Ledermann 2012

Methods	Randomised, double‐blind, multicentre, international phase 2 study (82 investigational sites in 16 countries)
Participants	326 women of whom 265 met the eligibility criteria. 136 women were randomly assigned to received OLA and 129 to receive placebo. Women 18 years of age and older with recurrent ovarian or fallopian tube cancer or primary peritoneal cancer (high‐grade (grade 2 or 3) serous features or a serous component) sensitive to platinum (objective response to a previous platinum‐based therapy for more than 6 months). Women had to complete 2 courses of platinum‐based chemotherapy and their most recent regimen induced an objective response (defined by RECIST guidelines or a CA125 response) with a normal CA125 prior to commencement of the study. Median age 58 years (OLA) and 59 years (placebo). Complete response to previous platinum chemotherapy: 57 (41.9%) (OLA); 63 (48.8%) (placebo)). BRCA mutation: 31 (22.8%) (OLA); 28 (21.7%) (placebo). Patients did not have mandatory BRCA1/2 testing as part of eligibility and factors known to affect BRCA status, e.g. Jewish ancestry, were balanced between groups. BRCA1/2 positive: 31 (22.8%) Arm A; 28 (21.7%) Arm B
Interventions	Arm 1: OLA 400 mg bd maintenance therapy Arm 2: Placebo tablets bd maintenance therapy All women within 8 weeks after completion of the last dose of platinum‐based chemotherapy
Outcomes	136 women OLA and 129 women placebo ‐ 1 woman in placebo arm withdrew consent prior to treatment and was not included in the analysis, since there were no follow‐up data available ‐ data based on remaining 264 women Survival and response outcomes 153 progression events (57.7% of women) Median PFS was 8.4 months (OLA) 4.8 months (placebo) HR progression or death 0.35; 95% CI 0.25 to 0.49; P value < 0.001 101 women (38%) had died: 52 (OLA) and 49 (placebo) (OLA HR for death 0.94, 95% CI 0.63 to 1.39; P value = 0.75) Median OS 29.7 months (OLA) and 29.9 months (placebo) 29 women were still receiving OLA after a period of at least 21 months, and 4 women were still receiving placebo Median time to progression (RECIST guidelines or CA‐125 level) 8.3 months (OLA) versus 3.7 months (placebo); HR for progression 0.35, 95% CI 0.25 to 0.47; P value < 0.001) Only 40% of women in the study had measurable disease by RECIST guidelines; the objective response rate (ORR) was 12% (7 of 57 women in the OLA group) versus 4% (2 of 48 women in the placebo group) (OR 3.36, 95% CI 0.75 to 23.72; P value = 0.12) Quality of life and adverse events outcomes 246 of 264 women had 1 or more adverse events, most grade 1 or 2 Adverse events with an incidence 10% higher or more in the OLA group than in the placebo group: nausea; fatigue; vomiting; anaemia. Incidence of grade 3 or 4 adverse events was 35.3% in the OLA group and 20.3% in the placebo group. Seven grade 4 events were reported in the OLA group (5.1% of women), and 2 were reported in the placebo group (1.6% of women)
Notes	Study sponsored by AstraZeneca: Clinical trial identifiers: NCT01081951; D0810C0041
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"computer generated"
Allocation concealment (selection bias)	Low risk	"Randomised by interactive voice response system"
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Double‐blinding. Unique identifiers generated during randomisation
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Review of CT scans was blinded. Blinded independent review of data
Incomplete outcome data (attrition bias) All outcomes	Low risk	326 patients screened; 61 did not meet inclusion criteria, 265 randomised, 1 withdrew consent, all patients accounted for at end of study and displayed on CONSORT flowchart
Selective reporting (reporting bias)	Low risk	Outcomes selected in ClinicalTrials.gov reported
Other bias	Unclear risk	Industry‐led study and some authors had documented conflict of interest, but blinding secure and low risk of selective reporting bias as pre‐determined at trial registration. Principle Investigators were not employed by AstraZeneca