Multicentre Study of Olaparib Maintenance Monotherapy in Platinum Sensitive Relapsed Non gBRCAm Ovarian Cancer Patients

Maintenance monotherapy with the potent polyadenosine 5'diphosphoribose \[Poly (ADP-ribose)\] polymerisation (PARP) inhibitor (PARPi) olaparib will significantly prolong progression-free survival (PFS) in platinum sensitive relapsed non-germline breast cancer susceptibility gene (BRCA) mutated ovarian cancer patients who are in complete or partial response following platinum based chemotherapy. Olaparib is a potent PARPi (PARP-1, -2 and -3) that is being developed as an oral therapy, both as a monotherapy (including maintenance) and for combination with chemotherapy and other anticancer agents. PARP inhibition is a novel approach to targeting tumours with deficiencies in DNA repair mechanisms. PARP enzymes are essential for repairing DNA single strand breaks (SSBs). Inhibiting PARP enzymes leads to the persistence of SSBs, which are then converted to the more serious DNA double strand breaks (DSBs) during the process of DNA replication. During the process of cell division, DSBs can be efficiently repaired in normal cells by homologous recombination (HR) repair. Tumours with HR deficiencies (HRDs), such as ovarian cancers in patients with BRCA1/2 mutations, cannot accurately repair the DNA damage, which may become lethal to cells as it accumulates. In such tumour types, olaparib may offer a potentially efficacious and less toxic cancer treatment compared with currently available chemotherapy regimens. While multiple randomized controlled trials (RCTs) have demonstrated that platinum sensitive BRCAm patients have profound response to maintenance treatment with PARP inhibitors, PARP inhibitors target cells with homologous recombination deficiency (HRD), of which BRCA mutation is only one type. Consistent with the mechanism of action of PARP inhibition, response has also been seen in multiple RCTs in patients who are platinum sensitive but whose tumours do not harbor BRCA mutations. Presumably these responders have defects in other components of HRR pathways, though currently available diagnostic technology is not adequate to reliably identify the full spectrum of HRR deficiencies. Instead, these data support the hypothesis that platinum sensitivity itself is a clinical selection factor for HRD.