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dc.contributor.authorMateo, J
dc.contributor.authorCarreira, S
dc.contributor.authorSandhu, S
dc.contributor.authorMiranda, S
dc.contributor.authorMossop, H
dc.contributor.authorPerez-Lopez, R
dc.contributor.authorNava Rodrigues, D
dc.contributor.authorRobinson, D
dc.contributor.authorOmlin, A
dc.contributor.authorTunariu, N
dc.contributor.authorBoysen, G
dc.contributor.authorPorta, N
dc.contributor.authorFlohr, P
dc.contributor.authorGillman, A
dc.contributor.authorFigueiredo, I
dc.contributor.authorPaulding, C
dc.contributor.authorSeed, G
dc.contributor.authorJain, S
dc.contributor.authorRalph, C
dc.contributor.authorProtheroe, A
dc.contributor.authorHussain, S
dc.contributor.authorJones, R
dc.contributor.authorElliott, T
dc.contributor.authorMcGovern, U
dc.contributor.authorBianchini, D
dc.contributor.authorGoodall, J
dc.contributor.authorZafeiriou, Z
dc.contributor.authorWilliamson, CT
dc.contributor.authorFerraldeschi, R
dc.contributor.authorRiisnaes, R
dc.contributor.authorEbbs, B
dc.contributor.authorFowler, G
dc.contributor.authorRoda, D
dc.contributor.authorYuan, W
dc.contributor.authorWu, YM
dc.contributor.authorCao, X
dc.contributor.authorBrough, R
dc.contributor.authorPemberton, H
dc.contributor.authorA'Hern, R
dc.contributor.authorSwain, A
dc.contributor.authorKunju, LP
dc.contributor.authorEeles, R
dc.contributor.authorAttard, G
dc.contributor.authorLord, CJ
dc.contributor.authorAshworth, A
dc.contributor.authorRubin, MA
dc.contributor.authorKnudsen, KE
dc.contributor.authorFeng, FY
dc.contributor.authorChinnaiyan, AM
dc.contributor.authorHall, E
dc.contributor.authorde Bono, JS
dc.date.accessioned2016-10-26T16:24:31Z
dc.date.available2016-10-26T16:24:31Z
dc.identifier.citationThe New England journal of medicine, 2015, 373 (18), pp. 1697 - 1708
dc.identifier.issn0028-4793
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/188
dc.identifier.eissn1533-4406
dc.identifier.doi10.1056/nejmoa1506859
dc.description.abstractProstate cancer is a heterogeneous disease, but current treatments are not based on molecular stratification. We hypothesized that metastatic, castration-resistant prostate cancers with DNA-repair defects would respond to poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibition with olaparib.We conducted a phase 2 trial in which patients with metastatic, castration-resistant prostate cancer were treated with olaparib tablets at a dose of 400 mg twice a day. The primary end point was the response rate, defined either as an objective response according to Response Evaluation Criteria in Solid Tumors, version 1.1, or as a reduction of at least 50% in the prostate-specific antigen level or a confirmed reduction in the circulating tumor-cell count from 5 or more cells per 7.5 ml of blood to less than 5 cells per 7.5 ml. Targeted next-generation sequencing, exome and transcriptome analysis, and digital polymerase-chain-reaction testing were performed on samples from mandated tumor biopsies.Overall, 50 patients were enrolled; all had received prior treatment with docetaxel, 49 (98%) had received abiraterone or enzalutamide, and 29 (58%) had received cabazitaxel. Sixteen of 49 patients who could be evaluated had a response (33%; 95% confidence interval, 20 to 48), with 12 patients receiving the study treatment for more than 6 months. Next-generation sequencing identified homozygous deletions, deleterious mutations, or both in DNA-repair genes--including BRCA1/2, ATM, Fanconi's anemia genes, and CHEK2--in 16 of 49 patients who could be evaluated (33%). Of these 16 patients, 14 (88%) had a response to olaparib, including all 7 patients with BRCA2 loss (4 with biallelic somatic loss, and 3 with germline mutations) and 4 of 5 with ATM aberrations. The specificity of the biomarker suite was 94%. Anemia (in 10 of the 50 patients [20%]) and fatigue (in 6 [12%]) were the most common grade 3 or 4 adverse events, findings that are consistent with previous studies of olaparib.Treatment with the PARP inhibitor olaparib in patients whose prostate cancers were no longer responding to standard treatments and who had defects in DNA-repair genes led to a high response rate. (Funded by Cancer Research UK and others; ClinicalTrials.gov number, NCT01682772; Cancer Research UK number, CRUK/11/029.).
dc.formatPrint
dc.format.extent1697 - 1708
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://www.rioxx.net/licenses/all-rights-reserved
dc.subjectHumans
dc.subjectProstatic Neoplasms
dc.subjectNeoplasm Metastasis
dc.subjectAnemia
dc.subjectFatigue
dc.subjectPiperazines
dc.subjectPhthalazines
dc.subjectAntineoplastic Agents
dc.subjectEnzyme Inhibitors
dc.subjectDNA Repair
dc.subjectDrug Resistance, Neoplasm
dc.subjectMutation
dc.subjectGenes, Tumor Suppressor
dc.subjectGenes, BRCA2
dc.subjectAdult
dc.subjectAged
dc.subjectMiddle Aged
dc.subjectMale
dc.subjectAtaxia Telangiectasia Mutated Proteins
dc.subjectPoly(ADP-ribose) Polymerase Inhibitors
dc.titleDNA-Repair Defects and Olaparib in Metastatic Prostate Cancer.
dc.typeJournal Article
dcterms.dateAccepted2015-10-01
rioxxterms.versionAM
rioxxterms.versionofrecord10.1056/nejmoa1506859
rioxxterms.licenseref.urihttps://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfThe New England journal of medicine
pubs.issue18
pubs.notesNot known
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Gene Function
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology/Development & Cancer
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Cancer Biomarkers
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Cancer Biomarkers
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/ICR-CTSU Urology and Head and Neck Trials Team
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Genetics and Epidemiology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Genetics and Epidemiology/Oncogenetics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Development & Cancer
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Gene Function
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Treatment Resistance
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Oncogenetics
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Gene Function
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology/Development & Cancer
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Cancer Biomarkers
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Cancer Biomarkers
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/ICR-CTSU Urology and Head and Neck Trials Team
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Genetics and Epidemiology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Genetics and Epidemiology/Oncogenetics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Development & Cancer
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Gene Function
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Treatment Resistance
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Oncogenetics
pubs.volume373
pubs.embargo.termsNot known
icr.researchteamCancer Biomarkers
icr.researchteamICR-CTSU Urology and Head and Neck Trials Team
icr.researchteamDevelopment & Cancer
icr.researchteamGene Function
icr.researchteamTreatment Resistance
icr.researchteamOncogenetics
icr.researchteamCancer Biomarkersen_US
icr.researchteamICR-CTSU Urology and Head and Neck Trials Teamen_US
icr.researchteamDevelopment & Canceren_US
icr.researchteamGene Functionen_US
icr.researchteamTreatment Resistanceen_US
icr.researchteamOncogeneticsen_US


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