MP46-20 CARMUSTINE AND SELENITE COMBINATION THERAPY EFFECTIVELY INHIBITS CASTRATION RESISTANT PROSTATE CANCER IN PRECLINICAL MODELS

Abstract

INTRODUCTION AND OBJECTIVES: Radium-223 dichloride (Xofigo, Bayer HealthCare Pharmaceuticals) is a first in class alpha particle emitter producing a survival benefit for patients with late stage bone metastatic castrate resistant prostate cancer (bmCRPC). Dosed at 45 kBq per kg every 4 weeks for 6 total injections, the bone seeking radionuclide delivers 4 high-energy alpha particles across a path length of only several cell diameters. Mechanism of action for the survival benefit is not fully understood, hampering our ability to best utilize this novel therapy. We tested Ra in naive and bone metastatic models of disease, to define the whole body and sub-organ distribution of the radionuclide. Our results shed light on important considerations for preand clinical evaluation of Ra for personalized radiotherapy. METHODS: Animals were dosed with 45 kBq per kg of clinical grade Ra. Whole body distribution was monitored by gamma counting in multiple skeletally-mature murine models. Organ and whole body retention were assessed at 1, 4 and 24 h. Detailed Ra microdistribution was assessed by cross-modality imaging of whole body and long bone autoradiography, histochemistry and alpha-camera imaging of whole-mount, undecalcified tissues. Uptake dependence and radiobiological effect of Ra on bone morphology were evaluated by 10 mm isotropic resolution mCT (SkyScan). RESULTS: In contrast to previous preclinical work, our distribution studies recapitulate the planar scintigraphy results in man (Carrasquillo et al., EJNMMI, 2013), with Ra accumulation observed in bowel, stomach, and spleen. In particular, whole-body autoradiography demonstrated the radioisotope bound to the contents of the digestive organs. Kinetic analysis revealed rapid clearance from the blood, and delayed clearance from kidney and intestine. In the bone, Ra predominantly localized to the growth plates; largely sparing the marrow cavity. In bone metastatic models, including the osteoblastic LNCaP, Ra uptake was significantly lower than that in the epiphyseal plate (Figure). CONCLUSIONS: Here we provide greater understanding of the in vivo biological fate of this radiopharmaceutical, with significant implications for enhanced dosing strategies in bmCRPC.