Anti-angiogenic agents in ovarian cancer: Past, present, and future

Angiogenesis plays a pivotal role in normal ovarian physiology as well as in the progression of ovarian cancer through ascitesformation and metastatic spread. Bevacizumab (Avastin®, Genentech; South San Francisco, CA, USA), a humanized antivascularendothelial growth factor (VEGF) monoclonal antibody, is the most widely studied anti-angiogenesis agent bothacross tumor types and specifically in epithelial ovarian cancer. In 2005, single-agent bevacizumab at 15 mg/kg (IV) every 3weeks was first reported to be active in a case of recurrent high-grade serous ovarian cancer after failing 11th line cytotoxictreatment. Since then, many case series, phase II and phase III trials have confirmed these results leading to regulatoryapproval in most countries including the US Food and Drug Administration in 2014. Guidelines now give clearrecommendations as to when and how bevacizumab should be integrated into the ovarian cancer treatmentparadigm. Other anti-VEGF agents such as the VEGF receptor (VEGFR) tyrosine kinase inhibitors have notshown increased activity or reduced toxicity relative to bevacizumab. However, anti-angiogenics other thananti-VEGF/VEGFR agents such as those targeting Angiopoietin-1 and -2 are in development as well as novelcombinations with vascular disrupting agents (VDAs), PARP inhibitors and immune checkpoint inhibitors. Clearly,the benefits of anti-angiogenic agents such as bevacizumab must be carefully weighed against the cost and associatedtoxicities. Although almost all patients with ovarian cancer will receive an anti-angiogenic compound, curesare not increased. Predictive biomarkers are an urgent unmet need.