Homologous Recombination Repair Gene Mutation Characterization by Liquid Biopsy: A Phase II Trial of Olaparib and Abiraterone in Metastatic Castrate-Resistant Prostate Cancer

Background: Phase III randomized trial data have confirmed the activity for olaparib in homologous recombination repair (HRR) mutated metastatic castration-resistant prostate cancer (mCRPC) post next-generation hormonal agent (NHA) progression. Preclinical data have suggested the potential for a com...

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Autores principales:	T. Hedley Carr, Carrie Adelman, Alan Barnicle, Iwanka Kozarewa, Sally Luke, Zhongwu Lai, Sally Hollis, Brian Dougherty, Elizabeth A. Harrington, Jinyu Kang, Fred Saad, Nuria Sala, Antoine Thiery-Vuillemin, Noel W. Clarke, Darren Hodgson, J. Carl Barrett
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	circulating tumour DNA (ctDNA) homologous recombination repair (HRR) prostate cancer next-generation sequencing (NGS) PARP inhibition metastasis Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/2776c1f382124ec398a96cb11dcfff23
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spelling	oai:doaj.org-article:2776c1f382124ec398a96cb11dcfff232021-11-25T17:04:31ZHomologous Recombination Repair Gene Mutation Characterization by Liquid Biopsy: A Phase II Trial of Olaparib and Abiraterone in Metastatic Castrate-Resistant Prostate Cancer10.3390/cancers132258302072-6694https://doaj.org/article/2776c1f382124ec398a96cb11dcfff232021-11-01T00:00:00Zhttps://www.mdpi.com/2072-6694/13/22/5830https://doaj.org/toc/2072-6694Background: Phase III randomized trial data have confirmed the activity for olaparib in homologous recombination repair (HRR) mutated metastatic castration-resistant prostate cancer (mCRPC) post next-generation hormonal agent (NHA) progression. Preclinical data have suggested the potential for a combined effect between olaparib and NHAs irrespective of whether an HRR gene alteration was present. NCT01972217 was a randomised double-blind Phase II study which evaluated olaparib and abiraterone versus placebo and abiraterone in mCRPC patients who had received prior chemotherapy containing docetaxel. The study showed that radiologic progression was significantly delayed by the combination of olaparib and abiraterone regardless of homologous recombination repair mutation (HRRm) status. The study utilized tumour, blood (germline), and circulating tumour DNA (ctDNA) analysis to profile patient HRRm status, but tumour tissue provision was not mandated, leading to relatively low tissue acquisition and DNA sequencing success rates not representative of real-world testing. Patients and methods: Further analysis of germline and ctDNA samples has been performed for the trial to characterize HRRm status more fully and robustly analyse patient response to treatment. Results: Germline and plasma testing increased the HRRm characterized population from 27% to 68% of 142 randomized patients. Tumour-derived variants were detectable with high confidence in 78% of patients with a baseline plasma sample (71% of randomized patients). There was high concordance across methodologies (plasma vs. tumour; plasma vs. germline). The HR for the exploratory analysis of radiographic progression-free survival was 0.54 (95% CI: 0.32–0.93) in favour of olaparib and abiraterone in the updated HRR wild type (HRRwt) group (<i>n</i> = 73) and 0.62 (95% CI: 0.23–1.65) in the HRRm group (<i>n</i> = 23). Conclusion: Our results confirm the value of plasma testing for HRRm status when there is insufficient high-quality tissue for multi-gene molecular testing. We show that patients with mCRPC benefit from the combination of olaparib and abiraterone treatment regardless of HRRm status. The combination is currently being further investigated in the Phase III PROpel trial.T. Hedley CarrCarrie AdelmanAlan BarnicleIwanka KozarewaSally LukeZhongwu LaiSally HollisBrian DoughertyElizabeth A. HarringtonJinyu KangFred SaadNuria SalaAntoine Thiery-VuilleminNoel W. ClarkeDarren HodgsonJ. Carl BarrettMDPI AGarticlecirculating tumour DNA (ctDNA)homologous recombination repair (HRR)prostate cancernext-generation sequencing (NGS)PARP inhibitionmetastasisNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENCancers, Vol 13, Iss 5830, p 5830 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	circulating tumour DNA (ctDNA) homologous recombination repair (HRR) prostate cancer next-generation sequencing (NGS) PARP inhibition metastasis Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	circulating tumour DNA (ctDNA) homologous recombination repair (HRR) prostate cancer next-generation sequencing (NGS) PARP inhibition metastasis Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 T. Hedley Carr Carrie Adelman Alan Barnicle Iwanka Kozarewa Sally Luke Zhongwu Lai Sally Hollis Brian Dougherty Elizabeth A. Harrington Jinyu Kang Fred Saad Nuria Sala Antoine Thiery-Vuillemin Noel W. Clarke Darren Hodgson J. Carl Barrett Homologous Recombination Repair Gene Mutation Characterization by Liquid Biopsy: A Phase II Trial of Olaparib and Abiraterone in Metastatic Castrate-Resistant Prostate Cancer
description	Background: Phase III randomized trial data have confirmed the activity for olaparib in homologous recombination repair (HRR) mutated metastatic castration-resistant prostate cancer (mCRPC) post next-generation hormonal agent (NHA) progression. Preclinical data have suggested the potential for a combined effect between olaparib and NHAs irrespective of whether an HRR gene alteration was present. NCT01972217 was a randomised double-blind Phase II study which evaluated olaparib and abiraterone versus placebo and abiraterone in mCRPC patients who had received prior chemotherapy containing docetaxel. The study showed that radiologic progression was significantly delayed by the combination of olaparib and abiraterone regardless of homologous recombination repair mutation (HRRm) status. The study utilized tumour, blood (germline), and circulating tumour DNA (ctDNA) analysis to profile patient HRRm status, but tumour tissue provision was not mandated, leading to relatively low tissue acquisition and DNA sequencing success rates not representative of real-world testing. Patients and methods: Further analysis of germline and ctDNA samples has been performed for the trial to characterize HRRm status more fully and robustly analyse patient response to treatment. Results: Germline and plasma testing increased the HRRm characterized population from 27% to 68% of 142 randomized patients. Tumour-derived variants were detectable with high confidence in 78% of patients with a baseline plasma sample (71% of randomized patients). There was high concordance across methodologies (plasma vs. tumour; plasma vs. germline). The HR for the exploratory analysis of radiographic progression-free survival was 0.54 (95% CI: 0.32–0.93) in favour of olaparib and abiraterone in the updated HRR wild type (HRRwt) group (<i>n</i> = 73) and 0.62 (95% CI: 0.23–1.65) in the HRRm group (<i>n</i> = 23). Conclusion: Our results confirm the value of plasma testing for HRRm status when there is insufficient high-quality tissue for multi-gene molecular testing. We show that patients with mCRPC benefit from the combination of olaparib and abiraterone treatment regardless of HRRm status. The combination is currently being further investigated in the Phase III PROpel trial.
format	article
author	T. Hedley Carr Carrie Adelman Alan Barnicle Iwanka Kozarewa Sally Luke Zhongwu Lai Sally Hollis Brian Dougherty Elizabeth A. Harrington Jinyu Kang Fred Saad Nuria Sala Antoine Thiery-Vuillemin Noel W. Clarke Darren Hodgson J. Carl Barrett
author_facet	T. Hedley Carr Carrie Adelman Alan Barnicle Iwanka Kozarewa Sally Luke Zhongwu Lai Sally Hollis Brian Dougherty Elizabeth A. Harrington Jinyu Kang Fred Saad Nuria Sala Antoine Thiery-Vuillemin Noel W. Clarke Darren Hodgson J. Carl Barrett
author_sort	T. Hedley Carr
title	Homologous Recombination Repair Gene Mutation Characterization by Liquid Biopsy: A Phase II Trial of Olaparib and Abiraterone in Metastatic Castrate-Resistant Prostate Cancer
title_short	Homologous Recombination Repair Gene Mutation Characterization by Liquid Biopsy: A Phase II Trial of Olaparib and Abiraterone in Metastatic Castrate-Resistant Prostate Cancer
title_full	Homologous Recombination Repair Gene Mutation Characterization by Liquid Biopsy: A Phase II Trial of Olaparib and Abiraterone in Metastatic Castrate-Resistant Prostate Cancer
title_fullStr	Homologous Recombination Repair Gene Mutation Characterization by Liquid Biopsy: A Phase II Trial of Olaparib and Abiraterone in Metastatic Castrate-Resistant Prostate Cancer
title_full_unstemmed	Homologous Recombination Repair Gene Mutation Characterization by Liquid Biopsy: A Phase II Trial of Olaparib and Abiraterone in Metastatic Castrate-Resistant Prostate Cancer
title_sort	homologous recombination repair gene mutation characterization by liquid biopsy: a phase ii trial of olaparib and abiraterone in metastatic castrate-resistant prostate cancer
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/2776c1f382124ec398a96cb11dcfff23
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Homologous Recombination Repair Gene Mutation Characterization by Liquid Biopsy: A Phase II Trial of Olaparib and Abiraterone in Metastatic Castrate-Resistant Prostate Cancer

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