Ursula A Matulonis1, Philipp Harter2, Charlie Gourley3, Michael Friedlander4, Ignace Vergote5, Gordon Rustin6, Clare Scott7, Werner Meier8, Ronnie Shapira-Frommer9, Tamar Safra10, Daniela Matei11, Anitra Fielding12, Stuart Spencer12, David Parry12, Lynda Grinsted12, Jonathan A Ledermann13. 1. Dana-Farber Cancer Institute, Boston, Massachusetts. 2. Kliniken Essen-Mitte, Essen, Germany. 3. Edinburgh Cancer Research UK Centre, University of Edinburgh, Edinburgh, United Kingdom. 4. Prince of Wales Hospital, Randwick, New South Wales, Australia. 5. University of Leuven, Leuven, Belgium. 6. Mount Vernon Hospital, Northwood, United Kingdom. 7. Royal Melbourne Hospital, Melbourne, Victoria, Australia. 8. Evangelical Hospital, Dusseldorf, Germany. 9. Chaim Sheba Medical Center, Tel Hashomer, Israel. 10. Tel Aviv Sourasky Medical Center, Tel Aviv, Israel. 11. Indiana University School of Medicine, Indianapolis, Indiana. 12. AstraZeneca, Macclesfield, United Kingdom. 13. University College London, London, United Kingdom.
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. Cancer 2016;122:1844-52.
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. Cancer 2016;122:1844-52.
Authors: Kent W Mouw; Michael S Goldberg; Panagiotis A Konstantinopoulos; Alan D D'Andrea Journal: Cancer Discov Date: 2017-06-19 Impact factor: 39.397
Authors: Smita Kumari; Sudhanshu Sharma; Dia Advani; Akanksha Khosla; Pravir Kumar; Rashmi K Ambasta Journal: Environ Sci Pollut Res Int Date: 2021-10-05 Impact factor: 5.190
Authors: Panagiotis A Konstantinopoulos; Barbara Norquist; Christina Lacchetti; Deborah Armstrong; Rachel N Grisham; Paul J Goodfellow; Elise C Kohn; Douglas A Levine; Joyce F Liu; Karen H Lu; Dorinda Sparacio; Christina M Annunziata Journal: J Clin Oncol Date: 2020-01-27 Impact factor: 44.544