Here, we investigate the potential role of the PARP inhibitor rucaparib (CO-338, formerly known as AG014699 and PF-01367338) for the treatment of sporadic ovarian cancer.
The discovery of the BRCA mutation and its role in ovarian cancer and the clinical application of the concept of synthetic lethality have been the rationale for the successful testing of PARP inhibitors in BRCA mutated ovarian cancer patients.
To define the relative contribution of PARP inhibition to the observed clinical activity, we conducted a randomized phase II trial to determine the response rate of veliparib in combination with cyclophosphamide compared with cyclophosphamide alone in patients with pretreated BRCA-mutant ovarian cancer or in patients with pretreated primary peritoneal, fallopian tube, or high-grade serous ovarian cancers (HGSOC).
The FDA approval of the PARP inhibitor olaparib for fourth-line therapy of germline BRCA1/2-mutated ovarian cancer represents the first registered indication for this class of drugs in any disease.
Several different PARP inhibitors are being trialled in ovarian cancer and this class of drugs has been shown to be a new selective therapy for high-grade ovarian cancer.
Targeting of these pathways, especially through PARP inhibition, is now being exploited therapeutically to effect significant clinical responses in subsets of individuals, particularly in patients with ovarian cancer or prostate cancer, including cancers with a marked metastatic burden.
Results from a phase III trial indicate that maintenance therapy with the PARP inhibitor niraparib is more effective than placebo in slowing the progression of recurrent platinum-sensitive ovarian cancer.
The PARP inhibitor Olaparib [AZD2281] has been approved by the FDA for use in pretreated ovarian cancer patients with defective BRCA1/2 genes, and by the EMEA for maintenance therapy in platinum sensitive ovarian cancer patients with defective BRCA1/2 genes.
Originally presumed to inhibit DNA repair, PARP inhibitors that have recently been approved by the FDA for the treatment of advanced ovarian cancer also act as DNA damaging agents by inducing PARP-DNA complexes.
Areas covered: Herein we will review cediranib as well as the evidence for its use in ovarian cancer, both as monotherapy and in combination with chemotherapy, PARP inhibitors and immunotherapy.
The recent approval of three different PARP inhibitors for the treatment of ovarian cancer provides the impetus for further developing targeted inhibitors of many of the kinases involved in the DDR, including inhibitors of ATR, ATM, CHEK1, CHEK2, DNAPK and WEE1.
Subjects with germline BRCA1/2 mutations (gBRCAm) have an increased risk of developing ovarian cancer and enhanced sensitivity to platinum-containing agents and PARP (poly[ADP-ribose] polymerase) inhibitors.
Among the PARP inhibitors introduced in clinical practice, niraparib showed interesting results in a phase III trial in the setting of maintenance treatment in ovarian cancer, after platinum-based chemotherapy.
The PARP inhibitor olaparib was recently granted Food and Drug Administration (FDA) accelerated approval in patients with advanced BRCA1/2 mutation ovarian cancer.
PARP inhibitors have been widely tested in clinical trials, especially for the treatment of breast cancer and ovarian cancer, and were shown to be highly successful.
Several PARP inhibitors, which are oral drugs and generally well tolerated, have now received FDA approval for various ovarian cancer and breast cancer indications.