Abstract: PARP inhibitors have shown significant promise in the treatment of ovarian cancer. Olaparib is a PARP inhibitor that has been approved for maintenance for BRCA-mutated ovarian cancer in the recurrent and front-line setting as well as for treatment of BRCA-mutated ovarian cancer in patients who have received multiple prior lines of chemotherapy. In this review, we focus on the use of olaparib in the maintenance setting including the evidence to date, ongoing research, and future directions.
Keywords: olaparib, PARP inhibitor, ovarian cancer, maintenance
Ovarian cancer is the seventh most common cancer in women worldwide and is the leading cause of death from gynecologic cancers in high-income countries.1,2 The five year survival rate in the United States is 48% and the proportion of women dying from their disease has not improved substantially over time as compared to other prevalent cancers.3 Standard treatment for newly diagnosed advanced ovarian cancer consists of cytoreductive surgery and platinum-based chemotherapy with or without concurrent and maintenance bevacizumab, a vascular endothelial growth factor (VEGF) A inhibitor.4 The majority of women with epithelial ovarian cancer respond well to first-line platinum-based chemotherapy however there is a high rate of recurrence with a chemotherapy-free interval before disease progression ranging from 10 to 26 months.5–9 Response to subsequent therapies is variable and often short-lived, underscoring the need for novel effective treatment options to improve long-term disease control for women with ovarian cancer.10,11
Homologous recombination (HR) is a DNA repair process crucial for the accurate repair of DNA damage. BRCA1/2 mutations are known to lead to defective HR and ultimately results in risk for malignant transformation of cells.12 BRCA mutations, both germline and somatic, are thought to occur in up to 25% of patients with newly diagnosed serous ovarian cancer.13 While BRCA1/2 mutations were initially thought to be responsible for the majority of hereditary epithelial ovarian cancers, further investigation has shown that compromise of the HR pathway can occur by several other potential mechanisms.14,15 Thus, it is thought that approximately 50% of high-grade serous ovarian cancers have a deficiency in HR.16
There have been several studies investigating the role of maintenance therapy in ovarian cancer which until recently have not been found to significantly prolong survival.6,17 However, poly (ADP-ribose) polymerase (PARP) inhibitors have shown significant promise with several clinical trials demonstrating a survival improvement in women with newly diagnosed and recurrent ovarian cancer without a substantial increase in adverse effects.18–25 The antitumor effects of PARP inhibitors rely on an exploitation of the defective DNA damage repair in cancer cells with dysfunctional HR. Olaparib is a PARP inhibitor that has several approved indications for use in ovarian cancer and has demonstrated a progression-free survival (PFS) advantage in several trials.19–22
Here, we review the use of olaparib as maintenance treatment for ovarian cancer. We will summarize the evolution of its use, current approved indications, and evidence with respect to its clinical safety and efficacy. Finally, we will provide guidance on treatment decisions with olaparib for patients with ovarian cancer as well as commentary regarding ongoing research and future directions.
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