Olaparib combined with chemotherapy for recurrent platinum-sensitive ovarian cancer: a randomised phase 2 trial

Summary

Background

The poly(ADP-ribose) polymerase inhibitor olaparib has shown antitumour activity in patients with platinum-sensitive, recurrent, high-grade serous ovarian cancer with or without BRCA1 or BRCA2 mutations. The aim of this study was to assess the efficacy and tolerability of olaparib in combination with chemotherapy, followed by olaparib maintenance monotherapy, versus chemotherapy alone in patients with platinum-sensitive, recurrent, high-grade serous ovarian cancer.

Methods

In this randomised, open-label, phase 2 study, adult patients with platinum-sensitive, recurrent, high-grade serous ovarian cancer who had received up to three previous courses of platinum-based chemotherapy and who were progression free for at least 6 months before randomisation received either olaparib (200 mg capsules twice daily, administered orally on days 1–10 of each 21-day cycle) plus paclitaxel (175 mg/m², administered intravenously on day 1) and carboplatin (area under the curve [AUC] 4 mg/mL per min, according to the Calvert formula, administered intravenously on day 1), then olaparib monotherapy (400 mg capsules twice daily, given continuously) until progression (the olaparib plus chemotherapy group), or paclitaxel (175 mg/m² on day 1) and carboplatin (AUC 6 mg/mL per min on day 1) then no further treatment (the chemotherapy alone group). Randomisation was done by an interactive voice response system, stratified by number of previous platinum-containing regimens received and time to disease progression after the previous platinum regimen. The primary endpoint was progression-free survival according to Response Evaluation Criteria in Solid Tumors version 1.1, analysed by intention to treat. Prespecified exploratory analyses included efficacy by BRCA mutation status, assessed retrospectively. This study is registered with ClinicalTrials.gov, number NCT01081951, and has been completed.

Findings

Between Feb 12 and July 30, 2010, 173 patients at 43 investigational sites in 12 countries were enrolled into the study, of whom 162 were eligible and were randomly assigned to the two treatment groups (81 to the olaparib plus chemotherapy group and 81 to the chemotherapy alone group). Of these randomised patients, 156 were treated in the combination phase (81 in the olaparib plus chemotherapy group and 75 in the chemotherapy alone group) and 121 continued to the maintenance or no further treatment phase (66 in the olaparib plus chemotherapy group and 55 in the chemotherapy alone group). BRCA mutation status was known for 107 patients (either at baseline or determined retrospectively): 41 (38%) of 107 had a BRCA mutation (20 in the olaparib plus chemotherapy group and 21 in the chemotherapy alone group). Progression-free survival was significantly longer in the olaparib plus chemotherapy group (median 12·2 months [95% CI 9·7–15·0]) than in the chemotherapy alone group (median 9·6 months [95% CI 9·1–9·7) (HR 0·51 [95% CI 0·34–0·77]; p=0·0012), especially in patients with BRCA mutations (HR 0·21 [0·08–0·55]; p=0·0015). In the combination phase, adverse events that were reported at least 10% more frequently with olaparib plus chemotherapy than with chemotherapy alone were alopecia (60 [74%] of 81 vs 44 [59%] of 75), nausea (56 [69%] vs 43 [57%]), neutropenia (40 [49%] vs 29 [39%]), diarrhoea (34 [42%] vs 20 [27%]), headache (27 [33%] vs seven [9%]), peripheral neuropathy (25 [31%] vs 14 [19%]), and dyspepsia (21 [26%] vs 9 [12%]); most were of mild-to-moderate intensity. The most common grade 3 or higher adverse events during the combination phase were neutropenia (in 35 [43%] of 81 patients in the olaparib plus chemotherapy group vs 26 [35%] of 75 in the chemotherapy alone group) and anaemia (seven [9%] vs five [7%]). Serious adverse events were reported in 12 (15%) of 81 patients in the olaparib plus chemotherapy group and 16 of 75 (21%) patients in the chemotherapy alone group.

Interpretation

Olaparib plus paclitaxel and carboplatin followed by maintenance monotherapy significantly improved progression-free survival versus paclitaxel plus carboplatin alone, with the greatest clinical benefit in BRCA-mutated patients, and had an acceptable and manageable tolerability profile.

Funding

AstraZeneca.

Introduction

Ovarian cancer is the fifth most common cancer in women in developed countries worldwide.1, 2 Despite significant initial response to platinum-based chemotherapies, many patients with ovarian cancer undergo relapse followed by disease progression within 1 year of treatment,3, 4, 5, 6, 7, 8 which emphasises the need for treatments that improve clinical outcomes. In roughly half of patients with high-grade serous ovarian carcinoma, deficiencies in homologous recombination repair in tumour cells prevent efficient repair of double-stranded DNA breaks.9, 10 Homologous recombination repair deficiencies are often caused by mutations in the tumour suppressor genes BRCA1 and BRCA2. The inhibition of poly(ADP-ribose) polymerase enzymes, which repair single-stranded DNA breaks mainly through the base-excision repair pathway, leads to the formation of double-stranded breaks that in tumours with homologous recombination repair deficiencies are then subject to low-fidelity repair by non-homologous end-joining; this absence of an accurate repair mechanism results in cell death.11, 12

Olaparib is a potent oral poly(ADP-ribose) polymerase inhibitor that causes synthetic lethality in BRCA1-deficient or BRCA2-deficient tumour cells.13, 14 In phase 1–2 monotherapy studies, olaparib treatment had demonstrable antitumour activity in patients with ovarian cancer with or without a BRCA mutation.15, 16, 17, 18, 19, 20 In patients with platinum-sensitive relapsed serous ovarian cancer, olaparib maintenance treatment significantly improved the duration of progression-free survival compared with placebo (hazard ratio [HR] 0·35 [95% CI 0·25–0·49]; p<0·0001), with the greatest clinical benefit recorded in patients with BRCA mutations (HR 0·18 [95% CI 0·10–0·31]; p<0·0001).21, 22

Preclinical data suggest that olaparib might potentiate the efficacy of DNA-damaging chemotherapies, including platinum-containing drugs such as carboplatin.13, 14 The combination of carboplatin with paclitaxel, a mitotic inhibitor, is widely used to treat patients with platinum-sensitive, recurrent, high-grade serous ovarian cancer.⁴ Recent trials assessing olaparib in combination with chemotherapy in patients with advanced ovarian, breast, and other solid tumours have shown encouraging efficacy.23, 24, 25

In this trial, we compared the efficacy and tolerability of olaparib capsules plus carboplatin and paclitaxel, followed by olaparib monotherapy as a maintenance treatment, versus carboplatin and paclitaxel chemotherapy alone (with no further treatment) in patients with platinum-sensitive, recurrent, high-grade serous ovarian cancer.