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13-12-2016 | PARP inhibitors | Article

Delivering widespread BRCA testing and PARP inhibition to patients with ovarian cancer

Authors: Angela George, Stan Kaye, Susana Banerjee

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Abstract

The treatment of patients with ovarian cancer is rapidly changing following the success of poly [ADP-ribose] polymerase (PARP) inhibitors in clinical trials. Olaparib is the first PARP inhibitor to be approved by the EMA and FDA for BRCA-mutated ovarian cancer. Germ line BRCA mutation status is now established as a predictive biomarker of potential benefit from treatment with a PARP inhibitor; therefore, knowledge of the BRCA status of an individual patient with ovarian cancer is essential, in order to guide treatment decisions. BRCA testing was previously offered only to women with a family or personal history of breast and/or ovarian cancer; however, almost 20% of women with high-grade serous ovarian cancer are now recognized to harbour a germ line BRCA mutation, and of these, >40% might not have a family history of cancer and would not have received BRCA testing. A strategy to enable more widespread implementation of BRCA testing in routine care is, therefore, necessary. In this Review, we summarize data from key clinical trials of PARP inhibitors and discuss how to integrate these agents into the current treatment landscape of ovarian cancer. The validity of germ line BRCA testing and other promising biomarkers of homologous-recombination deficiency will also be discussed.

Nat Rev Clin Oncol 2017;14:284–296. doi:10.1038/nrclinonc.2016.191

Epithelial ovarian cancer is now recognized as a heterogeneous disease, with each histological subtype (high-grade serous, low-grade serous, clear cell, endometrioid and mucinous) having distinct clinical characteristics and underlying molecular pathway aberrations. Regardless of this knowledge, all forms of ovarian cancer, outside of clinical trials conducted in the past 20 years, have been treated as a single entity in clinical practice1. This view has now changed as a result of several pivotal clinical trials demonstrating the efficacy of the poly [ADP-ribose] polymerase (PARP) inhibitor olaparib in selected patients2, 3, 4, 5, 6. In December 2014, olaparib received European Medicines Agency (EMA) approval for use as a maintenance therapy in patients with platinum-sensitive, relapsed, breast cancer type 1 susceptibility protein (BRCA)-mutant (germ line or somatic), high-grade serous ovarian cancer7. At the same time, the FDA approved the use of olaparib for a different indication: the treatment of patients with recurrent, germ line BRCA-mutated, advanced-stage ovarian cancer who have received three or more prior lines of chemotherapy8. For the first time in the management of ovarian cancer, patients are now being selected in clinical practice for biomarker-directed therapy, based on the presence of a BRCA1 or BRCA2 mutation. In this Review, we summarize the key milestones in the development of PARP inhibitors and discuss the delivery of testing for BRCA mutations as a companion biomarker. Challenges to the integration of PARP inhibitors into the armamentarium of available treatments of ovarian cancer are also discussed.

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