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dc.contributorVall d'Hebron Barcelona Hospital Campus
dc.contributor.authorMateo Valderrama, Joaquim
dc.contributor.authorPorta, Nuria
dc.contributor.authorBianchini, Diletta
dc.contributor.authorMcGovern, Ursula
dc.contributor.authorElliott, Tony
dc.contributor.authorJones, Robert
dc.date.accessioned2021-08-20T10:01:53Z
dc.date.available2021-08-20T10:01:53Z
dc.date.issued2020-01-01
dc.identifier.citationMateo J, Porta N, Bianchini D, McGovern U, Elliott T, Jones R, et al. Olaparib in patients with metastatic castration-resistant prostate cancer with DNA repair gene aberrations (TOPARP-B): a multicentre, open-label, randomised, phase 2 trial. Lancet Oncol. 2020 Jan;21(1):162-174.
dc.identifier.issn1474-5488
dc.identifier.urihttp://hdl.handle.net/11351/6228
dc.descriptionProstate cancer; Olaparib; Gene aberrations
dc.description.abstractBackground: 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.
dc.language.isoeng
dc.publisherElsevier
dc.relation.ispartofseriesThe Lancet Oncology;21(1)
dc.rightsAttribution 4.0 International
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.sourceScientia
dc.subjectMedicaments antineoplàstics - Ús terapèutic
dc.subjectPròstata - Càncer
dc.subjectADN - Reparació
dc.subject.meshProstatic Neoplasms, Castration-Resistant
dc.subject.mesh/drug therapy
dc.subject.meshDNA Repair
dc.titleOlaparib in patients with metastatic castration-resistant prostate cancer with DNA repair gene aberrations (TOPARP-B): a multicentre, open-label, randomised, phase 2 trial
dc.typeinfo:eu-repo/semantics/article
dc.identifier.doi10.1016/S1470-2045(19)30684-9
dc.subject.decsneoplasias prostáticas resistentes a la castración
dc.subject.decs/farmacoterapia
dc.subject.decsreparación del ADN
dc.relation.publishversionhttps://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(19)30684-9/fulltext
dc.type.versioninfo:eu-repo/semantics/publishedVersion
dc.audienceProfessionals
dc.contributor.organismesInstitut Català de la Salut
dc.contributor.authoraffiliation[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
dc.identifier.pmid31806540
dc.identifier.wos000505211900062
dc.rights.accessrightsinfo:eu-repo/semantics/openAccess


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