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

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 >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.

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.

FUNDING:

AstraZeneca.

• Authors: 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, Andrew Tutt
• Journal: Lancet (London, England) (Lancet) Vol. 376 Issue 9737 Pg. 245-51 (Jul 24 2010) ISSN: 1474-547X [Electronic] England
• PMID: 20609468 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2010 Elsevier Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents
• Phthalazines
• Piperazines
• Poly(ADP-ribose) Polymerase Inhibitors
• olaparib

Topics

• Adult
• Aged
• Antineoplastic Agents (therapeutic use)
• Female
• Genes, BRCA1
• Genes, BRCA2
• Germ-Line Mutation
• Humans
• Maximum Tolerated Dose
• Middle Aged
• Neoplasm Recurrence, Local (drug therapy)
• Ovarian Neoplasms (drug therapy, genetics, pathology)
• Phthalazines (therapeutic use)
• Piperazines (therapeutic use)
• Poly(ADP-ribose) Polymerase Inhibitors
• Prospective Studies