Elsevier

The Lancet Oncology

Volume 15, Issue 8, July 2014, Pages 852-861
The Lancet Oncology

Articles
Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial

https://doi.org/10.1016/S1470-2045(14)70228-1Get rights and content

Summary

Background

Maintenance monotherapy with the PARP inhibitor olaparib significantly prolonged progression-free survival (PFS) versus placebo in patients with platinum-sensitive recurrent serous ovarian cancer. We aimed to explore the hypothesis that olaparib is most likely to benefit patients with a BRCA mutation.

Methods

We present data from the second interim analysis of overall survival and a retrospective, preplanned analysis of data by BRCA mutation status from our randomised, double-blind, phase 2 study that assessed maintenance treatment with olaparib 400 mg twice daily (capsules) versus placebo in patients with platinum-sensitive recurrent serous ovarian cancer who had received two or more platinum-based regimens and who had a partial or complete response to their most recent platinum-based regimen. Randomisation was by an interactive voice response system, stratified by time to progression on penultimate platinum-based regimen, response to the most recent platinum-based regimen before randomisation, and ethnic descent. The primary endpoint was PFS, analysed for the overall population and by BRCA status. This study is registered with ClinicalTrials.gov, number NCT00753545.

Findings

Between Aug 28, 2008, and Feb 9, 2010, 136 patients were assigned to olaparib and 129 to placebo. BRCA status was known for 131 (96%) patients in the olaparib group versus 123 (95%) in the placebo group, of whom 74 (56%) versus 62 (50%) had a deleterious or suspected deleterious germline or tumour BRCA mutation. Of patients with a BRCA mutation, median PFS was significantly longer in the olaparib group than in the placebo group (11·2 months [95% CI 8·3–not calculable] vs 4·3 months [3·0–5·4]; HR 0·18 [0·10–0·31]; p<0·0001); similar findings were noted for patients with wild-type BRCA, although the difference between groups was lower (7·4 months [5·5–10·3] vs 5·5 months [3·7–5·6]; HR 0·54 [0·34–0·85]; p=0·0075). At the second interim analysis of overall survival (58% maturity), overall survival did not significantly differ between the groups (HR 0·88 [95% CI 0·64–1·21]; p=0·44); similar findings were noted for patients with mutated BRCA (HR 0·73 [0·45–1·17]; p=0·19) and wild-type BRCA (HR 0·99 [0·63–1·55]; p=0·96). The most common grade 3 or worse adverse events in the olaparib group were fatigue (in ten [7%] patients in the olaparib group vs four [3%] in the placebo group) and anaemia (seven [5%] vs one [<1%]). Serious adverse events were reported in 25 (18%) patients who received olaparib and 11 (9%) who received placebo. Tolerability was similar in patients with mutated BRCA and the overall population.

Interpretation

These results support the hypothesis that patients with platinum-sensitive recurrent serous ovarian cancer with a BRCA mutation have the greatest likelihood of benefiting from olaparib treatment.

Funding

AstraZeneca.

Introduction

In developed countries, ovarian cancer is the fifth highest cause of cancer deaths in women.1, 2 Patients with platinum-sensitive recurrent cancer (defined as relapse ≥6 months after platinum-based chemotherapy) are thought to be likely to respond to further platinum treatment, and re-treatment with platinum-based chemotherapy is common. However, cumulative toxicities and the emergence of resistance limit the use of these drugs.3 An alternative and preferable approach is to consolidate and prolong tumour responses to platinum-based chemotherapy using maintenance therapy with an effective and well tolerated oral antitumour agent; this approach could delay disease progression and defer initiation of subsequent chemotherapy.

Up to 50% of patients with high-grade serous ovarian cancer are deficient in homologous recombination—a key pathway for repair of DNA damage—due to germline or somatically acquired BRCA1 or BRCA2 mutations, epigenetic inactivation of BRCA1, or BRCA-independent defects in the homologous recombination pathway.4, 5 The proportion of patients with germline BRCA mutations is greater in those with high-grade serous ovarian cancer6 than in the overall ovarian cancer population (22·6% vs ≤15%).7, 8 Furthermore, BRCA mutations occur more frequently in patients with platinum-sensitive epithelial ovarian cancer than in patients with platinum-resistant disease (38% vs 17%).9 Additionally, a higher frequency of women without a germline BRCA mutation who responded to platinum-based treatment had a somatic BRCA mutation than did women with unselected high-grade serous ovarian cancer.6

PARP inhibitors induce synthetic lethality in tumours with homologous recombination deficiency due to, for example, loss-of-function BRCA mutations.10, 11, 12 Olaparib is a potent oral PARP inhibitor that has shown antitumour activity in phase 1/2 trials in patients with BRCA-mutated or sporadic high-grade serous ovarian cancer.13, 14, 15, 16, 17 Irrespective of whether the origin of the BRCA mutation is germline or somatic, tumours in patients with a BRCA mutation are postulated to be sensitive to PARP inhibition because of the loss of function of the gene within the tumour.18

Previously, we reported the results of a randomised, double-blind phase 2 study,19 in which maintenance treatment with olaparib 400 mg (capsule formation) twice daily led to a significant improvement in median progression-free survival (PFS) compared with placebo in patients with platinum-sensitive recurrent serous ovarian cancer (8·4 months with olaparib vs 4·8 months with placebo; HR 0·35 [95% CI 0·25–0·49]; p<0·001). An interim analysis of overall survival (when 38% of patients had died) did not detect a benefit for olaparib compared with placebo (HR 0·94 [95% CI 0·63–1·39]; p=0·75).19 Although BRCA mutation status was known for only 98 (37%) of 265 patients at study entry, a preplanned subgroup analysis suggested that olaparib might lead to longer PFS in patients with a known BRCA mutation than those with an unknown mutation status.19

We aimed to update the efficacy and safety results (data cutoff Nov 26, 2012) from this phase 2 trial in a greatly expanded subset of patients who underwent retrospective germline and somatic BRCA mutation testing. More complete patient-reported outcomes will be presented separately.

Section snippets

Study design and patients

This study was a preplanned retrospective analysis of data from our phase 2, randomised, double-blind, multicentre trial, undertaken at 82 sites in 16 countries. The institutional review boards or independent ethics committees of all investigational sites approved the protocol and informed consent details. The study was done in accordance with the Declaration of Helsinki, Good Clinical Practice, and the AstraZeneca policy on bioethics.20

Eligible patients were aged 18 years or older and had

Results

Between Aug 28, 2008, and Feb 9, 2010, 326 patients were enrolled. On the basis of local germline BRCA mutation testing reported on case report forms, germline BRCA mutation status was known for 98 (37%) of 265 patients (50 [37%] of 136 in the olaparib group vs 48 [37%] of 129 in the placebo group (figure 1). Further germline BRCA or tumour BRCA testing (or both) was done in patients who had provided consent and samples at study entry, with germline BRCA status being established retrospectively

Discussion

In this retrospective analysis, we postulated that the subgroup of patients with platinum-sensitive relapsed serous ovarian cancer with BRCA-mutated disease would be most likely to benefit from treatment with a PARP inhibitor. Initial subgroup analyses of PFS suggested promising results in patients with a germline BRCA mutation. To improve confidence in these results, BRCA mutation testing was done retrospectively in all patients who provided appropriate consent and samples: the results

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