TY - JOUR
T1 - Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer
T2 - A proof-of-concept trial
AU - Audeh, M. William
AU - Carmichael, James
AU - Penson, Richard T.
AU - Friedlander, Michael
AU - Powell, Bethan
AU - Bell-McGuinn, Katherine M.
AU - Scott, Clare
AU - Weitzel, Jeffrey N.
AU - Oaknin, Ana
AU - Loman, Niklas
AU - Lu, Karen
AU - Schmutzler, Rita K.
AU - Matulonis, Ursula
AU - Wickens, Mark
AU - Tutt, Andrew
N1 - Funding Information:
MWA has received honoraria for consultancy from AstraZeneca and Myriad Genetic Laboratories, and funding support for travel to investigators' meetings from AstraZeneca and to advisory board meetings from Myriad Genetic Laboratories. RTP has received honoraria and funding support for travel to investigators' meetings from AstraZeneca, and RTP's institution has received grants from AstraZeneca. MF has received honoraria as a clinical advisory board member and funding support for travel to investigators' meetings from AstraZeneca. BP's institution has received funding support for patient care, and BP has received funding support for travel to an investigators' meeting from AstraZeneca. KMB's institution has received study grants, and KMB has received funding support for travel to investigators' meetings from AstraZeneca. CS has received funding support for travel to investigators' meetings from AstraZeneca. NL's institution has received funding support for the conduct of the study and travel to investigators' meetings from AstraZeneca, and NL has received honoraria for lectures to patient groups that were organised and funded by AstraZeneca. RKS's institution has received fees to cover study expenses, and RKS has received funding support for travel to investigators' meetings from AstraZeneca. UM's institution has received fees to cover study expenses, and UM has received funding support for travel to investigators' meetings from AstraZeneca. MW and JC are employees of AstraZeneca, and JC has AstraZeneca stock options. AT has received a payment from the UK Institute of Cancer Research's rewards to inventors programme for work on use of PARP inhibitors to target cancers associated with BRCA1 and BRCA2 mutations, and has received funding support for travel to investigators' meetings and an honorarium for an academic lecture from AstraZeneca. AO, KL, and JNW declare that they have no conflicts of interest.
PY - 2010/7/1
Y1 - 2010/7/1
N2 - Background Olaparib is a novel, orally active poly(ADP-ribose) polymerase (PARP) inhibitor that induces synthetic lethality in homozygous BRCA-deficient cells. We aimed to assess the efficacy and safety of olaparib for treatment of advanced ovarian cancer in patients with BRCA1 or BRCA2 mutations. Methods In this international, multicentre, phase 2 study, we enrolled two sequential cohorts of women (aged ≥18 years) with confirmed genetic BRCA1 or BRCA2 mutations, and recurrent, measurable disease. The study was undertaken in 12 centres in Australia, Germany, Spain, Sweden, and the USA. The first cohort (n=33) was given continuous oral olaparib at the maximum tolerated dose of 400 mg twice daily, and the second cohort (n=24) was given continuous oral olaparib at 100 mg twice daily. The primary efficacy endpoint was objective response rate (ORR). This study is registered with ClinicalTrials.gov, number NCT00494442. Findings Patients had been given a median of three (range 1-16) previous chemotherapy regimens. ORR was 11 (33%) of 33 patients (95% CI 20-51) in the cohort assigned to olaparib 400 mg twice daily, and three (13%) of 24 (4-31) in the cohort assigned to 100 mg twice daily. In patients given olaparib 400 mg twice daily, the most frequent causally related adverse events were nausea (grade 1 or 2, 14 [42%]; grade 3 or 4, two [6%]), fatigue (grade 1 or 2, ten [30%]; grade 3 or 4, one [3%]), and anaemia (grade 1 or two, five [15%]; grade 3 or 4, one [3%]). The most frequent causally related adverse events in the cohort given 100 mg twice daily were nausea (grade 1 or 2, seven [29%]; grade 3 or 4, two [8%]) and fatigue (grade 1 or 2, nine [38%]; none grade 3 or 4). Interpretation Findings from this phase 2 study provide positive proof of concept of the efficacy and tolerability of genetically targeted treatment with olaparib in BRCA-mutated advanced ovarian cancer.
AB - Background Olaparib is a novel, orally active poly(ADP-ribose) polymerase (PARP) inhibitor that induces synthetic lethality in homozygous BRCA-deficient cells. We aimed to assess the efficacy and safety of olaparib for treatment of advanced ovarian cancer in patients with BRCA1 or BRCA2 mutations. Methods In this international, multicentre, phase 2 study, we enrolled two sequential cohorts of women (aged ≥18 years) with confirmed genetic BRCA1 or BRCA2 mutations, and recurrent, measurable disease. The study was undertaken in 12 centres in Australia, Germany, Spain, Sweden, and the USA. The first cohort (n=33) was given continuous oral olaparib at the maximum tolerated dose of 400 mg twice daily, and the second cohort (n=24) was given continuous oral olaparib at 100 mg twice daily. The primary efficacy endpoint was objective response rate (ORR). This study is registered with ClinicalTrials.gov, number NCT00494442. Findings Patients had been given a median of three (range 1-16) previous chemotherapy regimens. ORR was 11 (33%) of 33 patients (95% CI 20-51) in the cohort assigned to olaparib 400 mg twice daily, and three (13%) of 24 (4-31) in the cohort assigned to 100 mg twice daily. In patients given olaparib 400 mg twice daily, the most frequent causally related adverse events were nausea (grade 1 or 2, 14 [42%]; grade 3 or 4, two [6%]), fatigue (grade 1 or 2, ten [30%]; grade 3 or 4, one [3%]), and anaemia (grade 1 or two, five [15%]; grade 3 or 4, one [3%]). The most frequent causally related adverse events in the cohort given 100 mg twice daily were nausea (grade 1 or 2, seven [29%]; grade 3 or 4, two [8%]) and fatigue (grade 1 or 2, nine [38%]; none grade 3 or 4). Interpretation Findings from this phase 2 study provide positive proof of concept of the efficacy and tolerability of genetically targeted treatment with olaparib in BRCA-mutated advanced ovarian cancer.
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U2 - 10.1016/S0140-6736(10)60893-8
DO - 10.1016/S0140-6736(10)60893-8
M3 - Article
C2 - 20609468
AN - SCOPUS:77955039099
SN - 0140-6736
VL - 376
SP - 245
EP - 251
JO - The Lancet
JF - The Lancet
IS - 9737
ER -