Olaparib in Patients With BRCA Mutated Platinum-Sensitive Relapsed Serous Ovarian Cancer: New Data Presented at ASCO
CHICAGO--(BUSINESS WIRE)-- A retrospective subgroup analysis of a Phase II study (Study 19) shows the effect that an investigational drug, olaparib, has on progression-free survival (PFS) compared with placebo in platinum-sensitive relapsed serous ovarian cancer patients with BRCA mutations.
Study 19 was a randomized, double-blinded Phase II clinical trial evaluating the efficacy and safety of olaparib 400mg twice daily maintenance therapy compared with placebo in 265 platinum-sensitive, relapsed, high grade serous ovarian cancer patients who had received two or more previous platinum regimens and who were in a partial or complete response following their last platinum-containing regimen. The primary endpoint was PFS. Results from the full study population, first presented at American Society of Clinical Oncology (ASCO) 2011 and later published in the New England Journal of Medicine (NEJM) in 2012, showed that olaparib maintenance therapy significantly extended PFS compared with placebo (HR=0.35;95% CI 0.25-0.49 P<0.001, median PFS 8.4 vs. 4.8 months), however an interim overall survival (OS) analysis did not detect a benefit for olaparib compared with placebo (HR=0.94; 95% CI, 0.63 - 1.39 P<0.75).
The initial pre-planned subgroup analysis of PFS and OS in patients with a BRCA mutation suggested an improved outcome compared to the overall study population. However, mutation status was known for only a minority of patients in the study (36.6%) at that time and additional biomarker work was therefore conducted to further investigate this signal. BRCA mutation status was subsequently determined for patients from either blood samples (taken pre-randomization) and/or archival tumor samples and BRCA mutation status was eventually documented for 254 (96%) of the 265 patients in Study 19 confirming that 136 (51%) patients in the study had a BRCA mutation (BRCAm).
Retrospective results, in the total BRCAm population showed that olaparib maintenance therapy prolonged PFS compared with placebo (HR 0.18; 95% CI 0.11-0.31; p<0.00001, median PFS 11.2 vs 4.3 months). This result was statistically significant. A second interim analysis of OS for olaparib (58% maturity) in the BRCAm group did not demonstrate a statistical significant difference between the two arms. A numerical advantage on the olaparib arm compared with placebo was observed (HR 0.74; 95% CI 0.46-1.19, p=0.21; median OS 34.9 mo vs. 31.9 mo). 23% of the BRCAm patients who received placebo (14/62) subsequently received a PARP inhibitor, potentially confounding the OS data in this subgroup.
The most common adverse reactions occurring more frequently in the BRCAm patients treating with olaparib were low grade nausea, fatigue, vomiting and anemia, similar to those seen in patients without BRCA mutations.
Jonathan Ledermann, MD, UCL Cancer Institute, University College London and lead study investigator, said: "These are encouraging results for patients with ovarian cancer who carry a BRCA mutation. The statistically significant seven month difference in progression-free survival in the subgroup of patients with a BRCA mutation supports the hypothesis that a personalized therapeutic approach based on BRCA mutation status could preferentially benefit this patient population. This warrants further investigation of olaparib in a Phase III clinical trial."
BRCA are human genes that belong to a type of genes known as tumor suppressors. Mutation of these genes has been linked to hereditary breast and ovarian cancer and a woman's risk of developing breast and/or ovarian cancer is greatly increased if she inherits a BRCA1 or BRCA2 mutation. Only 15% of ovarian cancers are found before the cancer has spread outside the ovary. Despite advances in treatment and diagnosis, for patients with ovarian cancer that has spread beyond the ovary, the 5-year survival rate is well below 50%.
As a result of these Phase II data, AstraZeneca has announced that it is developing Phase III clinical trial program to further evaluate olaparib in BRCA mutated ovarian cancer. AstraZeneca has submitted a Letter of Intent to file for approval with the European Medicines Agency for olaparib in ovarian cancer patients with BRCA mutations.
Jane Robertson, Global Product Vice President for olaparib at AstraZeneca, said: "We are committed to conducting further studies of olaparib in patients with BRCA mutated tumors and to assessing its full potential in these and other cancers. We look forward to continuing to work with our collaborators and partners to strengthen our understanding of which patients are likely to benefit most from olaparib through a program of translational science and pre-clinical research."
Additional olaparib data to be presented at ASCO 2013 include:
Abstract #4013 - Olaparib plus paclitaxel in patients with recurrent or metastatic gastric cancer: A randomized, double-blind phase II study (Study 39)
Abstract #2579 - Phase I study of olaparib in combination with carboplatin and/or paclitaxel in patients with advanced solid tumors. (Study 4)
Abstract #11024 - Olaparib monotherapy in patients with advanced cancer and a germ-line BRCA1/2 mutation: An open-label phase II study. (Study 42)
NOTES TO EDITORS
About Study 19
Study 19 is a randomized, double-blind Phase II clinical trial to evaluate the efficacy of olaparib maintenance therapy compared to placebo in platinum-sensitive, relapsed, high grade serous ovarian cancer patients.
Results from the full study population were first presented at ASCO 2011 and were published in NEJM in 2012.
Olaparib is an innovative, potential first-in-class oral poly ADP ribose polymerase (PARP) inhibitor that has been shown in pre-clinical models to exploit DNA repair pathway deficiencies to preferentially kill cancer cells. This mode of action gives olaparib the potential for activity in a range of tumor types with DNA repair deficiencies.
AstraZeneca is a global, innovation-driven biopharmaceutical business that focuses on the discovery, development and commercialisation of prescription medicines, primarily for the treatment of cardiovascular, metabolic, respiratory, inflammation, autoimmune, oncology, infection and neuroscience diseases. AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. For more information please visit: www.astrazeneca.com.
David Ginivan, +44 16 2551 6973 (Global)
Elizabeth Renz +1-302-885-1936 (US)
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