Olaparib in the Treatment of Ovarian Cancer

Abstract

The poly ADP ribose polymerase olaparib is currently approved in front line BRCA-associated epithelial ovarian cancer (EOC), platinum-sensitive recurrence agnostic to BRCA status and for gBRCA as treatment in the fourth line and beyond. Women who are diagnosed with advanced stage EOC face a formidable challenge in overcoming their disease and achieving long-term, disease-free survival. The qualifier here is disease free. EOC is largely exquisitely chemosensitive, especially in the treatment naive (first line) setting and the expectation is that the vast majority of women will complete front line platinum-based chemotherapy with a response. When unselected (not selected by BRCA) women are enrolled on clinical trials, the response rate among those who have measurable disease at the time of chemotherapy initiation is 48% for carboplatin/paclitaxel and 67% for carboplatin/paclitaxel plus bevacizumab. When one considers the addition of women who start chemotherapy without measurable disease, they will likely also end chemotherapy without measurable disease and the overall rate of no evidence of disease at conclusion of chemotherapy approaches 80%. Despite this, the majority of women will suffer relapse of their disease, typically within the first 3 years following completion of therapy. Once recurrent, the disease is highly treatable for many years but no longer considered curable. This review will cover indications for olaparib in ovarian cancer as well as ongoing combination trials and rationale for these combinations.

BBIT20 inhibits homologous DNA repair with disruption of the BRCA1–BARD1 interaction in breast and ovarian cancer

“…The discovery of effective therapeutic alternatives for the personalized therapy of triple‐negative breast and high‐grade ovarian cancer is still a challenge, with patients treatment mostly relying on chemotherapeutics as platinum drugs (Chalakur‐Ramireddy & Pakala, 2018; Ellsworth et al, 2019; Mehanna et al, 2019). On the field of targeted therapies, PARP inhibitors are currently in the frontline for the treatment of breast and ovarian cancer with mutBRCA1 (Robson et al, 2017; Washington et al, 2019). However, once PARP inhibitors efficacy relates to homozygous mutBRCA1 and a complete loss of homologous DNA repair function, tumours with wt, heterozygous mutBRCA1 or loss of heterozygosity are commonly associated with PARP inhibitors resistance, due to a remaining homologous DNA repair activity (Johnson et al, 2016; Y. Kim et al, 2017; Noordermeer & van Attikum, 2019; Tarsounas & Sung, 2020).…”

Aberrantly Expressed RECQL4 Helicase Supports Proliferation and Drug Resistance of Human Glioma Cells and Glioma Stem Cells

“…Inhibition of PARP is toxic in cells with defective DNA base excision repair and PAPR inhibitors are recently explored as anti-glioma treatments [ 29 , 30 ]. In this study, olaparib had weaker effects on cell cycle regulators, pro-apoptotic proteins, phospho-H2AX levels and did not significantly affect proliferation and viability of LN18 cells.…”

Roads to the strategic targeting of ovarian cancer treatment

“…Regarding other drugs, the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib is the first personalized treatment recently approved for patients with high-grade serous ovarian cancer with a germline or somatic BRCA1 or BRCA2 mutation. Moreover, this drug could be received much earlier as a maintenance drug in patients that have responded to first-line platinumbased chemotherapy, and 60% of patients receiving olaparib have had no progression of cancer after 3 years vs 27% receiving the placebo (Washington et al 2019).…”

“…Ovarian cancer tumor biology: new approaches R7 Reproduction (2021) 161 R1-R11 types of tumors (Moore et al 2019). In particular, a phase Ib clinical study has recently evaluated the doselimiting toxicities and the maximum tolerated dose of Ipafricept (also known as OMP-54F28) in ovarian cancer, where its efficacy was tested in combination with carboplatin and paclitaxel (Le et al 2015, Harb et al 2019.…”