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Radium-223 chloride, a first-in-class alpha-pharmaceutical with a benign safety profile for patients with castration-resistant prostate cancer (CRPC) and bone metastases: Combined analysis of phase I and II clinical trials.
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2010
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Radium-223 ChloridePharmacotherapyMetronomic ChemotherapyRadiation MedicineMetronomic TherapyHematologyClinical TrialsRadiopharmaceutical TherapyBenign Safety ProfileClinical Radiation OncologyDiagnostic SciencesRadiation OncologyNuclear MedicineCancer ResearchRadiologyHealth SciencesRadiation TherapyMedicineRadionuclide TherapyCastration-resistant Prostate CancerCancer TreatmentProstatic DiseasePharmacologyUrologyRadium-223 GroupOncologyPlacebo Group
4678 Background: Radium-223 chloride (Alpharadin) is a first-in-class alpha- pharmaceutical which has a potent and highly targeted antitumor effect on bone metastases. Efficacy, safety and tolerability of this agent were evaluated in a combined analysis of phase I/II trials. Methods: Two open-label phase I trials (37 pts) and three double-blind phase II trials (255 pts) were performed in mainly CRPC pts with bone metastases. Doses of radium-223 varied from 5 to 250 kBq/kg b.w. The trials included assessments of safety (haematology and AEs), efficacy (survival, PSA, b-ALP, pain) and dosimetry. Results: Radium-223 wasrapidly eliminated from blood with uptake into bone metastases and excretion into the small intestine with no hepatobiliary excretion, and minimal activity in kidneys, liver or other internal organs. Among 292 pts <1% experienced CTC grade 4 haematological toxicity, about 4% experienced grade 3 anemia, and <3% grade 3 platelets, neutrophils or WBC. Common AEs seen in all studies were nausea (33%), bone pain (30%), fatigue (26%), diarrhea (26%), vomiting (20%) and constipation (20%). No signs of renal or hepatic toxicity were seen. Bone markers and PSA decreased significantly and pain relief was demonstrated. In the placebo-controlled phase II study (placebo n=31 pts; radium-223 n=33 pts) there were more AEs in the placebo group than in the radium-223 group (174 vs 155), and more serious AEs in the placebo group (19 vs 12). Median overall survival improved in the radium-223 group compared to the placebo group (65 vs 46 wks; p=0.017). Conclusions: Radium-223 has shown a promising survival benefit, a benign safety profile and an improvement in pain in CRPC patients with bone metastases. A randomized phase III survival study is ongoing worldwide. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Algeta ASA Algeta ASA Algeta ASA Algeta ASA