Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial

Audeh, MW; Carmichael, J; Penson, RT; Friedlander, M; Powell, B; Bell-McGuinn, KM; Scott, C; Weitzel, JN; Oaknin, A; Loman, N; Lu, K; Schmutzler, RK; Matulonis, U; Wickens, M; Tutt, A

Author(s): Audeh, MW; Carmichael, J; Penson, RT; Friedlander, M; Powell, B; Bell-McGuinn, KM; Scott, C; Weitzel, JN; Oaknin, A; Loman, N; Lu, K; Schmutzler, RK; Matulonis, U; Wickens, M; Tutt, A;
Details: Publication Year 2010-07-24,Volume 376,Issue #9737,Page 245-251
Journal Title: LANCET
Publication Type: Journal Article
Abstract: 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%1; 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.
Publisher: ELSEVIER SCIENCE INC
Keywords: HOMOLOGY-DIRECTED REPAIR; MUTANT-CELLS; DNA-REPAIR; TUMORS; THERAPY; SENSITIVITY; DELETION; AZD2281; BREAKS; DEFECT
Publisher's Version: https://doi.org/10.1016/S0140-6736(10)60893-8
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Creation Date: 2010-07-24 12:00:00