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/m(2), 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/m(2) 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.