Olaparib maintenance therapy prolonged progression-free survival (PFS) and the time to disease progression after a second subsequent therapy (PFS2) in patients with platinum-sensitive relapsed serous ovarian cancer (SOC). The effect of olaparib was particularly robust in patients with a BRCA mutation in an updated analysis of Study 19 presented at the 2013 Annual Meeting of ASCO.
In patients with a BRCA mutation, the median improvement with olaparib versus placebo was 6.9 months for PFS and 8.5 months for PFS2, both of which were statistically significant. Overall survival (OS) was improved by 3 months compared with placebo, but this difference did not reach statistical significance.
“Olaparib maintenance therapy led to the greatest clinical benefit compared with placebo in patients with a BRCA mutation. As a result of these compelling data, phase 3 confirmatory trials will begin this year in SOC patients with a BRCA mutation,” stated presenting author Jonathan Ledermann, BSc, MD, FRCP, Professor of Medical Oncology in the UCL Cancer Institute, University College London, and an Honorary Consultant Medical Oncologist at UCL Hospitals. Ledermann presented these findings at the 2013 Annual Meeting of ASCO.
Study 19 randomized 265 patients with platinum- sensitive SOC to either maintenance olaparib 400 mg bid or placebo until disease progression.
The primary results of Study 19 showed that olaparib maintenance therapy significantly extended PFS in SOC patients compared with placebo (P<.00001). OS was not prolonged with olaparib, however (Ledermann J, et al. N Engl J Med. 2012;366:1382-1392).
Updated Analysis of Patients With BRCA Mutations
A prespecified subgroup analysis of Study 19 showed that patients with a known BRCA mutation had improved survival on olaparib maintenance compared with placebo.
This observation led to a retrospective analysis of the study to see the effect of olaparib maintenance in patients with BRCA mutations. Using 2 different assays, 136 patients were identified with a germline BRCA mutation or a somatic BRCA mutation, and 118 had wild-type BRCA (a total of 94%).
In 136 patients with BRCA mutations, a highly significant 82% reduction in risk of progression was observed for ola-parib maintenance therapy (P<.00005). Median PFS was 11.2 months with olaparib versus 4.3 months with placebo. A significant but less robust advantage was also observed for olaparib in patients with wild-type BRCA (P=.007).
For all patients, no OS difference was observed for olaparib versus placebo, but there was a trend toward improved OS for olaparib in patients with a BRCA mutation. Ledermann said that longer-term follow-up may show a difference in favor of olaparib.
Median PFS2 significantly favored olaparib maintenance therapy in BRCA-mutated patients (P=.0063); median PFS2 was 23.8 months versus 15.3 months, respectively. PFS2 was also 2.4 months longer with olaparib in the wild-type patients.
Olaparib and placebo had similar effects on quality of life in patients with BRCA mutations. Tolerability was similar in mutated and wild-type patients, with low-grade nausea and fatigue as the most commonly reported adverse events.
Formal discussant of this trial, Paul Sabbatini, MD, attending physician at Memorial Sloan-Kettering Cancer Center in New York City, pointed out 2 important issues: the effect of subsequent therapies confounding outcomes in the 2 groups, and the timing of maintenance therapy.
It is difficult to show a survival advantage for maintenance olaparib in patients treated with several subsequent lines of treatment, he continued.
Evidence is accruing to suggest that maintenance therapy is most effective in ovarian cancer when initiated later in the course of disease, and this question is being addressed in clinical trials, he noted.
The take-home point from this study, Sabbatini stated, is that the BRCA mutation is a robust biomarker for the benefit of olaparib and will be included in phase 3 studies going forward. But, he continued, study of PARP inhibitors should not be limited to patients with BRCA mutations, as they show efficacy in other patient populations as well.
Reference
Ledermann JA, Harter P, Gourley C, et al. Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer (SOC) and a BRCA mutation (BRCAm). J Clin Oncol. 2013;31(suppl):Abstract 5505.