Olaparib in patients with metastatic castration-resistant prostate cancer with DNA repair gene aberrations (TOPARP-B): a multicentre, open-label, randomised, phase 2 trial

Prostate cancer; Olaparib; Gene aberrations

Detalles Bibliográficos
Autores: Mateo Valderrama, Joaquim, Porta, Nuria, Bianchini, Diletta, McGovern, Ursula, Elliott, Tony, Jones, Robert
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2020
País:España
Institución:Departament de Salut de la Generalitat de Catalunya (DS)
Repositorio:Scientia. Dipòsit d'Informació Digital del Departament de Salut
OAI Identifier:oai:scientiasalut.gencat.cat:11351/6228
Acceso en línea:https://hdl.handle.net/11351/6228
Access Level:acceso abierto
Palabra clave:Medicaments antineoplàstics - Ús terapèutic
Pròstata - Càncer
ADN - Reparació
DISEASES::Neoplasms::Neoplasms by Site::Urogenital Neoplasms::Genital Neoplasms, Male::Prostatic Neoplasms::Prostatic Neoplasms, Castration-Resistant
Other subheadings::Other subheadings::Other subheadings::/drug therapy
PHENOMENA AND PROCESSES::Genetic Phenomena::DNA Repair
ENFERMEDADES::neoplasias::neoplasias por localización::neoplasias urogenitales::neoplasias de los genitales masculinos::neoplasias de la próstata::neoplasias prostáticas resistentes a la castración
Otros calificadores::Otros calificadores::Otros calificadores::/farmacoterapia
FENÓMENOS Y PROCESOS::fenómenos genéticos::reparación del ADN
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oai_identifier_str oai:scientiasalut.gencat.cat:11351/6228
network_acronym_str ES
network_name_str España
repository_id_str
dc.title.none.fl_str_mv Olaparib in patients with metastatic castration-resistant prostate cancer with DNA repair gene aberrations (TOPARP-B): a multicentre, open-label, randomised, phase 2 trial
title Olaparib in patients with metastatic castration-resistant prostate cancer with DNA repair gene aberrations (TOPARP-B): a multicentre, open-label, randomised, phase 2 trial
spellingShingle Olaparib in patients with metastatic castration-resistant prostate cancer with DNA repair gene aberrations (TOPARP-B): a multicentre, open-label, randomised, phase 2 trial
Mateo Valderrama, Joaquim
Medicaments antineoplàstics - Ús terapèutic
Pròstata - Càncer
ADN - Reparació
DISEASES::Neoplasms::Neoplasms by Site::Urogenital Neoplasms::Genital Neoplasms, Male::Prostatic Neoplasms::Prostatic Neoplasms, Castration-Resistant
Other subheadings::Other subheadings::Other subheadings::/drug therapy
PHENOMENA AND PROCESSES::Genetic Phenomena::DNA Repair
ENFERMEDADES::neoplasias::neoplasias por localización::neoplasias urogenitales::neoplasias de los genitales masculinos::neoplasias de la próstata::neoplasias prostáticas resistentes a la castración
Otros calificadores::Otros calificadores::Otros calificadores::/farmacoterapia
FENÓMENOS Y PROCESOS::fenómenos genéticos::reparación del ADN
title_short Olaparib in patients with metastatic castration-resistant prostate cancer with DNA repair gene aberrations (TOPARP-B): a multicentre, open-label, randomised, phase 2 trial
title_full Olaparib in patients with metastatic castration-resistant prostate cancer with DNA repair gene aberrations (TOPARP-B): a multicentre, open-label, randomised, phase 2 trial
title_fullStr Olaparib in patients with metastatic castration-resistant prostate cancer with DNA repair gene aberrations (TOPARP-B): a multicentre, open-label, randomised, phase 2 trial
title_full_unstemmed Olaparib in patients with metastatic castration-resistant prostate cancer with DNA repair gene aberrations (TOPARP-B): a multicentre, open-label, randomised, phase 2 trial
title_sort Olaparib in patients with metastatic castration-resistant prostate cancer with DNA repair gene aberrations (TOPARP-B): a multicentre, open-label, randomised, phase 2 trial
dc.creator.none.fl_str_mv Mateo Valderrama, Joaquim
Porta, Nuria
Bianchini, Diletta
McGovern, Ursula
Elliott, Tony
Jones, Robert
author Mateo Valderrama, Joaquim
author_facet Mateo Valderrama, Joaquim
Porta, Nuria
Bianchini, Diletta
McGovern, Ursula
Elliott, Tony
Jones, Robert
author_role author
author2 Porta, Nuria
Bianchini, Diletta
McGovern, Ursula
Elliott, Tony
Jones, Robert
author2_role author
author
author
author
author
dc.contributor.none.fl_str_mv Institut Català de la Salut
[Mateo J] The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, UK. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Porta N] The Institute of Cancer Research, London, UK. [Bianchini D] The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, UK. [McGovern U] University College Hospital, University College London Hospitals NHS Foundation Trust, London, UK. [Elliott T] The Christie NHS Foundation Trust, Manchester, UK. [Jones R] University of Glasgow and Beatson West of Scotland Cancer Centre, Glasgow, UK
Vall d'Hebron Barcelona Hospital Campus
dc.subject.none.fl_str_mv Medicaments antineoplàstics - Ús terapèutic
Pròstata - Càncer
ADN - Reparació
DISEASES::Neoplasms::Neoplasms by Site::Urogenital Neoplasms::Genital Neoplasms, Male::Prostatic Neoplasms::Prostatic Neoplasms, Castration-Resistant
Other subheadings::Other subheadings::Other subheadings::/drug therapy
PHENOMENA AND PROCESSES::Genetic Phenomena::DNA Repair
ENFERMEDADES::neoplasias::neoplasias por localización::neoplasias urogenitales::neoplasias de los genitales masculinos::neoplasias de la próstata::neoplasias prostáticas resistentes a la castración
Otros calificadores::Otros calificadores::Otros calificadores::/farmacoterapia
FENÓMENOS Y PROCESOS::fenómenos genéticos::reparación del ADN
topic Medicaments antineoplàstics - Ús terapèutic
Pròstata - Càncer
ADN - Reparació
DISEASES::Neoplasms::Neoplasms by Site::Urogenital Neoplasms::Genital Neoplasms, Male::Prostatic Neoplasms::Prostatic Neoplasms, Castration-Resistant
Other subheadings::Other subheadings::Other subheadings::/drug therapy
PHENOMENA AND PROCESSES::Genetic Phenomena::DNA Repair
ENFERMEDADES::neoplasias::neoplasias por localización::neoplasias urogenitales::neoplasias de los genitales masculinos::neoplasias de la próstata::neoplasias prostáticas resistentes a la castración
Otros calificadores::Otros calificadores::Otros calificadores::/farmacoterapia
FENÓMENOS Y PROCESOS::fenómenos genéticos::reparación del ADN
description Prostate cancer; Olaparib; Gene aberrations
publishDate 2020
dc.date.none.fl_str_mv 2020
2021
2021
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/11351/6228
url https://hdl.handle.net/11351/6228
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv The Lancet Oncology;21(1)
https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(19)30684-9/fulltext
dc.rights.none.fl_str_mv Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv Scientia
reponame:Scientia. Dipòsit d'Informació Digital del Departament de Salut
instname:Departament de Salut de la Generalitat de Catalunya (DS)
instname_str Departament de Salut de la Generalitat de Catalunya (DS)
reponame_str Scientia. Dipòsit d'Informació Digital del Departament de Salut
collection Scientia. Dipòsit d'Informació Digital del Departament de Salut
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869412175505784832
spelling Olaparib in patients with metastatic castration-resistant prostate cancer with DNA repair gene aberrations (TOPARP-B): a multicentre, open-label, randomised, phase 2 trialMateo Valderrama, JoaquimPorta, NuriaBianchini, DilettaMcGovern, UrsulaElliott, TonyJones, RobertMedicaments antineoplàstics - Ús terapèuticPròstata - CàncerADN - ReparacióDISEASES::Neoplasms::Neoplasms by Site::Urogenital Neoplasms::Genital Neoplasms, Male::Prostatic Neoplasms::Prostatic Neoplasms, Castration-ResistantOther subheadings::Other subheadings::Other subheadings::/drug therapyPHENOMENA AND PROCESSES::Genetic Phenomena::DNA RepairENFERMEDADES::neoplasias::neoplasias por localización::neoplasias urogenitales::neoplasias de los genitales masculinos::neoplasias de la próstata::neoplasias prostáticas resistentes a la castraciónOtros calificadores::Otros calificadores::Otros calificadores::/farmacoterapiaFENÓMENOS Y PROCESOS::fenómenos genéticos::reparación del ADNProstate cancer; Olaparib; Gene aberrationsCàncer de pròstata; Olaparib; Aberracions de gensCáncer de próstata; Olaparib; Aberraciones de genesBackground: Metastatic castration-resistant prostate cancer is enriched in DNA damage response (DDR) gene aberrations. The TOPARP-B trial aims to prospectively validate the association between DDR gene aberrations and response to olaparib in metastatic castration-resistant prostate cancer. Methods: In this open-label, investigator-initiated, randomised phase 2 trial following a selection (or pick-the-winner) design, we recruited participants from 17 UK hospitals. Men aged 18 years or older with progressing metastatic castration-resistant prostate cancer previously treated with one or two taxane chemotherapy regimens and with an Eastern Cooperative Oncology Group performance status of 2 or less had tumour biopsies tested with targeted sequencing. Patients with DDR gene aberrations were randomly assigned (1:1) by a computer-generated minimisation method, with balancing for circulating tumour cell count at screening, to receive 400 mg or 300 mg olaparib twice daily, given continuously in 4-week cycles until disease progression or unacceptable toxicity. Neither participants nor investigators were masked to dose allocation. The primary endpoint of confirmed response was defined as a composite of all patients presenting with any of the following outcomes: radiological objective response (as assessed by Response Evaluation Criteria in Solid Tumors 1.1), a decrease in prostate-specific antigen (PSA) of 50% or more (PSA50) from baseline, or conversion of circulating tumour cell count (from ≥5 cells per 7·5 mL blood at baseline to <5 cells per 7·5 mL blood). A confirmed response in a consecutive assessment after at least 4 weeks was required for each component. The primary analysis was done in the evaluable population. If at least 19 (43%) of 44 evaluable patients in a dose cohort responded, then the dose cohort would be considered successful. Safety was assessed in all patients who received at least one dose of olaparib. This trial is registered at ClinicalTrials.gov, NCT01682772. Recruitment for the trial has completed and follow-up is ongoing. Findings: 711 patients consented for targeted screening between April 1, 2015, and Aug 30, 2018. 161 patients had DDR gene aberrations, 98 of whom were randomly assigned and treated (49 patients for each olaparib dose), with 92 evaluable for the primary endpoint (46 patients for each olaparib dose). Median follow-up was 24·8 months (IQR 16·7-35·9). Confirmed composite response was achieved in 25 (54·3%; 95% CI 39·0-69·1) of 46 evaluable patients in the 400 mg cohort, and 18 (39·1%; 25·1-54·6) of 46 evaluable patients in the 300 mg cohort. Radiological response was achieved in eight (24·2%; 11·1-42·3) of 33 evaluable patients in the 400 mg cohort and six (16·2%; 6·2-32·0) of 37 in the 300 mg cohort; PSA50 response was achieved in 17 (37·0%; 23·2-52·5) of 46 and 13 (30·2%; 17·2-46·1) of 43; and circulating tumour cell count conversion was achieved in 15 (53·6%; 33·9-72·5) of 28 and 13 (48·1%; 28·7-68·1) of 27. The most common grade 3-4 adverse event in both cohorts was anaemia (15 [31%] of 49 patients in the 300 mg cohort and 18 [37%] of 49 in the 400 mg cohort). 19 serious adverse reactions were reported in 13 patients. One death possibly related to treatment (myocardial infarction) occurred after 11 days of treatment in the 300 mg cohort. Interpretation: Olaparib has antitumour activity against metastatic castration-resistant prostate cancer with DDR gene aberrations, supporting the implementation of genomic stratification of metastatic castration-resistant prostate cancer in clinical practice.Cancer Research UK, AstraZeneca, Prostate Cancer UK, the Prostate Cancer Foundation, the Experimental Cancer Medicine Centres Network, and the National Institute for Health Research Biomedical Research Centres.ElsevierInstitut Català de la Salut[Mateo J] The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, UK. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Porta N] The Institute of Cancer Research, London, UK. [Bianchini D] The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, UK. [McGovern U] University College Hospital, University College London Hospitals NHS Foundation Trust, London, UK. [Elliott T] The Christie NHS Foundation Trust, Manchester, UK. [Jones R] University of Glasgow and Beatson West of Scotland Cancer Centre, Glasgow, UKVall d'Hebron Barcelona Hospital Campus202120212020info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/11351/6228Scientiareponame:Scientia. Dipòsit d'Informació Digital del Departament de Salutinstname:Departament de Salut de la Generalitat de Catalunya (DS)InglésThe Lancet Oncology;21(1)https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(19)30684-9/fulltextAttribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:scientiasalut.gencat.cat:11351/62282026-06-12T09:38:37Z
score 15,81155

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