Abstract IA01: PARP inhibitors as single agents and in combinations for ovarian cancer: What lies ahead?

Abstract

Abstract Poly (ADP ribose) polymerase (PARP) inhibitors are an exciting and promising new class of anticancer drugs. Initial clinical trials of PARP inhibitors began over a decade ago following the discovery that PARP inhibitors in vitro had heightened anticancer activity in BRCA mutated cancer cells compared to BRCA wild-type cells. PARP inhibitor clinical development has taken several strategies, including single-agent and combination testing. Single-agent PARP inhibitors have been used as either primary treatment of recurrent ovarian cancer or as maintenance treatment following anticancer response after platinum-based chemotherapy. Three PARP inhibitors are now FDA approved for recurrent ovarian cancer, all as single agents: 1) olaparib for patients with recurrent germline BRCA mutated ovarian cancer who have received 3 or more prior lines of chemotherapy and also as maintenance therapy post-platinum therapy for patients with platinum sensitive recurrence who are in response to platinum-based chemotherapy and regardless of BRCA or tumor HR status; 2) rucaparib for patients with BRCA mutated ovarian cancer (either deleterious tumor or germline mutation) who have received at least 2 prior lines of chemotherapy; and 3) niraparib for platinum-sensitive recurrent ovarian cancer patients as maintenance therapy who are in response to platinum-based chemotherapy and regardless of BRCA or tumor HR status. Because of the myelosuppression observed with PARP inhibitors, combining these agents with chemotherapy has been difficult and has required lowering the doses of either the PARP inhibitor and/or the chemotherapy agents and often abbreviating the treatment schedule; several negative phase III studies have been reported. Combining PARP inhibitors with biologic agents is another strategy currently being tested in clinical trials and one that avoids overlapping toxicities. The combination of the PARP inhibitor olaparib and the antivascular endothelial growth factor receptor agent cediranib has shown promising phase II results against olaparib alone, especially in BRCA wild-type ovarian cancer. These results have led to phase III studies comparing the olaparib and cediranib combination to standard therapies (NCT02502266 and NCT02446600). Other studies are under way testing PARP inhibitors with other biologic agents such as immunotherapy agents and other targeted agents such as ATR inhibitors, PI3 kinase inhibitors, and heat shock protein 90 inhibitors. Citation Format: Ursula A. Matulonis. PARP inhibitors as single agents and in combinations for ovarian cancer: What lies ahead? [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr IA01.