Abstract 5712: Alpharadin (Radium-223 chloride) completely prevents tumor growth in bone and increases survival in a mouse model of breast cancer bone metastases in preventive and micro-metastatic settings

Abstract

Abstract Radium-223 chloride is an alpha-emitting radiopharmaceutical that has been shown to improve overall survival in the phase III clinical study (ALSYMPCA) in the treatment of castration resistant prostate cancer with bone metastases (Parker et al. ECCO/ESMO 2011, abstract LBA1). As a calcium mimetic, radium-223 localizes to bone, where the emission of alpha-particles provide an efficient and localized radiation treatment to metastatic skeletal tumor lesions. As previously reported, radium-223 decreases osteolysis and also tumor burden in established model of breast cancer bone metastasis in nude mice (Suominen et al. AACR 2011, abstract 2664). In this study, we investigated the effects of radium-223 on the development of breast cancer bone metastases when administered in the preventive and micro-metastastic settings. The effects of radium-223 were studied in a breast cancer bone metastatic model using intra-cardiac injection of human MDA-MB-231SA/GFP cells in nude mice at day 0. In the first study, the animals were randomized into four groups (n=7) and dosed with either vehicle or a single dose of radium-223 (300 kBq/kg) at days -1, 2 or 15. Three mice were also sacrificed at day 2 for immunohistochemical (pan-cytokeratin and GFP) detection of tumor cells in the bone marrow. Radiography and fluorescence imaging were performed at sacrifice (day 25). Tumor burden was also analysed from mid-sagittal sections of both hind limbs. The second study was a survival study, in which the animals were randomized to three groups (n=12) and dosed with either vehicle or a single dose of radium-223 (300 kBq/kg) at days -1 or 2. Radiography and fluorescence imaging were performed only on animals surviving to day 50. In the first study there were disseminated tumor cells in the bone marrow of all three animals (altogether 18/18 positive sections) sacrificed at day 2, as detected by IHC staining. Radium-223 decreased whole body tumor burden by 81, 84 and 55% and osteolysis by 98, 99.6 and 82%, when administered at days -1, 2 or 15, respectively. No tumor foci were detected in the bone sections of mice treated at days -1 and 2, and tumor area was decreased by 65% in animals treated at day 15. In the survival study, median survival was 24.5 days in the control group, 39.5 days (p <0.001 vs ctrl) in the group administered at day -1, and 35.5 days (p<0.001 vs ctrl) in the group administered at day 2. Three of twelve animals, all administered at day -1, survived until day 50 and two of them had only minimal residual disease. In summary, Alpharadin (radium-223) administered in a preventive or micro-metastatic setting completely prevented progression of osteolytic breast cancer bone metastases and increased survival in this preclinical model. These findings strongly support the clinical development of radium-223 for patients at risk of developing bone metastases. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5712. doi:1538-7445.AM2012-5712