Radium-223 emits high energy alpha particles over a short range resulting in a localized potent antitumor effect and inhibition of tumor-induced osteoblastic activity in preclinical models. Radium-223 dichloride (radium-223), a targeted alpha therapy, is incorporated into newly formed bone in areas of osteoblast activity and increased bone turnover surrounding prostate cancer bone metastases. The study was registered with, number NCT01618370 on Jand the European Union Clinical Trials Register, EudraCT number 2012–000075-16 on April 4, 2012. Using radium-223 earlier in the disease course, when patients are asymptomatic or minimally symptomatic, may enable patients to complete treatment and optimize treatment outcome compared to symptomatic patients, and therefore may allow sequencing with other life-prolonging therapies. There were two treatment-related deaths, both in patients with baseline symptomatic disease. A lower proportion of asymptomatic patients reported treatment-emergent adverse events (TEAEs, 61% vs 79%), grade 3–4 TEAEs (29% vs 40%) and drug-related TEAEs (28% vs 44%). Alkaline phosphatase (ALP) response rates were similar (46% vs 47%), and ALP normalization (44% vs 25%) and prostate-specific antigen response rates (21% vs 13%) were higher in asymptomatic than symptomatic patients. Overall survival (hazard ratio 0.486), time to disease progression (HR 0.722) and time to first symptomatic skeletal event (HR 0.328) were better in asymptomatic than symptomatic patients. A higher proportion of asymptomatic (71%) versus symptomatic (55%) patients completed radium-223 treatment. A lower proportion of asymptomatic versus symptomatic patients had received prior abiraterone (25% vs 35%) and prior docetaxel (52% vs 62%).
Asymptomatic patients had more favorable baseline disease characteristics than symptomatic. Seven hundred eight patients received ≥1 radium-223 injection: 548 (77%) were symptomatic to various degrees, and 135 (19%) were asymptomatic. Asymptomatic status was defined as no pain and no opioid use at baseline. Post hoc analyses were performed according to baseline asymptomatic or symptomatic disease status. Co-primary endpoints were safety and overall survival. Patients with metastatic CRPC (malignant lymphadenopathy not exceeding 6 cm was allowed, visceral disease was excluded) received radium-223, 55 kBq/kg intravenously, every 4 weeks for up to 6 cycles. This was a prospective, single-arm phase 3b study. Data for radium-223 in asymptomatic CRPC patients with bone metastases are lacking. Radium-223, a targeted alpha therapy, is used to treat symptomatic patients with castration-resistant prostate cancer (CRPC) and bone metastases.
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