PG545 is a dual angiogenesis and heparanase inhibitor that recently entered clinical trials in advanced cancer. This compound has been shown to potently inhibit metastasis in several experimental and spontaneously arising metastatic tumour models, an effect that is purportedly due to inhibition of the enzymatic function of heparanase by PG545 . Heparanase is the only endoglycosidase known to cleave heparan sulfate (HS), an important component of the extracellular matrix (ECM). The degradation of HS by heparanase has been strongly implicated in tumour modification of the microenvironment, cell dissemination and the metastatic process. The limited number of studies using overall survival as an endpoint in mouse metastasis models has been raised as a factor affecting the success of new cancer treatments . This led us to examine the effect of PG545 on the progression of both primary tumour growth and spontaneously metastasizing disease in the 4T1 syngeneic breast carcinoma model in a non-surgical and surgical (mastectomy) setting. PG545 significantly inhibited primary tumour growth but also inhibited lung metastasis in treated mice, an effect not observed with the tyrosine kinase inhibitor sorafenib. Importantly, PG545 significantly enhanced overall survival compared to vehicle control or the sorafenib group, suggesting PG545’s inhibitory effect on heparanase could be critical for this anti-metastatic activity. In support of these observations, the levels of heparanase in the primary tumour and lung was significantly reduced by PG545 treatment. This reduction in heparanase appeared to be related to PG545 inhibition of growth factor signalling as indicated by the reduced level of ERK 1/2 signalling in the PG545 treated tumours. These results support the ongoing development of PG545 and highlight the potential utility in metastatic disease settings.