Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, non-randomised study.

Abstract

BACKGROUND:

Olaparib (AZD2281) is a small-molecule, potent oral poly(ADP-ribose) polymerase (PARP) inhibitor. We aimed to assess the safety and tolerability of this drug in patients without BRCA1 or BRCA2 mutations with advanced triple-negative breast cancer or high-grade serous and/or undifferentiated ovarian cancer.

METHODS:

In this phase 2, multicentre, open-label, non-randomised study, women with advanced high-grade serous and/or undifferentiated ovarian carcinoma or triple-negative breast cancer were enrolled and received olaparib 400 mg twice a day. Patients were stratified according to whether they had a BRCA1 or BRCA2 mutation or not. The primary endpoint was objective response rate by Response Evaluation Criteria In Solid Tumors (RECIST). All patients who received treatment were included in the analysis of toxic effects, and patients who had measurable lesions at baseline were included in the primary efficacy analysis. This trial is registered at ClinicalTrials.gov, number NCT00679783.

FINDINGS:

91 patients were enrolled (65 with ovarian cancer and 26 breast cancer) and 90 were treated between July 8, 2008, and Sept 24, 2009. In the ovarian cancer cohorts, 64 patients received treatment. 63 patients had target lesions and therefore were evaluable for objective response as per RECIST. In these patients, confirmed objective responses were seen in seven (41%; 95% CI 22-64) of 17 patients with BRCA1 or BRCA2 mutations and 11 (24%; 14-38) of 46 without mutations. No confirmed objective responses were reported in patients with breast cancer. The most common adverse events were fatigue (45 [70%] of patients with ovarian cancer, 13 [50%] of patients with breast cancer), nausea (42 [66%] and 16 [62%]), vomiting (25 [39%] and nine [35%]), and decreased appetite (23 [36%] and seven [27%]).

INTERPRETATION:

Our study suggests that olaparib is a promising treatment for women with ovarian cancer and further assessment of the drug in clinical trials is needed.

FUNDING:

AstraZeneca.

• Authors: Karen A Gelmon, Marc Tischkowitz, Helen Mackay, Kenneth Swenerton, André Robidoux, Katia Tonkin, Hal Hirte, David Huntsman, Mark Clemons, Blake Gilks, Rinat Yerushalmi, Euan Macpherson, James Carmichael, Amit Oza
• Journal: The Lancet. Oncology (Lancet Oncol) Vol. 12 Issue 9 Pg. 852-61 (Sep 2011) ISSN: 1474-5488 [Electronic] England
• PMID: 21862407 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents
• BRCA1 Protein
• BRCA1 protein, human
• BRCA2 Protein
• BRCA2 protein, human
• Biomarkers, Tumor
• Enzyme Inhibitors
• Phthalazines
• Piperazines
• Poly(ADP-ribose) Polymerase Inhibitors
• Receptors, Estrogen
• Receptors, Progesterone
• Poly(ADP-ribose) Polymerases
• ERBB2 protein, human
• Receptor, ErbB-2
• olaparib

Topics

• Administration, Oral
• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Agents (administration & dosage, adverse effects, therapeutic use)
• BRCA1 Protein (genetics)
• BRCA2 Protein (genetics)
• Biomarkers, Tumor (analysis)
• Breast Neoplasms (chemistry, drug therapy, enzymology, genetics, mortality, pathology)
• Canada
• Carcinoma (drug therapy, enzymology, genetics, mortality, secondary)
• Cell Differentiation
• Disease-Free Survival
• Enzyme Inhibitors (administration & dosage, adverse effects, therapeutic use)
• Female
• Humans
• Kaplan-Meier Estimate
• Middle Aged
• Mutation
• Neoplasm Recurrence, Local
• Ovarian Neoplasms (drug therapy, enzymology, genetics, mortality, pathology)
• Phthalazines (administration & dosage, adverse effects, therapeutic use)
• Piperazines (administration & dosage, adverse effects, therapeutic use)
• Poly(ADP-ribose) Polymerase Inhibitors
• Poly(ADP-ribose) Polymerases (metabolism)
• Receptor, ErbB-2 (analysis)
• Receptors, Estrogen (analysis)
• Receptors, Progesterone (analysis)
• Time Factors
• Treatment Outcome