PMID- 20609467
OWN - NLM
STAT- MEDLINE
DCOM- 20100817
LR  - 20220413
IS  - 1474-547X (Electronic)
IS  - 0140-6736 (Linking)
VI  - 376
IP  - 9737
DP  - 2010 Jul 24
TI  - Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or 
      BRCA2 mutations and advanced breast cancer: a proof-of-concept trial.
PG  - 235-44
LID - 10.1016/S0140-6736(10)60892-6 [doi]
AB  - BACKGROUND: 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.
CI  - Copyright 2010 Elsevier Ltd. All rights reserved.
FAU - Tutt, Andrew
AU  - Tutt A
AD  - Breakthrough Breast Cancer Research Unit, Guy's Hospital Campus, King's College 
      London School of Medicine, London, UK. andrew.tutt@icr.ac.uk
FAU - Robson, Mark
AU  - Robson M
FAU - Garber, Judy E
AU  - Garber JE
FAU - Domchek, Susan M
AU  - Domchek SM
FAU - Audeh, M William
AU  - Audeh MW
FAU - Weitzel, Jeffrey N
AU  - Weitzel JN
FAU - Friedlander, Michael
AU  - Friedlander M
FAU - Arun, Banu
AU  - Arun B
FAU - Loman, Niklas
AU  - Loman N
FAU - Schmutzler, Rita K
AU  - Schmutzler RK
FAU - Wardley, Andrew
AU  - Wardley A
FAU - Mitchell, Gillian
AU  - Mitchell G
FAU - Earl, Helena
AU  - Earl H
FAU - Wickens, Mark
AU  - Wickens M
FAU - Carmichael, James
AU  - Carmichael J
LA  - eng
SI  - ClinicalTrials.gov/NCT00494234
PT  - Clinical Trial, Phase II
PT  - Journal Article
PT  - Multicenter Study
PT  - Research Support, Non-U.S. Gov't
DEP - 20100706
PL  - England
TA  - Lancet
JT  - Lancet (London, England)
JID - 2985213R
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Phthalazines)
RN  - 0 (Piperazines)
RN  - 0 (Poly(ADP-ribose) Polymerase Inhibitors)
RN  - WOH1JD9AR8 (olaparib)
SB  - IM
CIN - Lancet. 2010 Jul 24;376(9737):211-3. PMID: 20656109
CIN - Nat Rev Clin Oncol. 2010 Oct;7(10):549. PMID: 20922827
CIN - Biomark Med. 2010 Dec;4(6):792-3. PMID: 21188745
MH  - Adult
MH  - Aged
MH  - Antineoplastic Agents/*therapeutic use
MH  - Breast Neoplasms/*drug therapy/*genetics/pathology
MH  - Female
MH  - Genes, BRCA1
MH  - Genes, BRCA2
MH  - Germ-Line Mutation
MH  - Humans
MH  - Maximum Tolerated Dose
MH  - Middle Aged
MH  - Phthalazines/*therapeutic use
MH  - Piperazines/*therapeutic use
MH  - *Poly(ADP-ribose) Polymerase Inhibitors
MH  - Prospective Studies
EDAT- 2010/07/09 06:00
MHDA- 2010/08/18 06:00
CRDT- 2010/07/09 06:00
PHST- 2010/07/09 06:00 [entrez]
PHST- 2010/07/09 06:00 [pubmed]
PHST- 2010/08/18 06:00 [medline]
AID - S0140-6736(10)60892-6 [pii]
AID - 10.1016/S0140-6736(10)60892-6 [doi]
PST - ppublish
SO  - Lancet. 2010 Jul 24;376(9737):235-44. doi: 10.1016/S0140-6736(10)60892-6. Epub 
      2010 Jul 6.