Clinical Application of Poly(ADP-Ribose) Polymerase Inhibitors in High-Grade Serous Ovarian Cancer

Abstract

High-grade serous ovarian cancer is characterized by genomic instability, with one half of all tumors displaying defects in the important DNA repair pathway of homologous recombination. Given the action of poly(ADP-ribose) polymerase (PARP) inhibitors in targeting tumors with deficiencies in this repair pathway by loss of BRCA1/2, ovarian tumors could be an attractive population for clinical application of this therapy. PARP inhibitors have moved into clinical practice in the past few years, with approval from the Food and Drug Administration (FDA) and European Medicines Agency (EMA) within the past 2 years. The U.S. FDA approval of olaparib applies to fourth line treatment in germline BRCA-mutant ovarian cancer, and European EMA approval to olaparib maintenance in both germline and somatic BRCA-mutant platinum-sensitive ovarian cancer. In order to widen the ovarian cancer patient population that would benefit from PARP inhibitors, predictive biomarkers based on a clear understanding of the mechanism of action are required. Additionally, a better understanding of the toxicity profile is needed if PARP inhibitors are to be used in the curative, rather than the palliative, setting. We reviewed the development of PARP inhibitors in phase I-III clinical trials, including combination trials of PARP inhibitors and chemotherapy/ antiangiogenics, the approval for these agents, the mechanisms of resistance, and the outstanding issues, including the development of biomarkers and the rate of long-term hematologic toxicities with these agents. The Oncologist 2016;21:586-593Implications for Practice: The poly(ADP-ribose) polymerase (PARP) inhibitor olaparib has recently received approval from the Food andDrugAdministration(FDA)andEuropeanMedicinesAgency(EMA), with a second agent (rucaparib) likely to be approved in the near future. However,the patient population with potential benefit from PARP inhibitors is likely wider than that ofgermline BRCA mutationassociated disease, and biomarkers are in development to enable the selection of patients with the potential for clinical benefit from these agents. Questions remain regarding the toxicities of PARP inhibitors, limiting the use of these agents in the prophylactic or adjuvant setting until more information is available. The indications for olaparib as indicated by the FDA and EMA are reviewed.

Corylin increases the sensitivity of hepatocellular carcinoma cells to chemotherapy through long noncoding RNA RAD51-AS1-mediated inhibition of DNA repair

“…This phenomenon desensitizes cancer cells to DNA damage induced by chemotherapy and radiotherapy and is a mechanism through which cancer cells develop drug resistance 46 , 47 . Therefore, in clinical practice, DNA repair inhibitors are administered as adjuvant agents to increase the efficacy of chemotherapy and radiotherapy 48 – 50 . This study has revealed that corylin that is extracted from P. corylifolia L. can inhibit DNA repair in cells and that this effect is mediated by the induction of lncRNA RAD51-AS1.…”

PARP inhibitors in pancreatic cancer: molecular mechanisms and clinical applications

“…This analysis can also distinguish germline mutations from somatic BRCA1/2 mutations. However, it cannot reflect the loss of functional HR as accurately as the BRCA1/2 mutant status [105]. Another biomarker technique in the pipeline is Myriad's HRD assay (Myriad Genetics, Salt Lake City, UT).…”

Apoptosis is augmented in high-grade serous ovarian cancer by the combined inhibition of Bcl-2/Bcl-xL and PARP

“…Olaparib is the first US Food and Drug Administration-approved PARP inhibitor (PARPi), licensed for use in heavily pretreated germ-line BRCA mutation-associated ovarian cancer (6). There are several other PARPi currently in the late phase clinical trial development, including niraparib, rucaparib, veliparib, and BMN 673 (talazoparib) (7). BMN 673 is a potent oral PARPi with a greater DNA-PARP trapping activity compared with other PARPi (8).…”