The Asco Post

Olaparib Shows Robust Progression-Free Survival Benefit in Patients With BRCA Mutations 

By Alice Goodman
September 1, 2013, Volume 4, Issue 14

Maintenance therapy with olaparib extended progression-free survival and the time to disease progression after a second subsequent therapy in patients with platinum-sensitive relapsed serous ovarian cancer and a BRCA mutation, according to an updated analysis of Study 19 presented at the 2013 ASCO Annual Meeting.1

Compelling Data

“Olaparib maintenance therapy led to the greatest clinical benefit compared with placebo in patients with a BRCA mutation, with a median improvement of 6.9 months in [progression-free survival], a median improvement in [time to second disease progression] of 8.5 months, and an overall survival improvement of 3 months compared with placebo. As a result of these compelling data, phase III confirmatory trials will begin this year in [serous ovarian cancer] 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. He is Head of the Cancer Research UK & UCL Cancer Trials Centre, within UCL Cancer Institute.

Study 19 enrolled 265 patients with serous ovarian cancer who responded to platinum-based chemotherapy to receive either maintenance olaparib at 400 mg twice daily or placebo.

The primary analysis of Study 19, presented 2 years ago, found that olaparib maintenance therapy significantly extended progression-free survival in patients with serous ovarian cancer compared with placebo (P < .00001).2 However, an interim analysis showed no overall survival advantage for olaparib maintenance.

Dr. Ledermann explained that the presence of a BRCA mutation was not required for study entry, but a significant number of patients turned out to have a BRCA mutation. At baseline 97 of 265 patients (36.6%) had a known BRCA mutation.

Subgroup Analysis

A prespecified subgroup analysis of Study 19 showed that patients with a known BRCA mutation had improved survival on olaparib maintenance compared with placebo.

To study further the effect of olaparib maintenance in patients with BRCA mutations, the investigators performed a retrospective analysis of germline BRCA mutation status in 280 patients who gave their consent (including the 97 with known BRCA status at baseline) using Myriad’s genetics assay. They also looked for somatic BRCA mutations within patients’ tumors (n = 209) using an assay from Foundation Medicine.

A total of 136 patients had either a germline mutation or a somatic BRCA mutation, and 118 had wild-type BRCA (total number = 257, 94%).

In the updated efficacy analysis, in addition to the progression-free survival endpoint, the investigators assessed the time from randomization to time of the start of a second subsequent therapy for disease progression or death. In the 136 patients with BRCA mutations, a highly significant 82% reduction in risk of progression was observed for olaparib maintenance therapy (P < .00005). Median progression-free survival was 11.2 months with olaparib vs 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, the updated analysis showed no overall survival difference for olaparib vs placebo. However, a trend toward improved overall survival was observed in the olaparib group with a BRCA mutation at the time of analysis, with a 3-month difference. Longer-term analysis may show an overall survival difference, Dr. Ledermann noted.

The time from randomization to progression after a second subsequent therapy also significantly favored olaparib maintenance therapy in the BRCA-mutated patients (P = .0063), with median time to second progression of 23.8 vs 15.3 months, respectively. Time to second progression was also a median of 2.4 months longer with olaparib in the wild-type patients.

Clinically Meaningful Benefit

“This is a clinically meaningful benefit,” he said. The effect of olaparib carried on beyond progression in patients for whom a second subsequent therapy failed.

Quality of life in patients with BRCA mutations was no different on either treatment arm.

The study closed in 2012, and as of May of 2013, 26 of the original 265 patients remain on therapy—23 on olaparib and 3 on placebo.

The tolerability of olaparib is similar in the patients with BRCA mutations and wild-type BRCA. The most common adverse events are low-grade nausea and fatigue.

Dr. Ledermann said it is difficult to show a survival benefit in these patients who are treated with subsequent multiple lines of therapy.

“Subsequent treatment gradually abrogates any differences between treatment arms that might exist early on. This doesn’t necessarily devalue the treatment,” he noted. ■

Disclosure: Dr. Ledermann has received support for travel to meetings as well as supplementary financial support for investigator-led clinical trials from AstraZeneca.

References

1. 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). 2013 ASCO Annual Meeting. Abstract 5505. Presented June 1, 2013.

2. Ledermann J, Harter P, Gourley C, et al: Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N Engl J Med 366:1382-1392, 2012.

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