PARP inhibitors for BRCA1/2-mutated and sporadic ovarian cancer: current practice and future directions
- PMID: 27736844
- PMCID: PMC5104889
- DOI: 10.1038/bjc.2016.311
PARP inhibitors for BRCA1/2-mutated and sporadic ovarian cancer: current practice and future directions
Abstract
Poly(ADP-ribose) polymerase (PARP) inhibitors cause targeted tumour cell death in homologous recombination (HR)-deficient cancers, including BRCA-mutated tumours, by exploiting synthetic lethality. PARP inhibitors are being evaluated in late-stage clinical trials of ovarian cancer (OC). Recently, olaparib was the first PARP inhibitor approved in the European Union and United States for the treatment of advanced BRCA-mutated OC. This paper reviews the role of BRCA mutations for tumorigenesis and PARP inhibitor sensitivity, and summarises the clinical development of PARP inhibitors for the treatment of patients diagnosed with OC. Among the five key PARP inhibitors currently in clinical development, olaparib has undergone the most extensive clinical investigation. PARP inhibitors have demonstrated durable antitumour activity in BRCA-mutated advanced OC as a single agent in the treatment and maintenance setting, particularly in platinum-sensitive disease. PARP inhibitors are well tolerated; however, further careful assessment of moderate and late-onset toxicity is mandatory in the maintenance and adjuvant setting, respectively. PARP inhibitors are also being evaluated in combination with chemotherapeutic and novel targeted agents to potentiate antitumour activities. Current research is extending the use of PARP inhibitors beyond BRCA mutations to other sensitising molecular defects that result in HR-deficient cancer, and is defining an HR-deficiency signature VSports手机版. Trials are underway to determine whether such a signature will predict sensitivity to PARP inhibitors in women with sporadic OC. .
Conflict of interest statement
GEK has received research grant support from Amgen, Novartis, Pfizer and has participated in advisory boards for Genentech, Clovis Oncology, and Medivation. RSK was involved in the development of rucaparib, participated in olaparib trials, and served an advisory role to Clovis Oncology V体育安卓版.
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