59 Olaparib in patients with biallelic BRCA1/2 inactivation by two independent clinical molecular biologists, assessing the actionability of the variant. Actionable variants were homozygous deletions and inactivating bi-allelic somatic mutations or inactivating germline mutations with LOH. They advised the study team on the driver likelihood, after which the decision to include the patient was made by the study team. For this cohort in DRUP, the general DRUP in- and exclusion criteria applied25. Additionally, patients were not eligible if they had previously been treated with a PARP inhibitor, if they were immunocompromised or if they had features suggestive of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Patients were considered evaluable for the primary endpoint if at least one cycle of olaparib was completed. Non-evaluable patients were excluded for the efficacy analysis, but included in the safety analysis. The study is conducted in accordance with the International Conference of Harmonization of Good Clinical Practice and the Declaration of Helsinki, and was approved by the independent ethics committee and by the institutional review boards in every participating hospital. Patients provided written informed consent upon enrollment. STUDY ENDPOINTS The primary end point of this study is the clinical benefit rate (CBR), defined as confirmed complete or partial response or stable disease for 16 weeks or more, according to RECIST 1.1 and measured at least twice, at least 28 days apart in a particular cohort. Tumor response was reported by the local investigator in the electronic case record form (eCRF). Tumor assessments were done at baseline and after every second treatment cycle. If patients were on treatment ≥ 6 months, tumor assessments were performed after every three cycles. Secondary endpoints include: objective response rate (ORR, defined as partial or complete response), duration of response, progression free survival (PFS), overall survival (OS) and treatment related CTCAE grade ≥ 3 adverse events. Exploratory endpoints include biomarker analysis on fresh frozen tumor biopsies. Safety is assessed by documentation of serious and study treatment-related grade ≥3 adverse events according to CTCAE v.4.03, and followed up until one month after the last dose of study drug. Safety within the trial is monitored by an Independent Data Monitoring Committee (IDMC) who is blinded for response rates per cohort during accrual. STATISTICAL ANALYSIS Cohorts are monitored using a Simon-like two-stage “admissible” monitoring plan28,29 to identify cohorts with evidence of activity. Clinical benefit (CB) of ≥ 30% is considered of sufficient clinical interest to warrant further study in a confirmatory expansion cohort (stage III within the DRUP30). The cohorts are evaluated in a two-stage design, if there would be 0 patients with CB in the first 8 participants in the cohort, the cohort would be closed. Otherwise, an additional 16 patients would be included in the cohort. Four or fewer patients with CB out of 3
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