All of them required regular analgesic medication or other treatment to address cancer-related bone pain.
These patients were stratified according to whether or not they had been treated with docetaxel or a bisphosphonate and according to their baseline alkaline phosphatase level, then randomly assigned to receive 6 monthly intravenous injections of either radium-223 (614 subjects) or matching placebo (307 subjects).
All of the study subjects concurrently received the best standard of care available at each of their treatment centers, which could include local external-beam radiation therapy, glucocorticoids, antiandrogens, ketoconazole, or estrogens. Thus, the study findings should be generalizable to routine clinical practice, Dr. Parker and his associates noted.
The primary endpoint, median overall survival, was 14.9 months in the radium-223 group, which was significantly longer than the 11.3-month median overall survival in the placebo group, the researchers said (N. Engl. J. Med. 2013 July 17 [doi:10.1056/NEJMoa1213755]).
A total of 528 patients in the intention-to-treat population died; 54% of the radium-223 group and 64% of the placebo group died. The risk of death from any cause was 30% lower among men who received radium-223 than among those who received placebo.
These differences in overall survival were consistent across all subgroups of patients, regardless of alkaline phosphatase level at baseline, current use of bisphosphonates, previous treatment with docetaxel, any use of opioids, and the extent of the underlying cancer.
Compared with placebo, radium-223 significantly prolonged the interval to the first symptomatic skeletal event (15.6 months vs. 9.8 months). It also prolonged the time until total alkaline phosphatase level and PSA level showed an increase.
In addition, a significantly higher proportion of patients who received the active treatment (25%) than placebo (16%) reported a meaningful improvement in quality of life, as measured by the FACT-P score.
The overall incidence of adverse events, that of serious adverse events, that of grade 3 or 4 adverse events, and that of hematologic adverse events all were lower with radium-223 than with placebo. The number of patients who discontinued the study drug also was lower with radium-223 than with placebo.
This favorable safety profile is attributed to the highly targeted action of radium-223, which "minimizes myelosuppression and has limited effects on normal tissue," Dr. Parker and his associates said.
The ALSYMPCA trial included an important subgroup of patients: those who declined or weren’t eligible for docetaxel therapy. Many patients with castration-resistant prostate cancer and bone metastases do not receive docetaxel because of their frail condition, the presence of coexisting conditions that preclude use of the drug, or their refusal of chemotherapy. Thus this study addressed "an important unmet need in a population that is not served by current therapies," they added.
The researchers noted that prostate cancer therapy has evolved since this trial was initiated, and new data have been accumulated regarding cabazitaxel, abiraterone, and enzalutamide. Future studies should assess whether radium-223 might be suitable for sequential or concurrent use with these agents.
A phase I-II trial is now under way evaluating the combination of radium-223 with docetaxel, they said.
The ALSYMPCA trial was funded, designed, and conducted by Algeta and Bayer HealthCare Pharmaceuticals in collaboration with the study investigators. Dr. Parker reported ties to Amgen, Astellas, Bayer, Janssen, Bristol-Myers Squibb, BN ImmunoTherapeutics, Takeda, and Sanofi-Aventis, and his associates reported ties to numerous industry sources.