In a trial (ALSYMPCA trial) reported in The New England Journal of Medicine, Chris Parker, MD, from Royal Marsden Hospital in Surrey, UK, and colleagues compared the alpha emitter radium-223 dichloride (Xofigo) with best standard of care in men with castration-resistant prostate cancer and bone metastases.1 Interim analysis showed that radium-223 treatment was associated with significantly prolonged overall survival, resulting in termination of the trial. An updated analysis, performed before crossover of the control group to radium-223 treatment, confirmed the overall survival advantage.
In this phase III double-blind trial, 921 patients who had received, were not eligible to receive, or declined docetaxel were randomly assigned to receive six injections of radium-223 at a dose of 50 kBq/kg (n = 614) or matching placebo (n = 307), one injection every 4 weeks, with all patients also receiving the best standard of care.
Patients in the radium-223 and placebo groups were well matched for age (median, 71 years in both), race (94% white in both), total alkaline phosphatase levels (< 220 U/L in 57% and 55%), current bisphosphonate use (41% and 40%), any previous use of docetaxel (57% in both), ECOG performance status (0 or 1 in 87% and 86%), WHO cancer pain ladder score (1 in 42% and 45%), extent of disease (6–20 metastases in 43% and 48%, >20 in 32% and 30%), and receipt of external-beam radiation therapy within 12 weeks after screening (16% in both). Median levels of hemoglobin, albumin, total alkaline phosphatase, and prostate-specific antigen (PSA) were similar at baseline.
Significantly Improved Overall Survival
A prespecified interim analysis involving 809 patients showed that radium-223 treatment was associated with significantly prolonged overall survival compared with placebo (median, 14.0 vs 11.2 months, hazard ratio [HR] = 0.70, P = .002). An updated analysis in all 921 patients, performed before crossover from placebo to radium-223, showed a similar survival advantage for radium-223 treatment (median, 14.9 vs 11.3 months, HR = 0.70, P < .001).
The investigators found no significant heterogeneity among subgroups, including those with baseline total alkaline phosphatase ≥ 220 U/L, with and without current bisphosphonate use, with and without previous docetaxel use, with performance status of 0 or 1, with 6 to 20 and > 20 metastases, and with or without opioid use. Thus, the evidence suggests that the benefit of radium-223 is consistent across all subgroups examined.
All main secondary efficacy endpoints supported the benefit of radium-223, including significantly prolonged time to first symptomatic skeletal event (median, 15.6 vs 9.8 months, HR = 0.66, P < .001), time to increase in total alkaline phosphatase level (HR = 0.17, P < .001), and time to increase in PSA level (HR = 0.64, P < .001). In addition, significantly more radium-223 recipients had alkaline phosphatase response (≥ 30% reduction, P < .001) and normalization of total alkaline phosphatase level (P < .001). A ≥ 30% reduction in PSA blood levels at week 12 occurred in more patients in the radium-223 group (16% vs 6%, P < .001), with this reduction being sustained 4 weeks after the last injection in more radium-223 patients (14% vs 4%, P < .001).
Radium-223 treatment was associated with lower rates of any adverse event (93% vs 96%, grade 3 or 4 adverse events (56% vs 62%), serious adverse events (47% vs 60%), and adverse events leading to study drug discontinuation (16% vs 21%).
Hematologic adverse events of grade 3 or higher included anemia in 13% of patients in both groups, thrombocytopenia in 6.5% and 2%, and neutropenia in 3% and 1%. Grade 3 febrile neutropenia occurred in one patient in each group. The most common nonhematologic adverse events of grade 3 or higher were bone pain (21% in the radium-223 group and 26% in the placebo group), fatigue (5% and 6%), and spinal cord compression (3.5% and 6%). Serious adverse events that occurred in ≥ 5% of patients in the radium-223 group or the placebo group consisted of bone pain (10% and 16%), anemia (8% and 9%), and spinal cord compression (4% and 5%).
Assessment of quality of life using the Functional Assessment of Cancer Therapy–Prostate (FACT-P) questionnaire showed that more patients in the radium-223 group had meaningful improvement (≥ 10 point increase in score) during treatment (25% vs 16%, P = .02) and that the radium-223 group had a smaller reduction in score from baseline to week 16 (mean change, −2.7 vs −6.8, P = .006).
The investigators noted, “The treatment of prostate cancer has evolved since the trial began, with new data on the use of cabazitaxel [Jevtana Kit], abiraterone [Zytiga], and enzalutamide [Xtandi] in patients who have received docetaxel. The excellent safety profile of radium-223 and the non-overlapping mechanism of action make radium-223 potentially suitable for use either sequentially or in combination with these other agents.” A phase I/II trial of radium-223 combined with docetaxel in patients with castration-resistant prostate cancer and bone metastases is underway (ClinicalTrials.gov number, NCT01106352). ■
Disclosure: The trial was funded by Algeta and Bayer HealthCare Pharmaceuticals.
1. Parker C, Nilsson S, Heinrich D, et al: Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med 369:213-223, 2013.
Metastasis to bone is the hallmark of prostate cancer and a major source of disease-related morbidity and mortality. In addition to prostate cancer cells, other major players in the vicious interactive cycle of prostate cancer bone metastasis are osteoblasts, osteoclasts, and mineralized bone...