Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial - 01/07/14
, Philipp Harter, MD b, Charlie Gourley, ProfPhD c, Michael Friedlander, ProfPhD d, Ignace Vergote, ProfMD e, Gordon Rustin, ProfMD f, Clare L Scott, PhD g, Werner Meier, ProfMD h, Ronnie Shapira-Frommer, MD i, Tamar Safra, MD j, Daniela Matei, MD k, Anitra Fielding, MBChB l, Stuart Spencer, MSc l, Brian Dougherty, PhD m, Maria Orr, PhD l, Darren Hodgson, PhD l, J Carl Barrett, PhD m, Ursula Matulonis, MD nSummary |
Background |
Maintenance monotherapy with the PARP inhibitor olaparib significantly prolonged progression-free survival (PFS) versus placebo in patients with platinum-sensitive recurrent serous ovarian cancer. We aimed to explore the hypothesis that olaparib is most likely to benefit patients with a BRCA mutation.
Methods |
We present data from the second interim analysis of overall survival and a retrospective, preplanned analysis of data by BRCA mutation status from our randomised, double-blind, phase 2 study that assessed maintenance treatment with olaparib 400 mg twice daily (capsules) versus placebo in patients with platinum-sensitive recurrent serous ovarian cancer who had received two or more platinum-based regimens and who had a partial or complete response to their most recent platinum-based regimen. Randomisation was by an interactive voice response system, stratified by time to progression on penultimate platinum-based regimen, response to the most recent platinum-based regimen before randomisation, and ethnic descent. The primary endpoint was PFS, analysed for the overall population and by BRCA status. This study is registered with ClinicalTrials.gov, number NCT00753545.
Findings |
Between Aug 28, 2008, and Feb 9, 2010, 136 patients were assigned to olaparib and 129 to placebo. BRCA status was known for 131 (96%) patients in the olaparib group versus 123 (95%) in the placebo group, of whom 74 (56%) versus 62 (50%) had a deleterious or suspected deleterious germline or tumour BRCA mutation. Of patients with a BRCA mutation, median PFS was significantly longer in the olaparib group than in the placebo group (11·2 months [95% CI 8·3–not calculable] vs 4·3 months [3·0–5·4]; HR 0·18 [0·10–0·31]; p<0·0001); similar findings were noted for patients with wild-type BRCA, although the difference between groups was lower (7·4 months [5·5–10·3] vs 5·5 months [3·7–5·6]; HR 0·54 [0·34–0·85]; p=0·0075). At the second interim analysis of overall survival (58% maturity), overall survival did not significantly differ between the groups (HR 0·88 [95% CI 0·64–1·21]; p=0·44); similar findings were noted for patients with mutated BRCA (HR 0·73 [0·45–1·17]; p=0·19) and wild-type BRCA (HR 0·99 [0·63–1·55]; p=0·96). The most common grade 3 or worse adverse events in the olaparib group were fatigue (in ten [7%] patients in the olaparib group vs four [3%] in the placebo group) and anaemia (seven [5%] vs one [<1%]). Serious adverse events were reported in 25 (18%) patients who received olaparib and 11 (9%) who received placebo. Tolerability was similar in patients with mutated BRCA and the overall population.
Interpretation |
These results support the hypothesis that patients with platinum-sensitive recurrent serous ovarian cancer with a BRCA mutation have the greatest likelihood of benefiting from olaparib treatment.
Funding |
AstraZeneca.
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Vol 15 - N° 8
P. 852-861 - juillet 2014 Retour au numéro
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