Update on Poly ADP-Ribose Polymerase Inhibitors in Ovarian Cancer With Non-BRCA Mutations

Abstract

Poly ADP-ribose polymerase inhibitor (PARPi) has become an important maintenance therapy for ovarian cancer after surgery and cytotoxic chemotherapy, which has changed the disease management model of ovarian cancer, greatly decreased the risk of recurrence, and made the prognosis of ovarian cancer better to certain extent. The three PARPis currently approved by the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of ovarian cancer are Olaparib, Niraparib and Rucaparib. With the incremental results from new clinical trials, the applicable population of PARPi for ovarian cancer have expanded to population with non-BRCA mutations. Although BRCA mutated population are still the main beneficiaries of PARPi, recent clinical trials indicated PARPis' therapeutic potential in non-BRCA mutated population, especially in homologous recombination repair deficiency (HRD) positive population. However, lack of unified HRD status detection method poses a challenge for the accurate selection of PARPi beneficiaries. The reversal of homologous recombination (HR) function during the treatment will not only cause resistance to PARPis, but also reduce the accuracy of the current method to determine HRD status. Therefore, the development of reliable HRD status detection methods to determine the beneficiary population, as well as rational combination treatment are warranted. This review mainly summarizes the latest clinical trial results and combination treatment of PARPis in ovarian cancer with non-BRCA mutations, and discusses the application prospects, including optimizing combination therapy against drug resistance, developing unified and accurate HRD status detection methods for patient selection and stratification. This review further poses an interesting topic: the efficacy and safety in patients retreated with PARPis after previous PARPi treatment---"PARPi after PARPi".

Keywords: HRD status detection; combination therapy; homologous recombination deficiency; ovarian cancer; poly ADP-ribose polymerase inhibitors.

FIGURE 1

The mechanism of action of PARP1. PARP1 binds to DNA nicks and breaks, which results in activation of catalytic activity causing poly (ADP) ribosylation of PARP1 itself, and of acceptor proteins. The components of DNA repair pathways will be recruited, then DNA get repaired. PARP: poly ADP-ribose polymerase: PAR: poly ADP-ribose: SSB: single-strand breaks.

FIGURE 2

Mechanism of synthetic lethality between HRD and PARP inhibitors. SSBs of DNA are normally efficiently repaired by BER. PARP inhibitors prevent the separation of PARP from the broken DNA single strand, PARylation is inhibited and the BER pathway is impaired, SSBs will persist. A replication fork may encounter persistent SSBs during DNA replication, which causes the replication fork to collapse or the formation of DSBs. DSBs are usually repaired by HRR, when some key homologous recombination genes are damaged or dysregulated, HRD will occur. And then DNA cannot be required, or is repaired by alternative pathways that are highly error prone, which results in gross genomic instability and cell death. SSB: single-strand breaks; DSB: double-strands breaks: BER: base excision repair; HRR: homologous recombination repair; HRD: homologous recombination deficiency; NHEJ: non-homologous end joining: MMEJ: microhomology-mediated end joining.

FIGURE 3

Geographical distribution map of the subjects in some selected key studies of PARP inhibitors in ovarian cancer with non-BRCA mutations. The subjects in study 19, OPINION study, NOVA trial, QUADRA trial, PRIMA trail, NORA trail, ARIEL2 trail, ARIEL3 trail, PAOLA-1 trail and AVANOVA2 trail are marked with dots of different colors. It can be seen that most of the subjects came from the United States, Canada, and some countries in Europe.