69 Olaparib in patients with biallelic BRCA1/2 inactivation DRUP to study olaparib in BRCA1/2-mutated tumors. Based on our current findings and previous reports13, we have refined the qualifying biomarker to bi-allelic (somatic or germline) loss of function of BRCA1 or BRCA2, and only off-label tumor types (non-BRCA histologies) will be eligible. In this expansion cohort, the financial risk will be shared between the manufacturer of olaparib and the insurance companies. For the first 16 weeks of treatment, the study drug is provided by the manufacturer. Upon confirmation of clinical benefit at 16 weeks, the subsequent treatment will be reimbursed by the health care insurance on an individual basis while efficacy and safety data collection continues to ultimately support expansion of the existing labeled indications of the drug. CONCLUSION Olaparib is an effective treatment option for patients with cancer harboring somatic and germline deleterious BRCA1/2 alterations regardless of tumor type, who exhausted other treatment options. The CBR in this cohort was 58%, and CB was predominantly observed in patients harboring tumors with bi-allelic LoF of BRCA and HRD. In patients with non-BRCA associated tumor types, 57% had clinical benefit, suggesting PARPi as a promising treatment strategy and justifying a broad molecular diagnostic approach in all patients. In patients in this cohort who had complete LoF of BRCA and HRD in tumor tissue, but without clinical benefit of olaparib, another potential oncogenic driver was discovered by WGS. Further investigation and confirmation of this CBR in patients with non-BRCA histologies in an independent expansion cohort is warranted, and is currently in preparation within DRUP for patients with bi-allelic BRCA LoF. ACKNOWLEDGMENTS This Investigator Initiated study receives funding from the Dutch Cancer Society (KWF, grant number 10014/2016-1), Barcode for Life and receives equal funding from a number of pharmaceutical companies, among which AstraZeneca. Whole genome sequencing was performed free of charge at the Hartwig Medical Foundation. Study medication was made available free of charge by the manufacturer. 3
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