ISY-5-2 - HBOC management in PARP inhibitor development: Japanese perspective

Abstract

BRCA1 and BRCA2 mutations are responsible genes which give an autosomal-dominant inherited trait predisposing women to both breast cancer (BC) and ovarian cancer (OC). We call the BRCA deficient disease group as hereditary BC and OC (HBOC). Poly (ADP-ribose) polymerase (PARP) is one of the enzymes which involved in DNA-damage repair. PARP inhibition produce synthetic lethal in BRCA1/2 mutated tumors with defective DNA repair via homologous recombination. Phase I and II clinical trials show that PARP inhibitors have shown promising activity in patients with HBOC patients. Olaparib, an oral, small molecule, PARP inhibitor, has recently been the approved for ovarian cancer therapy by the FDA and EMA. An Indication is maintenance treatment of adult patients with platinum-sensitive relapsed BRCA-mutated high-grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete response or partial response to platinum-based chemotherapy. Phase III trial of olaparib vs. placebo in patients with the similar population with standard first line treatment, combining with platinum-Taxane chemotherapy and bevacizumab has just started (PAOLA). For BRCA-mutated breast cancer, phase III trials are ongoing in the adjuvant (OlympiA) and metastatic settings (OlympiAD). Some triple negative breast cancer (TNBC) has similar biological characteristics with HBOC, including high grade, p53 mutation, EGFR or cytokeratin 5/6 positive, chemo-sensitivity. Combination phase I/II study of olaparib with eribulin mesylate, a novel microtubule, for advanced TNBC has been conducted as investigator initiated trial in Japan. Currently, multiple PARPis are in various stages of clinical development, including in combination with other treatment modalities such as radiation, molecular targeted agents, and cytotoxic chemotherapies. In this session, I am going to focus the future strategy of the PARP inhibitors and clinical management of HBOC.