Abstract CT159: Olaparib combinations (OLAPCO)for homology-directed DNA repairdefects (HDR)

Abstract

Abstract INTRODUCTION: Genetic profiling of tumors used to identify treatment choices for cancer patients focus on kinase mutations and well-defined translocations; multiple clinical trials have been initiated for specific kinase-targeted agents. About 15-20% of patients have actionable mutations. HDR have been found in ~ 20 % of patient tumors molecularly profiled at the Yale Cancer Center. Mutations in HDR related genes often occur in addition to other mutations in signaling pathways. Specific targeted treatment options for these patients are limited, as breast and ovarian cancer mutations are the only indication for the HDR pathway targeted PARP inhibitors. Additional drugs are in development, but few clinical studies based on HDR other than BRCA1/2 mutations are open. METHODS: The OLAPCO study targets HDR in patients irrespective of tumor origin. The protocol includes four arms to which patients can be enrolled based on tumor profiling results: olaparib monotherapy (PARP inhibitor) for HDR; olaparib & AZD5363 ( AKT inhibitor) for PIK3CA/AKT/PTEN pathway dysregulation and ARID1A mutations; olaparib & AZD1775 ( wee1 inhibitor) for TP53 mutations and olaparib & AZD6738 (ATR inhibitor) for HDR and olaparib pre-treated patients. The clinical endpoints are to determine tumor overall response rate (ORR) and clinical benefit rate (CBR) by RECIST after 16 weeks of treatment. RESULTS: Arms a and b are open to patient accrual. Together, 34 pts have been treated, 12 remain on treatment, with no new or > Gr 2 (CTCAE4) treatment-related toxicities. TABLE 1Olaparib total = 23; median # cycles= 2, range 1-10+ ; 7 ongoingMutationATMBRCA1IDH1/2FHPALB2CHK2BAP1ARID 1A#52821212ORR1 PRCBR10201000TABLE 2Olaparib & AZD 5363 total = 12; median # cycles = 2, range 1-8+; 5 ongoingMutationAKT1AKT3AKT2 & PALB2ARID 1AARID 1A & PIK3CAPTEN#321411ORR1CBR10101 DISCUSSION: HDR defects are actionable mutations, increasing the number of patients for whom tumor profiling can identify a therapeutic option. This exploratory trial is expanding the therapeutic spectrum of olaparib alone and in combination, to include heretofore non-canonical alterations in HDR, beyond BRCA1/2. This trial design allows additional molecular targets, agents & combinations to be rapidly evaluated. AstraZeneca support is gratefully acknowledged. Citation Format: Joseph P. Eder, Geoffrey I. Shapiro, James M. Cleary, Vickie L. Keedy, Vickie L. Keedy, Ranjit Bindra, Brian Shuch, Jeffrey Sklar, Khanh Do, Juliane Juergensmeier. Olaparib combinations (OLAPCO)for homology-directed DNA repairdefects (HDR) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT159.