Patients with bi-allelic BRCA1/2 inactivation respond to olaparib treatment across histologic tumor types
van der Wijngaart, Hanneke; Hoes, Louisa R; van Berge Henegouwen, J Maxime; van der Velden, Daphne L; Zeverijn, Laurien J; Roepman, Paul; van Werkhoven, Erik; de Leng, Wendy W J; Jansen, Anne M L; Mehra, Niven; Robbrecht, Debbie G J; Labots, Mariette; de Groot, Derk Jan A; Hoeben, Ann; Hamberg, Paul; Gelderblom, Hans; Voest, Emile E; Verheul, Henk M W
(2021) Clinical cancer research : an official journal of the American Association for Cancer Research, volume 27, issue 22, pp. 6106 - 6114
(Article)
Abstract
Purpose: To assess the efficacy of olaparib, a PARP inhibitor (PARPi) in patients with tumors with BRCA1/2 mutations, regardless of histologic tumor type. Patients and Methods: Patients with treatment-refractory BRCA1/2-mutated cancer were included for treatment with offlabel olaparib 300 mg twice daily until disease progression or unacceptable toxicity. In Drug
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Rediscovery Protocol (DRUP), patients with treatment-refractory solid malignancies receive offlabel drugs based on tumor molecular profiles while whole-genome sequencing (WGS) is performed on baseline tumor biopsies. The primary endpoint was clinical benefit (CB; defined as objective response or stable disease ≥ 16 weeks according to RECIST 1.1). Per protocol patients were enrolled using a Simon-like two-stage model. Results: Twenty-four evaluable patients with nine different tumor types harboring BRCA1/2 mutations were included, 58% had CB from treatment with olaparib. CB was observed in patients with complete loss of function (LoF) of BRCA1/2, while 73% of patients with biallelic BRCA LoF had CB. In 17 patients with and seven without current labeled indication, 10 and four patients had CB, respectively. Treatment resistance in four patients with biallelic loss might be explained by an additional oncogenic driver which was discovered by WGS, including Wnt pathway activation, FGFR amplification, and CDKN2A loss, in three tumor types. Conclusions: These data indicate that using PARPis is a promising treatment strategy for patients with non-BRCA-associated histologies harboring biallelic BRCA LoF. WGS allows to accurately detect complete LoF of BRCA and homologous repair deficiency (HRD) signature as well as oncogenic drivers that may contribute to resistance, using a single assay.
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Keywords: Oncology, Cancer Research, Journal Article
ISSN: 1078-0432
Publisher: American Association for Cancer Research Inc.
Note: Funding Information: This Investigator Initiated study receives funding from the 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. Funding Information: This Investigator Initiated study receives funding from the 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. Publisher Copyright: © 2021 American Association for Cancer Research.
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