A Randomized, Double-Blind, Dose-Finding, Multicenter, Phase 2 Study of Radium Chloride (Ra 223) in Patients with Bone Metastases and Castration-Resistant Prostate Cancer

作者：Parker Christopher C^*; Pascoe Sarah; Chodacki Ales; O' Sullivan Joe M; Germa Josep R; O' Bryan Tear Charles Gillies; Haider Trond; Hoskin Peter

来源：European Urology, 2013, 63(2): 189-197.

DOI：10.1016/j.eururo.2012.09.008

• alpha-Pharmaceutical
• Bone alkaline phosphatase
• Bone metastases
• Castration-resistant prostate cancer
• Prostate-specific antigen
• Radium chloride Ra 223
• Targeted alpha-emitter

Background: Patients with castration-resistant prostate cancer (CRPC) and bone metastases have an unmet clinical need for effective treatments that improve quality of life and survival with a favorable safety profile. %26lt;br%26gt;Objective: To prospectively evaluate the efficacy and safety of three different doses of radium chloride (Ra 223) in patients with CRPC and bone metastases. %26lt;br%26gt;Design, setting, and participants: In this phase 2 double-blind multicenter study, 122 patients were randomized to receive three injections of Ra 223 at 6-wk intervals, at doses of 25 kBq/kg (n = 41), 50 kBq/kg (n = 39), or 80 kBq/kg (n = 42). The study compared the proportion of patients in each dose group who had a confirmed decrease of %26gt;= 50% in baseline prostate-specific antigen (PSA) levels. %26lt;br%26gt;Outcome measurements and statistical analysis: Efficacy was evaluated using blood samples to measure PSA and other tumor markers, recorded skeletal-related events, and pain assessments. Safety was evaluated using adverse events (AEs), physical examination, and clinical laboratory tests. The Jonckheere-Terpstra test assessed trends between groups. %26lt;br%26gt;Results and limitations: The study met its primary end point with a statistically significant dose-response relationship in confirmed %26gt;= 50% PSA declines for no patients (0%) in the 25-kBq/kg dose group, two patients (6%) in the 50-kBq/kg dose group, and five patients (13%) in the 80-kBq/kg dose group (p = 0.0297). A %26gt;= 50% decrease in bone alkaline phosphatase levels was identified in six patients (16%), 24 patients (67%), and 25 patients (66%) in the 25-, 50-, and 80-kBq/kg dose groups, respectively (p %26lt; 0.0001). The most common treatment-related AEs (%26gt;= 10%) occurring up to week 24 across all dose groups were diarrhea (21%), nausea (16%), and anemia (14%). No difference in incidence of hematologic events was seen among dose groups. Potential limitations include small patient numbers and differences among dose groups at baseline. %26lt;br%26gt;Conclusions: Ra 223 had a dose-dependent effect on serum markers of CRPC activity, suggesting that control of bone disease with Ra 223 may affect cancer-related outcomes. Ra 223 was well tolerated at all doses. %26lt;br%26gt;Trial registration: ClinicalTrials.gov: NCT00337155.

• 出版日期2013-2