The Current Status of PARP Inhibitors in Ovarian Cancer

Abstract

Recent advances in our understanding of the molecular biology of epithelial ovarian cancer have led to the development of a number of targeted therapies, including poly-ADP-ribose polymerase (PARP) inhibitors. PARP inhibitors are a novel class of therapeutic agents that target tumors with deficiencies in the homologous recombination DNA repair pathway. Early studies have shown significant efficacy for PARP inhibitors in patients with germline BRCA1/2 mutations. It has become evident that BRCA wild-type patients with other defects in the homologous recombination repair pathway benefit from this therapeutic approach. Importantly, companion homologous recombination deficiency scores are being developed to help guide the selection of patients most likely to gain clinical benefit from PARP inhibition. Olaparib, the first and most extensively investigated PARP inhibitor, is now licensed in Europe for maintenance treatment of patients with platinum-sensitive relapsed BRCA-mutated (germline or somatic) high-grade serous ovarian cancer who have responded to platinum-based chemotherapy. In the United States, olaparib is licensed for treatment of patients with germline BRCA-mutated ovarian cancer who have received 3 or more lines of chemotherapy. There are a number of other PARP inhibitors in late phase clinical development in ovarian cancer including rucaparib, niraparib, veliparib, and talazoparib. This review will focus on the current evidence for PARP inhibitors in ovarian cancer and discuss ongoing clinical trials and future research directions in this rapidly evolving area.

Advances in ovarian cancer therapy

“…Multiple trials were designed to evaluate PARP inhibitors in ovarian cancer: (1) in a first-line treatment (SOLO1/NCT01844986, NCT02470585, PRIMA/NCT02655016, PAOLA1/ NCT02477644, NEO/NCT02489006), (2) in the treatment of platinum-sensitive relapse (ENGOT-OV24/AVANOVA/NCT02354131, NCI-OVM1403/NCT02446600, SOLO3/ NCT02282020, ARIEL4/NCT02855944), (3) in maintenance after chemotherapy in platinum-sensitive disease (ENGOT-OV16 NOVA/NCT01847274, SOLO 2/NCT01874353, ARIEL3/NCT01968213) or (4) in the treatment for platinum-resistant disease, and (5) in combination with immune checkpoint inhibitors and other biological drugs (widely reviewed in: [ 54 , 76 – 78 ]).…”

Diverse BRCA1 and BRCA2 Reversion Mutations in Circulating Cell-Free DNA of Therapy-Resistant Breast or Ovarian Cancer

“…BRCA1 or BRCA2 breast and ovarian cancers are reported to be sensitive to platinum-based chemotherapy and PARP inhibition (7–10), with platinum-based chemotherapy serving as the mainstay of treatment of ovarian cancer patients. Several PARP inhibitors have recently been approved for the treatment of advanced BRCA1 - or BRCA2 -mutant ovarian cancer (11), and are in phase III clinical trials for patients with BRCA1 - or BRCA2 -mutant breast cancer (12). Importantly, several mechanisms of resistance to these agents have been reported in preclinical models and in clinical studies (3,4).…”

Emerging Therapeutics to Overcome Chemoresistance in Epithelial Ovarian Cancer: A Mini-Review

“…Using poly(ADP-ribose) polymerase (PARP) inhibitors for treating breast cancer 1 (BRCA) or HR deficient HGSOC is a highly active area of research with several FDA-approved therapies in the recurrent and maintenance setting [ 114 ]. PARP is an enzyme responsible for the correct repair of DNA damage, and it does this through directly interacting with the repair machinery on the damaged site.…”