Development of Olaparib for BRCA-Deficient Recurrent Epithelial Ovarian Cancer.

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. PARP is a family of proteins involved in the repair of single-strand DNA breaks. High-grade serous ovarian carcinomas with BRCA deficiencies may be particularly vulnerable to both direct and indirect effects of PARP inhibition. This phenotype frequently arises as a consequence of defects in the repair of damaged DNA, rendering cancer cells susceptible to DNA-damaging platinum compounds and targeted therapies affecting homologous recombination repair (HRR). When cells already deficient in HRR are exposed to PARP inhibitors, apoptosis occurs by way of synthetic lethality. In this review, we trace the clinical development of olaparib for women with recurrent epithelial ovarian carcinoma harboring germline BRCA mutations, a biomarker for HRR deficiency present in 15% to 20% of cases. Clinical trials highlighted include not only those pivotal studies that have led to regulatory approval in the United States and in Europe, but also those in which olaparib was studied in novel combinations, including chemotherapy and antiangiogenesis agents.

Tewari KS ，Eskander RN ，Monk BJ 《-》

Homologous recombination deficiency and ovarian cancer.

The discovery that PARP inhibitors block an essential pathway of DNA repair in cells harbouring a BRCA mutation has opened up a new therapeutic avenue for high-grade ovarian cancers. BRCA1 and BRCA2 proteins are essential for high-fidelity repair of double-strand breaks of DNA through the homologous recombination repair (HRR) pathway. Deficiency in HRR (HRD) is a target for PARP inhibitors. The first PARP inhibitor, olaparib, has now been licensed for BRCA-mutated ovarian cancers. While mutated BRCA genes are individually most commonly associated with HRD other essential HRR proteins may be mutated or functionally deficient potentially widening the therapeutic opportunities for PARP inhibitors. HRD is the first phenotypically defined predictive marker for therapy with PARP inhibitors in 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. Around 20% of high-grade serous ovarian cancers harbour germline or somatic BRCA mutations and testing for BRCA mutations should be incorporated into routine clinical practice. The expanded use of PARP inhibitors in HRD deficient (non-BRCA mutant) tumours using a signature of HRD in clinical practice requires validation.

Ledermann JA ，Drew Y ，Kristeleit RS 《-》

Baseline clinical predictors of antitumor response to the PARP inhibitor olaparib in germline BRCA1/2 mutated patients with advanced ovarian cancer.

Rafii S ，Gourley C ，Kumar R ，Geuna E ，Ern Ang J ，Rye T ，Chen LM ，Shapira-Frommer R ，Friedlander M ，Matulonis U ，De Greve J ，Oza AM ，Banerjee S ，Molife LR ，Gore ME ，Kaye SB ，Yap TA ... -  《Oncotarget》

Olaparib maintenance monotherapy in platinum-sensitive, relapsed ovarian cancer without germline BRCA mutations: OPINION Phase IIIb study design.

Poveda AM ，Davidson R ，Blakeley C ，Milner A ... -  《-》

What Is the Place of PARP Inhibitors in Ovarian Cancer Treatment?

Liu JF ，Matulonis UA 《-》