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dc.contributor.authorTutt, Andrew
dc.contributor.authorRobson, Mark
dc.contributor.authorGarber, Judy E
dc.contributor.authorDomchek, Susan M
dc.contributor.authorAudeh, M William
dc.contributor.authorWeitzel, Jeffrey N
dc.contributor.authorFriedlander, Michael
dc.contributor.authorArun, Banu
dc.contributor.authorLoman, Niklas
dc.contributor.authorSchmutzler, Rita K
dc.contributor.authorWardley, Andrew M
dc.contributor.authorMitchell, Gillian
dc.contributor.authorEarl, Helena
dc.contributor.authorWickens, Mark
dc.contributor.authorCarmichael, James
dc.date.accessioned2010-09-14T10:04:15Z
dc.date.available2010-09-14T10:04:15Z
dc.date.issued2010-07-24
dc.identifier.citationOral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial. 2010, 376 (9737):235-44 Lanceten
dc.identifier.issn1474-547X
dc.identifier.pmid20609467
dc.identifier.doi10.1016/S0140-6736(10)60892-6
dc.identifier.urihttp://hdl.handle.net/10541/111116
dc.description.abstractBACKGROUND: Olaparib, a novel, orally active poly(ADP-ribose) polymerase (PARP) inhibitor, induced synthetic lethality in BRCA-deficient cells. A maximum tolerated dose and initial signal of efficacy in BRCA-deficient ovarian cancers have been reported. We therefore assessed the efficacy, safety, and tolerability of olaparib alone in women with BRCA1 or BRCA2 mutations and advanced breast cancer. METHODS: Women (aged >or=18 years) with confirmed BRCA1 or BRCA2 mutations and recurrent, advanced breast cancer were assigned to two sequential cohorts in a phase 2 study undertaken in 16 centres in Australia, Germany, Spain, Sweden, the UK, and the USA. The first cohort (n=27) was given continuous oral olaparib at the maximum tolerated dose (400 mg twice daily), and the second (n=27) was given a lower dose (100 mg twice daily). The primary efficacy endpoint was objective response rate (ORR). This study is registered with ClinicalTrials.gov, number NCT00494234. FINDINGS: Patients had been given a median of three previous chemotherapy regimens (range 1-5 in cohort 1, and 2-4 in cohort 2). ORR was 11 (41%) of 27 patients (95% CI 25-59) in the cohort assigned to 400 mg twice daily, and six (22%) of 27 (11-41) in the cohort assigned to 100 mg twice daily. Toxicities were mainly at low grades. The most frequent causally related adverse events in the cohort given 400 mg twice daily were fatigue (grade 1 or 2, 11 [41%]; grade 3 or 4, four [15%]), nausea (grade 1 or 2, 11 [41%]; grade 3 or 4, four [15%]), vomiting (grade 1 or 2, three [11%]; grade 3 or 4, three [11%]), and anaemia (grade 1 or 2, one [4%]; grade 3 or 4, three [11%]). The most frequent causally related adverse events in the cohort given 100 mg twice daily were nausea (grade 1 or 2, 11 [41%]; none grade 3 or 4) and fatigue (grade 1 or 2, seven [26%]; grade 3 or 4, one [4%]). INTERPRETATION: The results of this study provide positive proof of concept for PARP inhibition in BRCA-deficient breast cancers and shows a favourable therapeutic index for a novel targeted treatment strategy in patients with tumours that have genetic loss of function of BRCA1-associated or BRCA2-associated DNA repair. Toxicity in women with BRCA1 and BRCA2 mutations was similar to that reported previously in those without such mutations. FUNDING: AstraZeneca.
dc.language.isoenen
dc.subjectAnticancerous Agentsen
dc.subjectBreast Canceren
dc.subject.meshAdult
dc.subject.meshAged
dc.subject.meshAntineoplastic Agents
dc.subject.meshBreast Neoplasms
dc.subject.meshFemale
dc.subject.meshGenes, BRCA1
dc.subject.meshGenes, BRCA2
dc.subject.meshGerm-Line Mutation
dc.subject.meshHumans
dc.subject.meshMaximum Tolerated Dose
dc.subject.meshMiddle Aged
dc.subject.meshPhthalazines
dc.subject.meshPiperazines
dc.subject.meshPoly(ADP-ribose) Polymerases
dc.subject.meshProspective Studies
dc.titleOral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial.en
dc.typeArticleen
dc.contributor.departmentBreakthrough Breast Cancer Research Unit, Guy's Hospital Campus, King's College London School of Medicine, London, UK. andrew.tutt@icr.ac.uken
dc.identifier.journalLanceten
html.description.abstractBACKGROUND: Olaparib, a novel, orally active poly(ADP-ribose) polymerase (PARP) inhibitor, induced synthetic lethality in BRCA-deficient cells. A maximum tolerated dose and initial signal of efficacy in BRCA-deficient ovarian cancers have been reported. We therefore assessed the efficacy, safety, and tolerability of olaparib alone in women with BRCA1 or BRCA2 mutations and advanced breast cancer. METHODS: Women (aged >or=18 years) with confirmed BRCA1 or BRCA2 mutations and recurrent, advanced breast cancer were assigned to two sequential cohorts in a phase 2 study undertaken in 16 centres in Australia, Germany, Spain, Sweden, the UK, and the USA. The first cohort (n=27) was given continuous oral olaparib at the maximum tolerated dose (400 mg twice daily), and the second (n=27) was given a lower dose (100 mg twice daily). The primary efficacy endpoint was objective response rate (ORR). This study is registered with ClinicalTrials.gov, number NCT00494234. FINDINGS: Patients had been given a median of three previous chemotherapy regimens (range 1-5 in cohort 1, and 2-4 in cohort 2). ORR was 11 (41%) of 27 patients (95% CI 25-59) in the cohort assigned to 400 mg twice daily, and six (22%) of 27 (11-41) in the cohort assigned to 100 mg twice daily. Toxicities were mainly at low grades. The most frequent causally related adverse events in the cohort given 400 mg twice daily were fatigue (grade 1 or 2, 11 [41%]; grade 3 or 4, four [15%]), nausea (grade 1 or 2, 11 [41%]; grade 3 or 4, four [15%]), vomiting (grade 1 or 2, three [11%]; grade 3 or 4, three [11%]), and anaemia (grade 1 or 2, one [4%]; grade 3 or 4, three [11%]). The most frequent causally related adverse events in the cohort given 100 mg twice daily were nausea (grade 1 or 2, 11 [41%]; none grade 3 or 4) and fatigue (grade 1 or 2, seven [26%]; grade 3 or 4, one [4%]). INTERPRETATION: The results of this study provide positive proof of concept for PARP inhibition in BRCA-deficient breast cancers and shows a favourable therapeutic index for a novel targeted treatment strategy in patients with tumours that have genetic loss of function of BRCA1-associated or BRCA2-associated DNA repair. Toxicity in women with BRCA1 and BRCA2 mutations was similar to that reported previously in those without such mutations. FUNDING: AstraZeneca.


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