56 CHAPTER 3 ABSTRACT Purpose: To assess the efficacy of olaparib, a PARP inhibitor (PARPi) in patients with tumors with BRCA1/2 mutations, regardless of histological tumor type. Patients and methods: Patients with treatment-refractory BRCA1/2 mutated cancer were included for treatment with off-label olaparib 300 mg twice daily until disease progression or unacceptable toxicity. In DRUP, patients with treatment-refractory solid malignancies receive off-label 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 bi-allelic 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 bi-allelic 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. Conclusion: These data indicate that PARPi is a promising treatment strategy for patients with non-BRCA associated histologies harboring bi-allelic BRCA LoF. WGS allows to accurately detect complete LoF of BRCA and HRD signature as well as oncogenic drivers that may contribute to resistance, using a single assay.
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