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13-10-2016 | PARP inhibitors | Article

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

Authors:
G E Konecny, R S Kristeleit

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 BRCAmutations 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.

Brit J Cancer 2016;115:1157–1173. doi:10.1038/bjc.2016.311

Keywords

BRCA mutation; cytotoxic therapy; homologous recombination; ovarian cancer; PARP inhibitor; synthetic lethality

Current efforts to treat BRCA-associated ovarian cancer (OC) with poly(ADP-ribose) polymerase (PARP) inhibitors result from >25 years of basic and translational cancer research. Recently, olaparib, the first PARP inhibitor to treat BRCA mutation-positive patients, has been approved in the European Union and United States (US). Clinical studies have shown that BRCA1/2-deficient tumours are sensitive to PARP inhibitors and platinum agents (Fong et al, 2009; Byrski et al, 2010). PARP inhibitors are molecules that inhibit the activity of PARP proteins, which are involved in a variety of DNA damage repair pathways. The European Commission granted marketing authorisation for the PARP inhibitor olaparib as monotherapy in the maintenance treatment of adult patients with platinum-sensitive, relapsed BRCA-mutated (germline and/or somatic) high-grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete response (CR) or partial response (PR) following platinum-based chemotherapy (Lynparza prescribing information, 2014). In the United States, olaparib received accelerated approval by the Food and Drug Administration (FDA) as monotherapy in patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) advanced OC and who have been treated with three or more prior lines of chemotherapy (Lynparza prescribing information, 2014). Confirmatory phase III trials are underway. This article will review the current role of BRCA proteins and PARP inhibitors in OC, summarise completed and ongoing clinical studies with PARP inhibitors, and outline future directions for this new drug class.

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