Phase II study of olaparib for BRCAness phenotype in pancreatic cancer.

Abstract

297 Background: The subtype of pancreatic ductal adenocarcinoma cancer (PDAC) patients with DNA damage repair (DDR) deficiency from BRCA1/2 mutations has a favorable prognosis and is sensitive to platinum analogues and PARP inhibition. About 10-20% of PDAC patients have DDR deficiency without BRCA mutations (BRCA ness). The efficacy of olaparib in this population is unknown. Methods: Two parallel phases II trials (Israel and U.S.) are ongoing to determine the efficacy of olaparib in advanced PDAC with BRCA ness. Inclusion criteria: ≥ 1 prior systemic therapy for advanced PDAC, ECOG 0-1, germline BRCA 1/ 2 ( gBRCA) mutation negative, previously known DDR genetic aberrations (DDR-GA), family history of BRCA-associated cancers in ≥2 first-degree relatives (without DDR-GA), ATM loss by IHC (Israel only). Primary and secondary endpoints are objective response rate and PFS, respectively. With an type I error rate α of 0.1 and a β error rate of 0.2, and assuming P0 and P1 are 5% and 20%, respectively, study will enroll 24 patients at each site. Results: Thus far, 21 and 11 patients treated in Israel and U.S; respectively. DDR phenotype: Family history of BRCA cancer without DDR-GA (n = 14), DDR-GA (n = 12), ATM loss by IHC (n = 5). DDR-GAs were ATM (n = 6), PALB2 (n = 1), BRCA somatic (2), FANCB (1), PTEN (1) and CCNE1 (1). Efficacy data are in Table. Common toxicities were grade 1-2 anemia, fatigue and nausea. No responses were observed in platinum refractory cases. Conclusions: Olaparib was tolerated well in this study population. Olaparib showed encouraging initial antitumor activity in platinum-sensitive, gBRCA negative PDAC patients with DDR GA and in patients with family history of BRCA cancers (without identifiable DDR-GA). Clinical trial information: NCT02677038 ; NCT02511223. [Table: see text]