dc.contributor.author | Mateo, J | |
dc.contributor.author | Carreira, S | |
dc.contributor.author | Sandhu, S | |
dc.contributor.author | Miranda, S | |
dc.contributor.author | Mossop, H | |
dc.contributor.author | Perez-Lopez, R | |
dc.contributor.author | Nava Rodrigues, D | |
dc.contributor.author | Robinson, D | |
dc.contributor.author | Omlin, A | |
dc.contributor.author | Tunariu, N | |
dc.contributor.author | Boysen, G | |
dc.contributor.author | Porta, N | |
dc.contributor.author | Flohr, P | |
dc.contributor.author | Gillman, A | |
dc.contributor.author | Figueiredo, I | |
dc.contributor.author | Paulding, C | |
dc.contributor.author | Seed, G | |
dc.contributor.author | Jain, S | |
dc.contributor.author | Ralph, C | |
dc.contributor.author | Protheroe, A | |
dc.contributor.author | Hussain, S | |
dc.contributor.author | Jones, R | |
dc.contributor.author | Elliott, T | |
dc.contributor.author | McGovern, U | |
dc.contributor.author | Bianchini, D | |
dc.contributor.author | Goodall, J | |
dc.contributor.author | Zafeiriou, Z | |
dc.contributor.author | Williamson, CT | |
dc.contributor.author | Ferraldeschi, R | |
dc.contributor.author | Riisnaes, R | |
dc.contributor.author | Ebbs, B | |
dc.contributor.author | Fowler, G | |
dc.contributor.author | Roda, D | |
dc.contributor.author | Yuan, W | |
dc.contributor.author | Wu, Y-M | |
dc.contributor.author | Cao, X | |
dc.contributor.author | Brough, R | |
dc.contributor.author | Pemberton, H | |
dc.contributor.author | A'Hern, R | |
dc.contributor.author | Swain, A | |
dc.contributor.author | Kunju, LP | |
dc.contributor.author | Eeles, R | |
dc.contributor.author | Attard, G | |
dc.contributor.author | Lord, CJ | |
dc.contributor.author | Ashworth, A | |
dc.contributor.author | Rubin, MA | |
dc.contributor.author | Knudsen, KE | |
dc.contributor.author | Feng, FY | |
dc.contributor.author | Chinnaiyan, AM | |
dc.contributor.author | Hall, E | |
dc.contributor.author | de Bono, JS | |
dc.date.accessioned | 2016-10-26T16:24:31Z | |
dc.date.available | 2016-10-26T16:24:31Z | |
dc.date.issued | 2015-10-29 | |
dc.identifier.citation | The New England journal of medicine, 2015, 373 (18), pp. 1697 - 1708 | |
dc.identifier.issn | 0028-4793 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/188 | |
dc.identifier.eissn | 1533-4406 | |
dc.identifier.doi | 10.1056/nejmoa1506859 | |
dc.description.abstract | BACKGROUND: Prostate 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.format | Print | |
dc.format.extent | 1697 - 1708 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | MASSACHUSETTS MEDICAL SOC | |
dc.rights.uri | https://www.rioxx.net/licenses/all-rights-reserved | |
dc.subject | Humans | |
dc.subject | Prostatic Neoplasms | |
dc.subject | Neoplasm Metastasis | |
dc.subject | Anemia | |
dc.subject | Fatigue | |
dc.subject | Piperazines | |
dc.subject | Phthalazines | |
dc.subject | Antineoplastic Agents | |
dc.subject | Enzyme Inhibitors | |
dc.subject | DNA Repair | |
dc.subject | Drug Resistance, Neoplasm | |
dc.subject | Mutation | |
dc.subject | Genes, Tumor Suppressor | |
dc.subject | Genes, BRCA2 | |
dc.subject | Adult | |
dc.subject | Aged | |
dc.subject | Middle Aged | |
dc.subject | Male | |
dc.subject | Ataxia Telangiectasia Mutated Proteins | |
dc.subject | Poly(ADP-ribose) Polymerase Inhibitors | |
dc.title | DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2015-10-01 | |
rioxxterms.version | AM | |
rioxxterms.versionofrecord | 10.1056/nejmoa1506859 | |
rioxxterms.licenseref.uri | https://www.rioxx.net/licenses/all-rights-reserved | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | The New England journal of medicine | |
pubs.issue | 18 | |
pubs.notes | Not 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.volume | 373 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Cancer Biomarkers | |
icr.researchteam | ICR-CTSU Urology and Head and Neck Trials Team | |
icr.researchteam | Development & Cancer | |
icr.researchteam | Gene Function | |
icr.researchteam | Treatment Resistance | |
icr.researchteam | Oncogenetics | |
icr.researchteam | Cancer Biomarkers | |
icr.researchteam | ICR-CTSU Urology and Head and Neck Trials Team | |
icr.researchteam | Development & Cancer | |
icr.researchteam | Gene Function | |
icr.researchteam | Treatment Resistance | |
icr.researchteam | Oncogenetics | |
dc.contributor.icrauthor | Carreira, Suzanne | |
dc.contributor.icrauthor | Miranda, Susana | |
dc.contributor.icrauthor | Nava Rodrigues, Daniel | |
dc.contributor.icrauthor | Porta, Nuria | |
dc.contributor.icrauthor | Gillman, Alexa | |
dc.contributor.icrauthor | Seed, George | |
dc.contributor.icrauthor | Goodall, Jane | |
dc.contributor.icrauthor | AHern, Roger | |
dc.contributor.icrauthor | Swain, Amanda | |
dc.contributor.icrauthor | Eeles, Rosalind | |
dc.contributor.icrauthor | Lord, Christopher | |
dc.contributor.icrauthor | Hall, Emma | |
dc.contributor.icrauthor | De Bono, Johann | |