Latest development of PARP inhibitors in ovarian cancer

Abstract

Abstract Ovarian cancer is a highly lethal gynecologic malignancy. Approximately 10000 new cases of ovarian cancers are diagnosed annually in Japan and 5,000 patients die per year. Almost half of patients are diagnosed as stage III or IV at the time of initial diagnosis, and despite the first-line aggressive treatment with surgery and platinum-based combination chemotherapy, the 5-year survival rate of stage III and IV is less than 25%. The improvement of new treatment for advanced ovarian cancer is of paramount importance. BRCA 1/2 gene is engaged in homologous recombination (HR), which is a major double-stranded DNA repair pathway. About 20% of high-grade serous ovarian carcinoma (HGSOC) harbor germline BRCA1/2 mutations, and about 50% of high-grade serous adenocarcinoma have somatic or germline mutations or epigenetic change in genes of HR DNA repair such as RAD51C, ATM, ATR, and FANCD2. Olaparib is an oral poly (ADP-ribose) polymerase inhibitor (PARPi) that inhibits single-stranded DNA damage repair. Olaparib has a significant clinical activity in BRCA1/2 mutation-associated breast and ovarian cancer, and also has activity in ovarian cancer. In the Study 19, maintenance therapy with olaparib significantly prolonged progression-free survival (PFS) versus placebo in patients with platinum-sensitive recurrent serous ovarian cancer. Moreover, subsequent phase 3 clinical trials show major improvement of prognosis in maintenance therapy by incorporating olaparib in a recurrent setting and recently in a first-line setting among patients with BRCA1/BRCA2 mutations. Furthermore, various combination treatment strategies such as other DNA damage response inhibitors such as ATR inhibitors, immune checkpoint inhibitors and molecular-targeted therapies such as VEGF inhibitors, has been examined to enhance the efficacy of PARP inhibitors. In this symposium, we discuss the current status and future perspectives of PARP inhibitors for ovarian cancer.