The role of PARP inhibitor combination therapy in ovarian cancer

Abstract

The use of PARP inhibitors (PARPi) has transformed the care of advanced high-grade serous/endometrioid ovarian cancer. PARPi are now available to patients in both the first-line and recurrent platinum-sensitive disease settings; therefore, most patients will receive PARPi at some point in their treatment pathway. The majority of this expanding population of patients eventually acquire resistance to PARPi, in addition to those with primary PARPi resistance. We discuss the rationale behind developing combination therapies, to work synergistically with PARPi and overcome mechanisms of resistance to restore drug sensitivity, and clinical evidence of their efficacy to date.

Keywords: PARP inhibitor; angiogenesis; combination therapy; epithelial ovarian cancer; homologous recombination deficiency.

Figure 1.

Simplified schematic of homologous recombination (HR) repair pathway. MRE-11-RAD50-NBS1 (MRN) complex recognizes double strand breaks (DSBs). ATM, ataxia telangiectasia and Rad3-related protein (ATR) and 53BP1 also sense DSBs. The MRN complex activates ATM kinase, which in turns initiates the DNA damage response pathway. BRCA1 is attracted to the DNA ends, displaces 53BP1 and stimulates 5′ to 3′ end resection via exonucleases, creating single-strand DNA (ssDNA) overhangs. The exposed ssDNA is coated with DNA replication protein A (RPA), which activates the ATR response to initiate HR repair and the ATR-Chk1 DNA damage checkpoint, which arrests the cell cycle and protects stalled replication forks. Then RAD51, facilitated by BRCA2 and PALB2, replaces RPA and performs homology sequence searching and strand invasion. DSBs are restored by DNA synthesis, ligation and resolution of Holliday junctions.