Several PARP inhibitors, which are oral drugs and generally well tolerated, have now received FDA approval for various ovarian cancer and breast cancer indications.
PARP inhibitors, such as Olaparib, have advanced the treatment of ovarian cancer by providing patients with an effective and molecularly-targeted maintenance therapy.
This study provides mechanistic rationales for combining CNDAC with PARP inhibitors, platinum compounds and taxanes in ovarian cancer lacking BRCA1/2 function.
Lastly, in ovarian cancer models, key proteins that coordinate recognition of DNA damage, ataxia-telangiectasia mutated (ATM) and PARP-1, were induced.
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.
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.
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.
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.
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.
Although PARP inhibitors have been undergoing various clinical trials and the PARP1/2 inhibitor olaparib was approved as monotherapy for BRCA-mutated ovarian cancer, their mode of action in killing tumour cells is not fully understood.
Approximately 25% of patients with ovarian cancer harbor a pathogenic <i>BRCA1/2</i> mutation that has been associated with favorable responses for targeted therapy with poly (ADP-ribose) polymerase 1 (PARP1) inhibitors compared to wild-type individuals.
The PARP inhibitor olaparib was recently granted Food and Drug Administration (FDA) accelerated approval in patients with advanced BRCA1/2 mutation ovarian cancer.
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.
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.
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.
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.
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.