Olaparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, has previously shown efficacy in a phase 2 study when given in capsule formulation to all-comer patients with platinum-sensitive, relapsed ...high-grade serous ovarian cancer. We aimed to confirm these findings in patients with a BRCA1 or BRCA2 (BRCA1/2) mutation using a tablet formulation of olaparib.
This international, multicentre, double-blind, randomised, placebo-controlled, phase 3 trial evaluated olaparib tablet maintenance treatment in platinum-sensitive, relapsed ovarian cancer patients with a BRCA1/2 mutation who had received at least two lines of previous chemotherapy. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status at baseline of 0–1 and histologically confirmed, relapsed, high-grade serous ovarian cancer or high-grade endometrioid cancer, including primary peritoneal or fallopian tube cancer. Patients were randomly assigned 2:1 to olaparib (300 mg in two 150 mg tablets, twice daily) or matching placebo tablets using an interactive voice and web response system. Randomisation was stratified by response to previous platinum chemotherapy (complete vs partial) and length of platinum-free interval (6–12 months vs ≥12 months) and treatment assignment was masked for patients, those giving the interventions, data collectors, and data analysers. The primary endpoint was investigator-assessed progression-free survival and we report the primary analysis from this ongoing study. The efficacy analyses were done on the intention-to-treat population; safety analyses included patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT01874353, and is ongoing and no longer recruiting patients.
Between Sept 3, 2013, and Nov 21, 2014, we enrolled 295 eligible patients who were randomly assigned to receive olaparib (n=196) or placebo (n=99). One patient in the olaparib group was randomised in error and did not receive study treatment. Investigator-assessed median progression-free survival was significantly longer with olaparib (19·1 months 95% CI 16·3–25·7) than with placebo (5·5 months 5·2–5·8; hazard ratio HR 0·30 95% CI 0·22–0·41, p<0·0001). The most common adverse events of grade 3 or worse severity were anaemia (38 19% of 195 patients in the olaparib group vs two 2% of 99 patients in the placebo group), fatigue or asthenia (eight 4% vs two 2%), and neutropenia (ten 5% vs four 4%). Serious adverse events were experienced by 35 (18%) patients in the olaparib group and eight (8%) patients in the placebo group. The most common in the olaparib group were anaemia (seven 4% patients), abdominal pain (three 2% patients), and intestinal obstruction (three 2% patients). The most common in the placebo group were constipation (two 2% patients) and intestinal obstruction (two 2% patients). One (1%) patient in the olaparib group had a treatment-related adverse event (acute myeloid leukaemia) with an outcome of death.
Olaparib tablet maintenance treatment provided a significant progression-free survival improvement with no detrimental effect on quality of life in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation. Apart from anaemia, toxicities with olaparib were low grade and manageable.
AstraZeneca.
Olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, has previously been shown to extend progression-free survival versus placebo when given to patients with relapsed high-grade serous or ...endometrioid ovarian cancer who were platinum sensitive and who had a BRCA1 or BRCA2 (BRCA1/2) mutation, as part of the SOLO2/ENGOT-Ov21 trial. The aim of this final analysis is to investigate the effect of olaparib on overall survival.
This double-blind, randomised, placebo-controlled, phase 3 trial was done across 123 medical centres in 16 countries. Eligible patients were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status at baseline of 0–1, had histologically confirmed, relapsed, high-grade serous or high-grade endometrioid ovarian cancer, including primary peritoneal or fallopian tube cancer, and had received two or more previous platinum regimens. Patients were randomly assigned (2:1) to receive olaparib tablets (300 mg in two 150 mg tablets twice daily) or matching placebo tablets using an interactive web or voice-response system. Stratification was by response to previous chemotherapy and length of platinum-free interval. Treatment assignment was masked to patients, treatment providers, and data assessors. The primary endpoint of progression-free survival has been reported previously. Overall survival was a key secondary endpoint and was analysed in all patients as randomly allocated. Safety was assessed in all patients who received at least one treatment dose. This trial is registered with ClinicalTrials.gov, NCT01874353, and is no longer recruiting patients.
Between Sept 3, 2013 and Nov 21, 2014, 295 patients were enrolled. Patients were randomly assigned to receive either olaparib (n=196 66%) or placebo (n=99 34%). One patient, randomised in error, did not receive olaparib. Median follow-up was 65·7 months (IQR 63·6–69·3) with olaparib and 64·5 months (63·4–68·7) with placebo. Median overall survival was 51·7 months (95% CI 41·5–59·1) with olaparib and 38·8 months (31·4–48·6) with placebo (hazard ratio 0·74 95% CI 0·54–1·00; p=0·054), unadjusted for the 38% of patients in the placebo group who received subsequent PARP inhibitor therapy. The most common grade 3 or worse treatment-emergent adverse event was anaemia (which occurred in 41 21% of 195 patients in the olaparib group and two 2% of 99 patients in the placebo group). Serious treatment-emergent adverse events were reported in 50 (26%) of 195 patients receiving olaparib and eight (8%) of 99 patients receiving placebo. Treatment-emergent adverse events with a fatal outcome occurred in eight (4%) of the 195 patients receiving olaparib, six of which were judged to be treatment-related (attributed to myelodysplastic syndrome n=3 and acute myeloid leukaemia n=3).
Olaparib provided a median overall survival benefit of 12·9 months compared with placebo in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation. Although statistical significance was not reached, these findings are arguably clinically meaningful and support the use of maintenance olaparib in these patients.
AstraZeneca and Merck.
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