Kaye 2012

Methods	Phase II, open‐label, randomised, multicentre study
Participants	97 women aged 18 years or older with histologically or cytologically confirmed recurrent epithelial ovarian, primary peritoneal or fallopian tube carcinoma Women had confirmed BRCA1/2 mutation (BRCA1 +ve: 81.3% (arm 1); 87.5% (arm 2); 81.8% (arm 3) Recurrence within 12 months of most recent platinum–based chemotherapy regimen (recurrence within 6 months ‐ i.e. platinum‐resistant disease: 56.3% (arm 1); 50.0% (arm 2); 42.4% (arm 3) Performance status (PS) 0 to 2; PS 0: 50.0% (arm 1); 59.4% (arm 2); 57.6% (arm 3) Life expectancy > 16 weeks and one or more measurable lesions according to RECIST No previous exposure to pegylated liposomal doxorubicin (PLD) Mean age: 57.2 (arm 1); 53.8 (arm 2); 54.3 (arm 3)
Interventions	Arm 1: Olaparib (OLA) 200 mg bd maintenance therapy Arm 2: OLA 400 mg bd maintenance therapy Arm 3: IV pegylated liposomal doxorubicin (PLD) 50 mg/m² every 28 days
Outcomes	97 women randomised; 32 women to (33%) OLA 200 mg, 32 women to (33%) OLA 400 mg, and 33 women to (34%) PLD 8 women who progressed on PLD crossed over from PLD to OLA 400 mg group Survival and response outcomes 59 RECIST‐defined progression events were documented (45/63 in arms 1 and 2 combined and 14/28 in arm 3) Median PFS times were 6.5 months (95% CI 5.5 to 10.1 months), 8.8 months (95% CI 5.4 to 9.2 months) and 7.1 months (95% CI 3.7 to 10.7 months) for OLA 200 mg, OLA 400 mg and PLD groups, respectively There was no difference in PFS between OLA (combined or individual doses) and PLD groups (HR 0.88, 95% CI 0.5 to 1.56; P value = 0.66 for arms 1 and 2 combined versus arm 3). OLA 200 mg versus PLD (HR 0.91, 80% CI 0.60 to 1.39; 95% CI 0.48 to 1.74; P value = 0.78); OLA 400 mg versus PLD (HR 0.86, 80% CI 0.56 to 1.30; 95% CI 0.45 to 1.62; Pvalue = 0.63) 9, 11 and 13 deaths in arms 1, 2 and 3, respectively Overall survival of PLD (arm 3) versus OLA 200 mg (arm 1 HR 0.66 (95% CI 0.27 to 1.55) and OLA 400 mg (arm 2 HR 1.01 (95% CI 0.44 to 2.27) Combined response rates (i.e. RECIST and/or GCIG CA125) were 38%, 59% and 39% in the OLA 200 mg, OLA 400 mg and PLD groups, respectively, with odds ratios of OLA 200 mg = 0.98 (P value = 0.97), OLA 400 mg = 2.76 (P value = 0.05) and OLA 200 and 400 mg = 1.64 (P value = 0.27) Quality of life and adverse events outcomes There were no significant differences in improvement or worsening rates between the OLA and PLD group for the FACT‐O Symptom Index and Trial Outcome Index scores. A higher improvement rate was noted for OLA 400 mg compared with PLD for the total FACT‐O score (odds ratio 7.23, 95% CI 1.09 to 143.3; P value = 0.039) Adverse events: Nausea: Grade 3 to 4: 3 (5%) versus 2 (6%) (Arms 1 and 2 versus Arm 3) Fatigue: Grade 3 to 4: 4 (6%) versus 3(9%) (Arms 1 and 2 versus Arm 3) Abdominal pain: Grade 3 to 4: 2 (3%) vs 2 (6%) (Arms 1 and 2 versus Arm 3) Vomiting: Grade 3 to 4: 1 (2%) versus 1 (3%) (Arms 1 and 2 versus Arm 3)
Notes	Same study as ICEBERG3 study identified as ongoing in initial version of review. Higher response rates in PLD group compared to other studies attributed to high proportion with BRCA mutation, as evidence from other studies that this improves response rate to PLD. Clinical trial identifiers: ICEBERG 3; NCT00628251; D0810C00012; EUCTR2007‐007622‐22‐ GB
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	''randomisation assignment list was computer‐generated using the Global Randomisation system (DRand)"
Allocation concealment (selection bias)	Low risk	"patients were randomly assigned sequentially using an Interactive Voice Response System"
Blinding of participants and personnel (performance bias) All outcomes	High risk	Open‐label
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	"centrally reviewed tumour assessment for all patients with RESIST scans were used for sensitivity analysis" Correspondence with authors confirmed that central reviewers were blinded to treatment groups, which is of low risk, but other outcomes at unclear risk of bias, as open‐label study
Incomplete outcome data (attrition bias) All outcomes	Low risk	No patients lost to follow‐up and all accounted for in CONSORT flowchart
Selective reporting (reporting bias)	Low risk	Outcome measures as declared at trial registration on www.ClinicalTrials.gov
Other bias	Unclear risk	Several investigators disclosed financial links to AstraZeneca