Spotlight on olaparib in the treatment of BRCA-mutated ovarian cancer: design, development and place in therapy

Abstract

Epithelial ovarian cancer is the sixth most common cancer among women worldwide and the first cause of death among gynecological malignancies. Most of the patients present recurrent disease and unfortunately cannot be cured. The unsatisfactory results obtained with salvage chemotherapy have elicited investigators to search for novel biological agents capable of achieving a better control of the disease. In the setting of homologous recombination deficiency, the DNA errors that occur cannot be accurately repaired, and the treatment with poly(ADP-ribose) polymerase (PARP) inhibition results in definitive cell death in a process called synthetic lethality. As a result of two positive clinical trials, Olaparib was approved in 2014 by U.S. Food and Drug Administration and European Medicines Agency as the first-in-class PARP inhibitor. Olaparib is effective and well tolerated in homologous recombination deficient patients. Several studies with Olaparib have been conducted in the recurrent setting either as maintenance in platinum-responsive patients or as a single agent. Ongoing trials are focused on the use of olaparib as maintenance in the first-line ovarian cancer setting alone or in combination with antiangiogenic agents. Future perspectives will probably investigate the association of olaparib with novel agents as check-point inhibitors and PI3K-AKT inhibitors. The PARP inhibitor era is just at the beginning.

Real‐world clinical outcomes of olaparib therapy in Chinese patients with advanced serous ovarian cancer treated in Macau

“…Nevertheless, our study is the first to investigate the real‐worldeffectiveness and safety profile of olaparib in Chinese patients with serous ovarian cancer and provides important insights into the use of olaparib in a largely different ethnic patient population compared with those studied in previous prospective trials. Ongoing trials are exploring olaparib for first‐line, maintenance treatment of serous ovarian cancer (SOLO‐1 trial; NCT01844986), or in combination with other chemotherapeutic agents such as bevacizumab (PAOLA‐1 trial; NCT02477644) . Future studies may explore the possibility of olaparib for first‐line, active treatment of serous ovarian cancer, or in combination with other targeted drugs.…”

Immune Checkpoint Inhibitors in Epithelial Ovarian Cancer: An Overview on Efficacy and Future Perspectives

“…Recently, several inhibitors of the enzyme poly ADP ribose polymerase (PARPi) have been approved in EOC: Olaparib for BRCA-mutated patients as maintenance after first-line chemotherapy and at platinum-sensitive relapse; Niraparib and Rucaparib at platinum-sensitive relapse regardless BRCA status. A progression-free survival (PFS) improvement was observed for all drugs but, to date, with no impact on overall survival (OS) [11][12][13][14][15][16][17] Starting from this background, there is clearly a need to develop new therapies. Substantial evidence indicates that EOCs express a multitude of known tumor-associated and mutational antigens (TAAs or neo-antigens, respectively), and a proportion of tumors are infiltrated by intraepithelial tumor-infiltrating lymphocytes (TILs), which correlate with improved survival [18][19][20].…”

Similar incidence of DNA damage response pathway alterations between clinically localized and metastatic prostate cancer

“…The present finding also has therapeutic implications. Currently, there are multiple agents such as olaparib, niraparib, and rucaparib [5,13,14] that target the DDR pathway. Among these PARP inhibitors, olaparib has been shown to be effective in men with mCRPC as a monotherapy and in combination with abiraterone [7,15].…”

“…High rates of genomic mutations in DNA damage repair (DDR) genes, such as breast cancer 2, early onset (BRCA2) and ataxia telangiectasia mutated (ATM) genes, have been detected in multiple malignancies [2][3][4]. More recently, it has been suggested that tumors with such homologous recombination defects may be sensitive to poly (adenosine diphosphate-ribose) polymerase (PARP) 1 inhibitors, such as olaparib [5,6].…”