ArticlesOlaparib 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
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
References (27)
- et al.
Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012
Eur J Cancer
(2013) - et al.
Newly diagnosed and relapsed epithelial ovarian carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up
Ann Oncol
(2013) - et al.
BRCA1/2 mutations and expression: response to platinum chemotherapy in patients with advanced stage epithelial ovarian cancer
Gynecol Oncol
(2012) Synthetic lethality: general principles, utility and detection using genetic screens in human cells
FEBS Lett
(2011)- et al.
Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial
Lancet
(2010) - et al.
Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, non-randomised study
Lancet Oncol
(2011) - et al.
ACMG recommendations for standards for interpretation and reporting of sequence variations: revisions 2007
Genet Med
(2008) Cancer facts & figures 2013
(2013)- et al.
Ovarian carcinomas with genetic and epigenetic BRCA1 loss have distinct molecular abnormalities
BMC Cancer
(2008) Integrated genomic analyses of ovarian carcinoma
Nature
(2011)