57 Olaparib in patients with biallelic BRCA1/2 inactivation INTRODUCTION Homologous recombination repair (HRR) is a crucial DNA repair pathway, essential for the repair of DNA double strand breaks (DSB)1 that the genome is continuously subjected to2. It allows for error-free restoration of DNA integrity and sequence, even when the genomic damage is extensive. The breast cancer susceptibility genes BRCA1 and BRCA2 are two of the most extensively studied tumor suppressor genes and are key players in the HR pathway3. Deleterious alterations in BRCA1 or BRCA2, both germline4-6 and somatic7,8, result in deficient homologous recombination repair (dHRR)9,10 and a high risk of developing cancer. dHRR due to bi-allelic loss of function (LoF) mutations in BRCA1 or BRCA2 is seen in 4.9% of patients with cancer across tumor types11-13. Tumor cells with dHRR can be specifically targeted by drugs inducing multiple DNA strand breaks. Inhibitors of poly(ADP-ribose) polymerase (PARP) specifically target the weakness of dHRR tumor cells14-16 by synthetic lethality17,18 leading to selective cytotoxicity and apoptosis. Olaparib, an oral inhibitor of PARP1, is approved by the Food and Drug Administration (FDA) and European Medicines Agency (EMA) for several indications, among which the maintenance treatment of ovarian, fallopian tube and primary peritoneal cancer with germline or somatic BRCA mutations after response to first line platinum-based chemotherapy and, irrespective of BRCA-status, for recurrent ovarian, fallopian tube and primary peritoneal cancer after response to platinum-based chemotherapy. Olaparib was most recently approved as monotherapy for patients with metastatic castration-resistant prostate cancer with germline or somatic BRCA mutations (EMA) and mutations in other homologous repair deficiency (HRD) genes (FDA)1921. Several other PARP inhibitors have been registered for the treatment of epithelial ovarian, fallopian tube and primary peritoneal cancer (rucaparib22, niraparib23) and gBRCAm breast cancer (talazoparib)24. The majority of the phase II-III clinical trials performed focused on efficacy of PARPi monotherapy in BRCA-associated cancer types, often only based on the presence of a germline BRCA mutation, and lacking detailed biomarker information such as confirmation of bi-allelic BRCA LoF in tumor tissue. Data on the effectivity of PARPi in patients with somatic BRCA mutations are scarce. In the Drug Rediscovery Protocol (DRUP, NCT02925234)25 patients are being treated based on their tumor molecular profile with registered targeted treatments outside their labeled indications, systematically recording efficacy and safety data. Moreover, the DRUP creates opportunities for extensive biomarker analysis by performing whole genome sequencing (WGS) on baseline tumor biopsies. Within DRUP, we initiated a cohort in which patients were treated with olaparib based on a germline or somatic BRCA1 or BRCA2 loss of function (LoF) genomic event. Patients with a malignancy for which olaparib was not available as standard treatment were considered for this cohort. We hypothesized that a PARPi may be an effective 3
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