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3633 Background: Extensive molecular profiling in cancer regularly reveals targets for which approved drugs are available in tumor types outside the registered label. Efficacy of off-label use of these drugs is unavailable. Access to these drugs for pts is challenging. In the Drug Rediscovery Protocol (DRUP, Van der Velden et al, Nature 2019), pts are treated based on their tumor molecular profile. Here, we present the results of the successful cohort “Olaparib for tumors with BRCA1/2 alterations”. Methods: Twenty five adult cancer patients (pts) who exhausted all treatment options and had BRCA1/2 loss of function (LoF) mutations (found in routine diagnostics) were included. No pts were eligible for on-label treatment with PARP inhibitors. Pts were treated with olaparib until disease progression or unacceptable toxicity. The primary endpoint was clinical benefit (CB: objective response or stable disease (SD) ≥ 16 weeks). Pts were enrolled using a Simon-like two-stage model, with 8 pts in stage 1 and up to 24 pts in stage 2 if at least 1 pt had CB in stage 1. A fresh frozen biopsy was obtained from each pt for whole genome sequencing (WGS) and target confirmation. Results: Fourteen pts (56%) had CB. The objective response rate was 32%. Nine different cancer types were included: prostate (n=11), breast (n=4), ovarian (n=2), pancreatic (n=3), colorectal (n=2), biliary tract (n=2), kidney (n=1), adrenal gland (n=1) and endometrial (n=1). WGS could be performed on 58% of baseline tumor biopsies, confirming the original BRCA1/2 mutations in 86%. CB was observed in pts with both somatic and germline BRCA alterations and across tumor types. CB was only observed in cases with biallelic loss of BRCA1/2 in the tumor and when classified as HRD by a pan-cancer homologous recombination deficiency classifier (CHORD), which relies on genome-wide SNV, indel, and SV mutational footprints for HRD detection. No evidence of complete BRCA loss and HRD was observed in 5 pts with PD, while 4 patients with effective BRCA complete loss and HRD also had PD. WGS analysis of these pts suggested resistance mechanisms due to other oncogenic drivers (e.g FGFR1 amplification, CTNNB1 stabilization, KEAP1 inactivation). Conclusions: Olaparib seems to be an effective treatment option for pts with BRCA1/2 LoF mutated malignancies, regardless of histology, for both germline and somatic alterations, which needs confirmation in an independent cohort. CB of olaparib was observed in malignancies showing biallelic loss of BRCA1/2 and when classified as HRD, indicating the importance of the BRCA/HRD signature status. Clinical trial information: NCT02925234 .

TPS3149 Background: With the emergence of large-scale genetic tumor profiling and the increasing availability of approved targeted therapies, precision medicine has become crucial in cancer treatment. However, for many cancers the relative contribution of either tumor type or genetic aberration to drug sensitivity often remains unknown. Since drug access is generally limited to the on-label indication and outcome of off-label use is not systematically collected in clinical practice, innovative trials facilitating drug access, whilst systematically analyzing treatment outcomes, are urgently needed. Methods: The Drug Rediscovery Protocol (DRUP) is an ongoing, prospective, non-randomized, multi-drug, and pan-cancer trial, in which patients with advanced cancer, who have exhausted all standard of care treatment options, are treated with either targeted or immunotherapy matched to their genetic tumor profile. All submitted patients are reviewed and enrolled in multiple parallel cohorts, preceded by a baseline tumor biopsy for whole genome sequencing to confirm previously identified variants and for exploratory biomarker analyses. Each cohort is defined by a study drug, histologic tumor type, and molecular tumor profile. Efficacy is analyzed per cohort: 8 patients in stage I and 16 more in stage II if ≥ 1 response is observed in the first stage. Primary endpoints include objective response rate, stable disease at 16 weeks, and grade ≥3 adverse events. Since the start of recruitment in September 2016, 870 patients have been submitted for review and 365 patients (42%) have started treatment in one of 101 opened cohorts. Eight cohorts have graduated to the second stage, two cohorts completed accrual in either their first or second stage, and one cohort was closed due to a registered indication. Twenty-two different study treatments (i.e. immunotherapy, monoclonal antibodies, and PARP/small molecule inhibitors), provided by 11 different pharmaceutical companies, are currently available in DRUP. Data sharing with similar trials such as TAPUR and CAPTUR enables to achieve completion of slow accruing cohorts and affirm conclusions. Clinical trial information: NCT02925234.