The Lynx Group

BRCA Mutation a Robust Biomarker for Olaparib Benefit in Patients with Ovarian Cancer

September 2013, Vol 4, No 7

Chicago, IL—Olaparib maintenance therapy prolonged progression-free survival (PFS) and the time to disease progression after a second subsequent therapy in patients with platinum-sensitive relapsed serous ovarian cancer. This effect was particularly robust in patients with a BRCA mutation, based on an updated analysis of Study 19.

“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 patients with serous ovarian cancer and a BRCA mutation, said Jonathan A. Ledermann, BSc, MD, Professor of Medical On­cology, University College London Cancer Institute, United Kingdom. Dr Ledermann presented these findings at the 2013 annual meeting of the American Society of Clinical Oncology.

Study 19 randomized 265 patients with platinum-sensitive serous ovarian cancer to olaparib 400 mg twice daily or to placebo, until disease progression.

The primary results showed that olaparib maintenance therapy significantly extended PFS in patients with serous ovarian cancer compared with placebo (P <.001). Overall survival (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 with olaparib maintenance compared with placebo.

This led to a retrospective analysis to analyze 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 the wild-type BRCA.

In the 136 patients with BRCA mutations, a significant 82% reduction in risk of progression was observed for olaparib maintenance therapy (P <.005). Median progression after a second subsequent therapy 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).

No OS difference was seen with olaparib versus placebo, but a trend toward improved OS was found with olaparib in patients with a BRCA mutation. Dr Ledermann said that longer-term follow-up may show a difference in favor of olaparib.

Median progression after a second subsequent therapy significantly favored olaparib maintenance therapy in patients with a BRCA mutation—23.8 months with olaparib versus 15.3 months with placebo.

Quality of life in patients with BRCA mutations was similar with olaparib and placebo. Tolerability was similar in patients with mutations and those with wild-type disease; low-grade nausea and fatigue were the most frequently reported adverse events.

Paul Sabbatini, MD, Deputy Phy­sician-in-Chief for Clinical Research, Memorial Sloan-Kettering Cancer Center, New York, pointed out that it is difficult to show a survival advantage for maintenance olaparib in patients who received several subsequent lines of treatment. 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, Dr 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.

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