• M William Audeh, James Carmichael, Richard T Penson, Michael Friedlander, Bethan Powell, Katherine M Bell-McGuinn, Clare Scott, Jeffrey N Weitzel, Ana Oaknin, Niklas Loman, Karen Lu, Rita K Schmutzler, Ursula Matulonis, Mark Wickens, and Andrew Tutt.
• Samuel Oschin Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. william.audeh@cshs.org
• Lancet. 2010 Jul 24; 376 (9737): 245251245-51.

BackgroundOlaparib 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.MethodsIn this international, multicentre, phase 2 study, we enrolled two sequential cohorts of women (aged >or=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.FindingsPatients 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).InterpretationFindings 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.FundingAstraZeneca.Copyright 2010 Elsevier Ltd. All rights reserved.

26 keywords...

hide…