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PARP inhibitors for BRCA1/2-mutated and sporadic ovarian cancer: current practice and future directions

Konecny, G; Kristeleit, RS; (2016) PARP inhibitors for BRCA1/2-mutated and sporadic ovarian cancer: current practice and future directions. British Journal of Cancer , 115 pp. 1157-1173. 10.1038/bjc.2016.311. Green open access

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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. Trials are underway to determine whether such a signature will predict sensitivity to PARP inhibitors in women with sporadic OC.

Type: Article
Title: PARP inhibitors for BRCA1/2-mutated and sporadic ovarian cancer: current practice and future directions
Open access status: An open access version is available from UCL Discovery
DOI: 10.1038/bjc.2016.311
Publisher version: http://dx.doi.org/10.1038/bjc.2016.311
Language: English
Additional information: This work is licensed under the Creative Commons Attribution-Non-Commercial-Share Alike 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/4.0/
Keywords: BRCA mutation; cytotoxic therapy; homologous recombination; ovarian cancer; PARP inhibitor; synthetic lethality
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology
URI: http://discovery.ucl.ac.uk/id/eprint/1524894
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