e23149 Background: Despite the approval of several new agents, taxanes remains the main treatment with survival benefits for castration-refractory metastatic prostate cancer/mCRPC. Still their mechanisms of action and therapeutic efficacy remain incompletely characterized. In the present study, we proposed to compare docetaxel/Doc and cabazitaxel/Cab, delivered as monotherapy or in combination with the anti-angiogenic and anti-tumoral Pigment Epithelium-Derived Factor/PEDF, on CRPC cells in vitro and in vivo. Methods: CRPCcells were assessed for cell growth, cell cycle, and apoptosis under taxane/control treatment by cytotoxicity, PI incorporation and TUNEL assays. CL1 cells that express PEDF/control were used in vivo. Tumor cells were injected s.c. into CB17-SCID mice. After two weeks, mice were randomized into groups: 1) Placebo; 2) Doc 5mg/kg i.p. d4; and 3) Cab 5-1-0.5-0.1mg/kg i.p. d4, d1-7, d2, daily. To assess the anti-tumor effect of the combination, tumor cell migration and phagocytosis were measured by Boyden chamber and confocal microscopy analyses of CL1-RAW264.7 macrophages co-cultures. Results: Cab was more cytotoxic than Doc in all the cell lines tested.This effect was concomitant to increased cell death, but was not due to autophagy or necrosis. Inversely, we showed that apoptosis was superior in Cab-treated cells than in Doc treatment. In vivo, while 0.5 and 0.1 mg/kg Cab did not improve PEDF efficacy on tumor growth, 1mg/kg was very toxic. In contrast, PEDF combined with 5mg/kg Cab lead to stabilization of the disease and was also found to be drastically more efficient than PEDF/Doc in delaying the disease. In vitro, PEDF/Cab inhibited tumor cell migration at a significant superior level compared to PEDF/Doc. Finally, tumor cells phagocytosis was induced in PEDF/Cab suggesting that the combination may target macrophages within the tumor microenvironment. Conclusions: Our data demonstrated the greater anti-tumor efficacy of Cab compared to Doc. They also insist on the fact that PEDF/Cab could be used as a novel combined therapy for CRPC, and emphasize on the importance in evaluating the cytotoxicity of the novel combination tested and investigating the role of the tumor microenvironment in the anti-tumor effect.