Details

Autor(en) / Beteiligte

• 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

Titel

Patients with Biallelic BRCA1/2 Inactivation Respond to Olaparib Treatment Across Histologic Tumor Types

Ist Teil von

• Clinical cancer research, 2021-11, Vol.27 (22), p.6106-6114

Ort / Verlag

United States

Erscheinungsjahr

2021

Quelle

MEDLINE

Beschreibungen/Notizen

• To assess the efficacy of olaparib, a PARP inhibitor (PARPi) in patients with tumors with mutations, regardless of histologic tumor type. Patients with treatment-refractory mutated cancer were included for treatment with off-label olaparib 300 mg twice daily until disease progression or unacceptable toxicity. In Drug Rediscovery Protocol (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. Twenty-four evaluable patients with nine different tumor types harboring mutations were included, 58% had CB from treatment with olaparib. CB was observed in patients with complete loss of function (LoF) of , while 73% of patients with biallelic 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, amplification, and loss, in three tumor types. These data indicate that using PARPis is a promising treatment strategy for patients with non- -associated histologies harboring biallelic LoF. WGS allows to accurately detect complete LoF of and homologous repair deficiency (HRD) signature as well as oncogenic drivers that may contribute to resistance, using a single assay.