58 CHAPTER 3 treatment option for patients with malignant tumors harboring BRCA12 LoF mutations, both germline and somatic , independent of histology. Here, we show that PARPi is a potentially effective treatment strategy for patients with complete LoF of BRCA1/2 in the DRUP cohort of 24 patients “Olaparib for tumors with a BRCA1/2 mutation”. The importance of WGS, performed on baseline biopsies, is demonstrated by the correlation between complete LoF of BRCA1/2 and clinical benefit from olaparib. WGS provides information on both germline and somatic mutations, and genomic mutational signatures, allowing for optimal patient selection using a single assay. PATIENTS AND METHODS STUDY DESIGN The Drug Rediscovery Protocol (DRUP) is an ongoing prospective, multicenter, non-randomized basket trial in which patients with advanced solid malignancies are being treated based on their tumor molecular profile, with targeted- or immunotherapy outside their registered indications25. The basket trial design allows for an unlimited number of parallel cohorts consisting of patients with the same histological tumor type, molecular target (defined at gene level) and study drug. Patients enrolled in the histology-agnostic cohort “Olaparib for tumors with a BRCA1 or BRCA2 mutation” received olaparib tablets 300 mg twice daily26 in 28-day cycles until occurrence of disease progression or intolerable side effects. Dose reductions were allowed up to a minimum dose of 200 mg twice daily. Patients were enrolled in nine out of the 32 DRUP-participating hospitals in the Netherlands, between September 2016 and October 2019. To date, accrual in other cohorts of the DRUP is still ongoing. This study is registered with ClinicalTrials.gov, number NCT02925234. PATIENTS Adult patients with advanced solid malignancies, for which standard treatment options were exhausted, and with no option for on-label or phase III study treatment with PARPi, were enrolled. Expansion of the reimbursed indications of olaparib during the course of the trial resulted in exclusion of patients with the new “on-label” histologies from that moment on. Patients with those histologies who were already enrolled in DRUP were not excluded, but continued treatment within the trial and were included in the efficacy analysis. Pre-enrollment, patients needed to have a pathogenic, inactivating BRCA1 or BRCA2 mutation or deletion confirmed in their tumor tissue, identified using any validated genetic test within the context of routine diagnostics or using WGS in the context of the Dutch CPCT-02 study27. At the start of the trial, confirmation of bi-allelic LoF of BRCA was not a requirement for eligibility yet. During the course of the trial, literature emerged reporting on the importance of complete LoF for response to PARP inhibitors. Therefore, we added bi-allelic LoF of BRCA as a second requirement for eligibility in this cohort. In all submitted cases, the variant was reviewed
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