TY - JOUR
T1 - Patients with Biallelic BRCA1/2 Inactivation respond to Olaparib treatment across Histologic tumor types
AU - Van Der Wijngaart, Hanneke
AU - Hoes, Louisa R.
AU - Van Berge Henegouwen, J. Maxime
AU - Van Der Velden, Daphne L.
AU - Zeverijn, Laurien J.
AU - Roepman, Paul
AU - Van Werkhoven, Erik
AU - De Leng, Wendy W.J.
AU - Jansen, Anne M.L.
AU - Mehra, Niven
AU - Robbrecht, Debbie G.J.
AU - Labots, Mariette
AU - De Groot, Derk Jan A.
AU - Hoeben, Ann
AU - Hamberg, Paul
AU - Gelderblom, Hans
AU - Voest, Emile E.
AU - Verheul, Henk M.W.
N1 - 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: J.M. van Berge Henegouwen reports personal fees from AstraZeneca outside the submitted work. W.W.J. de Leng reports grants from Roche, BMS, and Pfizer and personal fees from Janssen outside the submitted work. N. Mehra reports grants and personal fees from AstraZeneca during the conduct of the study; grants, personal fees, and other support from MSD and Astellas; grants and personal fees from Roche, Janssen-Cilag, Pfizer, and BMS; and personal fees from Bayer outside the submitted work. M. Labots reports other support from Bristol Myers Squibb outside the submitted work. E.E. Voest reports grants from AstraZeneca during the conduct of the study and grants from AstraZeneca outside the submitted work. No disclosures were reported by the other authors. 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.
PY - 2021/11/15
Y1 - 2021/11/15
N2 - 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 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.
AB - 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 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.
UR - http://www.scopus.com/inward/record.url?scp=85119927163&partnerID=8YFLogxK
U2 - https://doi.org/10.1158/1078-0432.CCR-21-1104
DO - https://doi.org/10.1158/1078-0432.CCR-21-1104
M3 - Article
C2 - 34475104
SN - 1078-0432
VL - 27
SP - 6106
EP - 6114
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 22
ER -