Western Regional Blog – BC, YK, AB, NWT and Nunavut
“TAKE-HOME MESSAGE The authors review the rapid of evolution of poly(ADP-ribose) polymerase (PARP) inhibitors for treatment of ovarian cancer from their success in vitro as single agents against BRCA-deficient cancer cells in 2005 to multiple recent phase III studies. High-grade serous cancers (HGSC) in particular are discussed, based on the high prevalence of mutations in BRCA and other DNA repair genes observed in these cancers. Combining PARP inhibitors with other biological agents for treatment of other histological subtypes of ovarian cancer is discussed; that prospect could expand the pool of eligible patients who might benefit from PARP inhibitor treatment. Current phase III trials that may result in FDA approval of one or more PARP inhibitors are reviewed, and future prospects for this class of anti-cancer agents are also explored.
Clinical investigation of poly(ADP-ribose) polymerase (PARP) inhibitors for ovarian cancer treatment has rapidly evolved from observations of single-agent in vitro activity of these agents in BRCA-deficient cancer cells in 2005 to the initiation of multiple phase III studies in 2013. With clinical trial design and treatment of ovarian cancer increasingly based on histological and molecular characteristics, PARP inhibitors are on the horizon of becoming the first biologic agents to be used to treat ovarian cancer based upon pre-selection characteristics of the patient’s cancer. PARP inhibitors are most active in ovarian cancers that have defects or aberrations in DNA repair; use of these agents has been of particular interest in high grade serous cancers (HGSC), where studies have shown that ~50% of HGSC have abnormalities of DNA repair through BRCA germline and somatic mutation, post-translational changes of BRCA, and abnormalities of other DNA repair molecules. In addition, as aberrant DNA pathways in other histological subtypes of ovarian cancer are identified, and through the combination of PARP inhibitors with other biologic agents, the pool of eligible patients who may benefit from PARP inhibitors will likely expand. Pending review by the Food and Drug Administration (FDA) and the outcome of confirmatory phase III studies, PARP inhibitors could become the first FDA-approved biologic agent for ovarian cancer and also the first new FDA-approval in ovarian cancer since carboplatin and gemcitabine were approved for platinum sensitive ovarian cancer in 2006. This review discusses the PARP inhibitors that are currently in testing for ovarian cancer treatment and the future of this class of anti-cancer agents.