Abstract PR06: Targeted chemotherapy for Homologous Repair Defects (HRD) in molecularly profiled cancer patients
Authors: Eder Joseph Paul , McLaughlin Joseph F. , Sklar Jeffrey , Walther Zenta , Finberg Karin , Minnella Alexandra , Juergensmeier Juliane M. 
Published: April 2017

Precision Medicine Tumor Boards (PMTB) are now established at many academic institutions and provide a forum for multidisciplinary teams to discuss tumor profiling results to aid treatment choices for cancer patients. PMTBs typically focus on kinase mutations and well defined translocations, mostly because of limited gene panels explored. Established treatments exist for some of these genetic aberrations and multiple clinical trials have been initiated for specific kinase-targeted investigational drugs in development.

The Yale 409 Gene Panel (Ion Torrent; AmpliSeq Comprehensive Cancer Panel) includes a large set of Homologous Recombinant Deficiencies (HRD) related genes. HRD have been found in ~ 25 % of patient tumors molecularly profiled at the Yale Cancer Center PMTB. Mutations in HRD related genes often occur in addition to other mutations in signaling pathways, including many kinases. Specific targeted treatment options for these patients are limited, as currently only one drug, olaparib, is approved for patients with BRCA1/2 mutations in serous ovarian cancer. A number of other drugs are in development, but few clinical studies based on HRD other than BRCA1/2 mutations are open and HRD related genes are not always part of the cancer mutation panels that are the basis for PMTBs.

The OLAParib COmbinations (OLAPCO) study was designed to develop therapeutic protocols for HRD in patients, irrespective of tumor origin. The protocol includes four initial arms, to which patients can be enrolled based on their tumor profiling results: a. olaparib monotherapy (PARP inhibitor) for HRD in the DNA damage recognition/response and homologous repair pathways, b. olaparib & AZD5363 (an AKT1 inhibitor) for PTEN/ PI3K/AKT pathway dysregulation, c. olaparib & AZD1775 (a wee1 inhibitor) for TP53 mutations and d. olaparib & AZD2014 (vistusertib, a mTOR inhibitor) for TSC1/2, TORC1/2 or LKB1 mutations. The clinical endpoints are to determine tumor overall response rate (ORR) and clinical benefit rate (CBR) in molecularly selected patients with measurable disease as assessed by the Response Evaluation Criteria in Solid Tumors (RECIST), before versus after 16 weeks of treatment. Translational endpoints are to correlate CBR associated with additional defects in DNA repair pathways as measured by genetic aberrations in the tumors, to compare genetic variants/mutations measured in tumor tissue in diagnostic archival specimen at baseline and on progression (when samples available), and correlate with tumor response and clinical benefit and to determine tumor mutations in ctDNA at baseline, on treatment, and at progression. The statistical design allows for early termination of ineffective arms and to focus on specific pathways or specific mutations that demonstrate efficacy. Ten patients have been enrolled to date in the two currently open arms of the study and results on these and additional patients will be updated.

This abstract is also being presented as Poster A41

Citation Format: Joseph Paul Eder, Joseph F. McLaughlin, Jeffrey Sklar, Zenta Walther, Karin Finberg, Alexandra Minnella, Juliane M. Juergensmeier. Targeted chemotherapy for Homologous Repair Defects (HRD) in molecularly profiled cancer patients [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montreal, QC, Canada. Philadelphia (PA): AACR; Mol Cancer Res 2017;15(4_Suppl):Abstract nr PR06.