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

Jonathan Ledermann, Philipp Harter, Charlie Gourley, Michael Friedlander, Ignace Vergote, Gordon Rustin, Clare L. Scott, Werner Meier, Ronnie Shapira-Frommer, Tamar Safra, Daniela Matei, Anitra Fielding, Stuart Spencer, Brian Dougherty, Maria Orr, Darren Hodgson, J. Carl Barrett, Ursula Matulonis

Research output: Contribution to journalArticle

626 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)852-861
Number of pages10
JournalThe Lancet Oncology
Volume15
Issue number8
DOIs
StatePublished - 2014

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Platinum
Ovarian Neoplasms
Placebos
Therapeutics
Mutation
Disease-Free Survival
Survival Analysis
Random Allocation
olaparib
Population
Capsules
Fatigue
Anemia
Maintenance

ASJC Scopus subject areas

  • Oncology

Cite this

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. / Ledermann, Jonathan; Harter, Philipp; Gourley, Charlie; Friedlander, Michael; Vergote, Ignace; Rustin, Gordon; Scott, Clare L.; Meier, Werner; Shapira-Frommer, Ronnie; Safra, Tamar; Matei, Daniela; Fielding, Anitra; Spencer, Stuart; Dougherty, Brian; Orr, Maria; Hodgson, Darren; Barrett, J. Carl; Matulonis, Ursula.

In: The Lancet Oncology, Vol. 15, No. 8, 2014, p. 852-861.

Research output: Contribution to journalArticle

Ledermann, J, Harter, P, Gourley, C, Friedlander, M, Vergote, I, Rustin, G, Scott, CL, Meier, W, Shapira-Frommer, R, Safra, T, Matei, D, Fielding, A, Spencer, S, Dougherty, B, Orr, M, Hodgson, D, Barrett, JC & Matulonis, U 2014, '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', The Lancet Oncology, vol. 15, no. 8, pp. 852-861. https://doi.org/10.1016/S1470-2045(14)70228-1
Ledermann, Jonathan ; Harter, Philipp ; Gourley, Charlie ; Friedlander, Michael ; Vergote, Ignace ; Rustin, Gordon ; Scott, Clare L. ; Meier, Werner ; Shapira-Frommer, Ronnie ; Safra, Tamar ; Matei, Daniela ; Fielding, Anitra ; Spencer, Stuart ; Dougherty, Brian ; Orr, Maria ; Hodgson, Darren ; Barrett, J. Carl ; Matulonis, Ursula. / 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. In: The Lancet Oncology. 2014 ; Vol. 15, No. 8. pp. 852-861.
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abstract = "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.",
author = "Jonathan Ledermann and Philipp Harter and Charlie Gourley and Michael Friedlander and Ignace Vergote and Gordon Rustin and Scott, {Clare L.} and Werner Meier and Ronnie Shapira-Frommer and Tamar Safra and Daniela Matei and Anitra Fielding and Stuart Spencer and Brian Dougherty and Maria Orr and Darren Hodgson and Barrett, {J. Carl} and Ursula Matulonis",
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TY - JOUR

T1 - Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer

T2 - A preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial

AU - Ledermann, Jonathan

AU - Harter, Philipp

AU - Gourley, Charlie

AU - Friedlander, Michael

AU - Vergote, Ignace

AU - Rustin, Gordon

AU - Scott, Clare L.

AU - Meier, Werner

AU - Shapira-Frommer, Ronnie

AU - Safra, Tamar

AU - Matei, Daniela

AU - Fielding, Anitra

AU - Spencer, Stuart

AU - Dougherty, Brian

AU - Orr, Maria

AU - Hodgson, Darren

AU - Barrett, J. Carl

AU - Matulonis, Ursula

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

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