Olaparib maintenance therapy in patients with platinum-sensitive, relapsed serous ovarian cancer and a BRCA mutation: Overall survival adjusted for postprogression poly(adenosine diphosphate ribose) polymerase inhibitor therapy

Ursula A. Matulonis, Philipp Harter, Charlie Gourley, Michael Friedlander, Ignace Vergote, Gordon Rustin, Clare Scott, Werner Meier, Ronnie Shapira-Frommer, Tamar Safra, Daniela Matei, Anitra Fielding, Stuart Spencer, David Parry, Lynda Grinsted, Jonathan A. Ledermann

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

BACKGROUND: Maintenance treatment with the oral poly(adenosine diphosphate ribose) polymerase (PARP) inhibitor olaparib (Lynparza) in Study 19 (study number, D0810C00019; ClinicalTrials.gov identifier, NCT00753545) significantly improved progression-free survival in comparison with a placebo for patients with platinum-sensitive, relapsed serous ovarian cancer with a BRCA1/2 mutation (BRCAm), but an interim analysis revealed no statistically significant overall survival (OS) benefit. However, 23% of the patients receiving the placebo switched to a PARP inhibitor after progression. To investigate whether this had a confounding effect on OS, this article reports an exploratory post hoc analysis that excluded all patients from sites where 1 or more placebo patients received postprogression PARP inhibitor treatment. METHODS: In Study 19, 136 of the 265 patients receiving olaparib or a placebo had a BRCAm. Sixteen patients treated at 11 of the 82 investigational sites received a PARP inhibitor after progression; these sites were excluded from this analysis, and 97 BRCAm patients at 50 sites were included. OS was assessed with a Cox proportional hazards model analogous to the primary study analysis. A supporting rank-preserving structural failure time (RPSFT) model analysis was undertaken for all 136 BRCAm patients. RESULTS: The OS hazard ratio (HR) was 0.52 (95% confidence interval [CI], 0.28-0.97) for the 97 BRCAm patients, whereas for the interim OS analysis with all 136 BRCAm patients, it was 0.73 (95% CI, 0.45-1.17). The supportive RPSFT analysis HR was approximately 0.66. CONCLUSIONS: The numerical improvement in the OS HR suggests that in Study 19, postprogression PARP inhibitor treatment had a confounding influence on the interim OS analysis for BRCAm patients. There is a degree of uncertainty due to the small sample size and the lack of data maturity.

Original languageEnglish (US)
JournalCancer
DOIs
StateAccepted/In press - 2016

Fingerprint

Poly Adenosine Diphosphate Ribose
Platinum
Ovarian Neoplasms
Mutation
Survival
Adenosine Diphosphate Ribose
Placebos
Therapeutics
Survival Analysis
olaparib
Confidence Intervals
Proportional Hazards Models
Sample Size
Disease-Free Survival
Uncertainty

Keywords

  • BRCA mutation
  • Olaparib
  • Ovarian cancer
  • Overall survival
  • Poly(adenosine diphosphate ribose) polymerase (PARP) inhibitor

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Olaparib maintenance therapy in patients with platinum-sensitive, relapsed serous ovarian cancer and a BRCA mutation : Overall survival adjusted for postprogression poly(adenosine diphosphate ribose) polymerase inhibitor therapy. / Matulonis, Ursula A.; Harter, Philipp; Gourley, Charlie; Friedlander, Michael; Vergote, Ignace; Rustin, Gordon; Scott, Clare; Meier, Werner; Shapira-Frommer, Ronnie; Safra, Tamar; Matei, Daniela; Fielding, Anitra; Spencer, Stuart; Parry, David; Grinsted, Lynda; Ledermann, Jonathan A.

In: Cancer, 2016.

Research output: Contribution to journalArticle

Matulonis, UA, Harter, P, Gourley, C, Friedlander, M, Vergote, I, Rustin, G, Scott, C, Meier, W, Shapira-Frommer, R, Safra, T, Matei, D, Fielding, A, Spencer, S, Parry, D, Grinsted, L & Ledermann, JA 2016, 'Olaparib maintenance therapy in patients with platinum-sensitive, relapsed serous ovarian cancer and a BRCA mutation: Overall survival adjusted for postprogression poly(adenosine diphosphate ribose) polymerase inhibitor therapy', Cancer. https://doi.org/10.1002/cncr.29995
Matulonis, Ursula A. ; Harter, Philipp ; Gourley, Charlie ; Friedlander, Michael ; Vergote, Ignace ; Rustin, Gordon ; Scott, Clare ; Meier, Werner ; Shapira-Frommer, Ronnie ; Safra, Tamar ; Matei, Daniela ; Fielding, Anitra ; Spencer, Stuart ; Parry, David ; Grinsted, Lynda ; Ledermann, Jonathan A. / Olaparib maintenance therapy in patients with platinum-sensitive, relapsed serous ovarian cancer and a BRCA mutation : Overall survival adjusted for postprogression poly(adenosine diphosphate ribose) polymerase inhibitor therapy. In: Cancer. 2016.
@article{f34dcb6ac4da4854b27995d9363804e5,
title = "Olaparib maintenance therapy in patients with platinum-sensitive, relapsed serous ovarian cancer and a BRCA mutation: Overall survival adjusted for postprogression poly(adenosine diphosphate ribose) polymerase inhibitor therapy",
abstract = "BACKGROUND: Maintenance treatment with the oral poly(adenosine diphosphate ribose) polymerase (PARP) inhibitor olaparib (Lynparza) in Study 19 (study number, D0810C00019; ClinicalTrials.gov identifier, NCT00753545) significantly improved progression-free survival in comparison with a placebo for patients with platinum-sensitive, relapsed serous ovarian cancer with a BRCA1/2 mutation (BRCAm), but an interim analysis revealed no statistically significant overall survival (OS) benefit. However, 23{\%} of the patients receiving the placebo switched to a PARP inhibitor after progression. To investigate whether this had a confounding effect on OS, this article reports an exploratory post hoc analysis that excluded all patients from sites where 1 or more placebo patients received postprogression PARP inhibitor treatment. METHODS: In Study 19, 136 of the 265 patients receiving olaparib or a placebo had a BRCAm. Sixteen patients treated at 11 of the 82 investigational sites received a PARP inhibitor after progression; these sites were excluded from this analysis, and 97 BRCAm patients at 50 sites were included. OS was assessed with a Cox proportional hazards model analogous to the primary study analysis. A supporting rank-preserving structural failure time (RPSFT) model analysis was undertaken for all 136 BRCAm patients. RESULTS: The OS hazard ratio (HR) was 0.52 (95{\%} confidence interval [CI], 0.28-0.97) for the 97 BRCAm patients, whereas for the interim OS analysis with all 136 BRCAm patients, it was 0.73 (95{\%} CI, 0.45-1.17). The supportive RPSFT analysis HR was approximately 0.66. CONCLUSIONS: The numerical improvement in the OS HR suggests that in Study 19, postprogression PARP inhibitor treatment had a confounding influence on the interim OS analysis for BRCAm patients. There is a degree of uncertainty due to the small sample size and the lack of data maturity.",
keywords = "BRCA mutation, Olaparib, Ovarian cancer, Overall survival, Poly(adenosine diphosphate ribose) polymerase (PARP) inhibitor",
author = "Matulonis, {Ursula A.} and Philipp Harter and Charlie Gourley and Michael Friedlander and Ignace Vergote and Gordon Rustin and Clare Scott and Werner Meier and Ronnie Shapira-Frommer and Tamar Safra and Daniela Matei and Anitra Fielding and Stuart Spencer and David Parry and Lynda Grinsted and Ledermann, {Jonathan A.}",
year = "2016",
doi = "10.1002/cncr.29995",
language = "English (US)",
journal = "Cancer",
issn = "0008-543X",
publisher = "John Wiley and Sons Inc.",

}

TY - JOUR

T1 - Olaparib maintenance therapy in patients with platinum-sensitive, relapsed serous ovarian cancer and a BRCA mutation

T2 - Overall survival adjusted for postprogression poly(adenosine diphosphate ribose) polymerase inhibitor therapy

AU - Matulonis, Ursula A.

AU - Harter, Philipp

AU - Gourley, Charlie

AU - Friedlander, Michael

AU - Vergote, Ignace

AU - Rustin, Gordon

AU - Scott, Clare

AU - Meier, Werner

AU - Shapira-Frommer, Ronnie

AU - Safra, Tamar

AU - Matei, Daniela

AU - Fielding, Anitra

AU - Spencer, Stuart

AU - Parry, David

AU - Grinsted, Lynda

AU - Ledermann, Jonathan A.

PY - 2016

Y1 - 2016

N2 - BACKGROUND: Maintenance treatment with the oral poly(adenosine diphosphate ribose) polymerase (PARP) inhibitor olaparib (Lynparza) in Study 19 (study number, D0810C00019; ClinicalTrials.gov identifier, NCT00753545) significantly improved progression-free survival in comparison with a placebo for patients with platinum-sensitive, relapsed serous ovarian cancer with a BRCA1/2 mutation (BRCAm), but an interim analysis revealed no statistically significant overall survival (OS) benefit. However, 23% of the patients receiving the placebo switched to a PARP inhibitor after progression. To investigate whether this had a confounding effect on OS, this article reports an exploratory post hoc analysis that excluded all patients from sites where 1 or more placebo patients received postprogression PARP inhibitor treatment. METHODS: In Study 19, 136 of the 265 patients receiving olaparib or a placebo had a BRCAm. Sixteen patients treated at 11 of the 82 investigational sites received a PARP inhibitor after progression; these sites were excluded from this analysis, and 97 BRCAm patients at 50 sites were included. OS was assessed with a Cox proportional hazards model analogous to the primary study analysis. A supporting rank-preserving structural failure time (RPSFT) model analysis was undertaken for all 136 BRCAm patients. RESULTS: The OS hazard ratio (HR) was 0.52 (95% confidence interval [CI], 0.28-0.97) for the 97 BRCAm patients, whereas for the interim OS analysis with all 136 BRCAm patients, it was 0.73 (95% CI, 0.45-1.17). The supportive RPSFT analysis HR was approximately 0.66. CONCLUSIONS: The numerical improvement in the OS HR suggests that in Study 19, postprogression PARP inhibitor treatment had a confounding influence on the interim OS analysis for BRCAm patients. There is a degree of uncertainty due to the small sample size and the lack of data maturity.

AB - BACKGROUND: Maintenance treatment with the oral poly(adenosine diphosphate ribose) polymerase (PARP) inhibitor olaparib (Lynparza) in Study 19 (study number, D0810C00019; ClinicalTrials.gov identifier, NCT00753545) significantly improved progression-free survival in comparison with a placebo for patients with platinum-sensitive, relapsed serous ovarian cancer with a BRCA1/2 mutation (BRCAm), but an interim analysis revealed no statistically significant overall survival (OS) benefit. However, 23% of the patients receiving the placebo switched to a PARP inhibitor after progression. To investigate whether this had a confounding effect on OS, this article reports an exploratory post hoc analysis that excluded all patients from sites where 1 or more placebo patients received postprogression PARP inhibitor treatment. METHODS: In Study 19, 136 of the 265 patients receiving olaparib or a placebo had a BRCAm. Sixteen patients treated at 11 of the 82 investigational sites received a PARP inhibitor after progression; these sites were excluded from this analysis, and 97 BRCAm patients at 50 sites were included. OS was assessed with a Cox proportional hazards model analogous to the primary study analysis. A supporting rank-preserving structural failure time (RPSFT) model analysis was undertaken for all 136 BRCAm patients. RESULTS: The OS hazard ratio (HR) was 0.52 (95% confidence interval [CI], 0.28-0.97) for the 97 BRCAm patients, whereas for the interim OS analysis with all 136 BRCAm patients, it was 0.73 (95% CI, 0.45-1.17). The supportive RPSFT analysis HR was approximately 0.66. CONCLUSIONS: The numerical improvement in the OS HR suggests that in Study 19, postprogression PARP inhibitor treatment had a confounding influence on the interim OS analysis for BRCAm patients. There is a degree of uncertainty due to the small sample size and the lack of data maturity.

KW - BRCA mutation

KW - Olaparib

KW - Ovarian cancer

KW - Overall survival

KW - Poly(adenosine diphosphate ribose) polymerase (PARP) inhibitor

UR - http://www.scopus.com/inward/record.url?scp=84963823064&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84963823064&partnerID=8YFLogxK

U2 - 10.1002/cncr.29995

DO - 10.1002/cncr.29995

M3 - Article

C2 - 27062051

AN - SCOPUS:84963823064

JO - Cancer

JF - Cancer

SN - 0008-543X

ER -