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Patient-reported outcomes and final overall survival results from the randomized phase 3 PENELOPE trial evaluating pertuzumab in low tumor human epidermal growth factor receptor 3 (HER3) mRNA-expressing platinum-resistant ovarian cancer
  1. Domenica Lorusso1,
  2. Felix Hilpert2,3,
  3. Antonio González Martin4,5,
  4. Joern Rau6,
  5. Petronella Ottevanger7,
  6. Elfriede Greimel8,
  7. Hans-Joachim Lück9,
  8. Frédéric Selle10,
  9. Nicoletta Colombo11,
  10. Judith R Kroep12,
  11. Mansoor R Mirza13,
  12. Regina Berger14,
  13. Beatriz Pardo15,
  14. Eva-Maria Grischke16,
  15. Dominique Berton-Rigaud17,
  16. Jeronimo Martinez-Garcia18,
  17. Ignace Vergote19,
  18. Andrés Redondo20,
  19. Andrés Cardona21,
  20. Lydie Bastière-Truchot21,
  21. Andreas du Bois22 and
  22. Christian Kurzeder22,23
  23. On behalf of the PENELOPE trial investigators
  1. 1Fondazione Policlinico Universitario A Gemelli IRCCS, Rome, Italy
  2. 2Arbeitsgemeinschaft Gynäkologische Onkologie (AGO) and Klinik für Gynäkologie und Geburtshilfe, Kiel, Germany (affiliation when work was performed)
  3. 3Mammazentrum am Krankenhaus Jerusalem, Hamburg, Germany
  4. 4Grupo Español de Investigación en Cáncer de Ovario (GEICO) and MD Anderson Cancer Center Spain, Madrid, Spain (affiliation when work was performed)
  5. 5Clínica Universidad de Navarra, Madrid, Spain
  6. 6Coordinating Center for Clinical Trials, Philipps-University of Marburg, Marburg, Germany
  7. 7Dutch Gynaecological Oncology Group (DGOG) and Department of Medical Oncology, Radboud University Medical Center, Nijmegen, Netherlands
  8. 8Medical University Graz, Graz, Austria
  9. 9AGO and Gynäkologisch-Onkologische Praxis am Pelikanplatz, Hannover, Germany
  10. 10Groupe d’Investigateurs Nationaux pour l’Etude des Cancers Ovariens (GINECO), Groupe Hospitalier Diaconesses Croix Saint-Simon and Alliance Pour la Recherche en Cancérologie, Paris, France
  11. 11Mario Negri Gynecologic Oncology (MaNGO) group, IEO, European Institute of Oncology IRCCS, and University of Milan-Bicocca, Milan, Italy
  12. 12DGOG and Department of Medical Oncology, Leids Universitair Medisch Centrum, Leiden, Netherlands
  13. 13Nordic Society of Gynaecological Oncology (NSGO) and Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
  14. 14AGO-Austria and University Hospital for Gynaecology and Obstetrics, Medical University of Innsbruck, Innsbruck, Austria
  15. 15GEICO and Medical Oncology Department, Institut Català d’Oncologia, Hospital Duran i Reynals, Barcelona, Spain
  16. 16AGO and University Hospital of Gynecology and Obstetrics, Tübingen, Germany
  17. 17GINECO and Integrated Center for Oncology Nantes-Angers, Nantes, France
  18. 18GEICO and Medical Oncology Service, Hospital Clínico Universitario Virgen de la Arrixaca, El Palmar, Spain
  19. 19AGO and Leuven Cancer Institute, University Hospital Leuven, Leuven, Belgium
  20. 20GEICO and Medical Oncology Department, Hospital Universitario La Paz-IdiPAZ, Madrid, Spain
  21. 21F. Hoffmann-La Roche, Basel, Switzerland
  22. 22AGO and Kliniken Essen Mitte, Essen, Germany
  23. 23Department of Gynecology and Gynecological Oncology, University Hospital Basel, University of Basel, Basel, Switzerland
  1. Correspondence to Dr Domenica Lorusso, Fondazione Policlinico Universitario A Gemelli IRCCS Largo Francesco Vito 1, Rome 00168, Italy; domenica.lorusso{at}


Introduction The PENELOPE trial evaluated pertuzumab added to chemotherapy for biomarker-selected platinum-resistant ovarian cancer. As previously reported, pertuzumab did not statistically significantly improve progression-free survival (primary end point: HR 0.74, 95% CI 0.50 to 1.11), although results in the paclitaxel and gemcitabine cohorts suggested activity. Here, we report final overall survival and patient-reported outcomes.

Patients and methods Eligible patients had ovarian carcinoma that progressed during/within 6 months of completing ≥4 platinum cycles, low tumor human epidermal growth factor receptor 3 (HER3) mRNA expression, and ≤2 prior chemotherapy lines. Investigators selected single-agent topotecan, gemcitabine or weekly paclitaxel before patients were randomized to either placebo or pertuzumab (840→420 mg every 3 weeks), stratified by selected chemotherapy, prior anti-angiogenic therapy, and platinum-free interval. Final overall survival analysis (key secondary end point) was pre-specified after 129 deaths. Patient-reported outcomes (secondary end point) were assessed at baseline and every 9 weeks until disease progression.

Results At database lock (June 9, 2016), 130 (83%) of 156 randomized patients had died. Median follow-up was 27 months in the pertuzumab arm versus 26 months in the control arm. In the intent-to-treat population there was no overall survival difference between treatment arms (stratified HR 0.90, 95% CI 0.61 to 1.32; p=0.60). Results in subgroups defined by stratification factors indicated heterogeneity similar to previous progression-free survival results. Updated safety was similar to previously published results. Compliance with patient-reported outcomes questionnaire completion was >75% for all validated patient-reported outcomes measures. Pertuzumab demonstrated neither beneficial nor detrimental effects on patient-reported outcomes compared with placebo, except for increased diarrhea symptoms.

Discussion Consistent with the primary results, adding pertuzumab to chemotherapy for low tumor HER3 mRNA-expressing platinum-resistant ovarian cancer did not improve overall survival, but showed trends in some cohorts. Except for increased diarrhea symptoms, pertuzumab had no impact on patient-reported outcomes. NCT01684878.

  • HER3
  • ovarian cancer
  • overall survival
  • patient-reported outcomes
  • pertuzumab

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  • DL and FH contributed equally.

  • Collaborators J.M. del Campo, I. Bover, P. Barretina-Ginesta, E. Ortega, Y. Garcia, I. Romero, A. Poveda, A. Herrero, L. Vidal, M.J. Rubio, M. Romeo, C. Mendiola, J.A. Arranz, A. Santaballa and A. Gomez de Liano (Grupo Español de Investigación en Cáncer de Ovario); F. Marmé, S. Mahner, U. Canzler, A. Zorr, M. Gropp-Meier, P. Cayir, B. Schmalfeldt, B. Rautenberg, W. Meier, A. Belau, B. Gerber, D. Rein, C. Jackisch, W. Janni and M. Heubner (Arbeitsgemeinschaft Gynaekologische Onkologie Study Group); P. Pautier, M. Fabbro, A. Floquet, B. You, L. Favier, F. Joly, B. Weber and A.-C. Hardy-Bessard (Group d’Investigateurs Nationaux pour l’Étude des Cancers Ovariens); A. Gadducci, G. Tognon and A. DeCensi (Mario Negri Gynecologic Oncology Group); A. Savarese and C. Pisano (Multicenter Italian Trials in Ovarian Cancer); G. Sonke and A. Reyners (Dutch Gynecologic Oncology Group); G. Kristensen, M. Bjurberg and P. Rosenberg (Nordic Society of Gynaecological Oncology); and C. Marth (Arbeitsgemeinschaft Gynaekologische Onkologie-Austria).

  • Contributors Conception and design: CK, JR, IV, LB-T, AdB. Provision of study materials or patients: DL, AG-M, PO, H-JL, FS, NC, JRK, MRM, BP, E-MG, DB-R, JM-G, IV, AR, AdB, CK. Data analysis and interpretation: DL, FH, JR, AC, CK. Manuscript writing: All authors. Final approval of manuscript: All authors.

  • Funding This work was supported by F. Hoffmann-La Roche, Basel, Switzerland. No grant number applicable. F. Hoffmann-La Roche was involved in the design of the trial in collaboration with the Steering Committee. Authors representing F. Hoffmann-La Roche contributed to analysis and interpretation of the data and critical review of the manuscript. The decision to submit the paper for publication was the responsibility of the joint first authors and the Principal Investigator.

  • Competing interests DL has participated in advisory boards for Roche, AstraZeneca, Clovis, Merck and Tesaro; her institution has received research support from Clovis, PharmaMar and Merck. FH has a consultant and advisory relationship with Roche, AstraZeneca and MSD. AGM has consulting and advisory relationships with Roche, Tesaro, AstraZeneca, Pfizer, Clovis, PharmaMar and ImmunoGen. PO has a consulting or advisory role with Novartis, GSK, MSD, Clovis and Tesaro. FS has served as a consultant for Roche and Tesaro. NC has received personal fees from AstraZeneca, Clovis, Tesaro, Roche, PharmaMar, Takeda and Pfizer. BP has participated in advisory boards for Clovis and Tesaro. IV has participated in advisory boards for Advaxis Inc, Eisai Inc, MSD Belgium, Roche NV, Genmab A/S, F. Hoffmann-La Roche Ltd, PharmaMar, Millennium Pharmaceuticals, Clovis Oncology Inc, AstraZeneca NV, Novocure GMBH, Morphotek Inc, Mateon Therapeutics Inc, Immunogen Inc, Eli Lilly Benelux NV, Amgen Inc, Pfizer Inc, Vifor Pharma België NV, Novartis Pharma AG, Oxigene Inc, Nektar Therapeutics and Bayer Pharma AG, has contract research (via K U Leuven) with Oncoinvent AS and Genmab A/S – Genmab B.V., has received grants for corporate-sponsored research from Amgen and Roche, and has received accommodation/travel expenses from Takeda Oncology, PharmaMar, Genmab, Roche and AstraZeneca. AR has consultant and advisory roles with Roche, Tesaro, AstraZeneca, Clovis, PharmaMar, Amgen, Lilly and Novartis, and research funding from Roche, PharmaMar and Eisai. AC and LB-T are employees of and shareholders in Roche. AdB has a consulting and advisory relationship with AstraZeneca, Roche, Tesaro, Pfizer, Clovis, PharMar and Genmab. CK has a consultant and advisory relationships with Roche, AstraZeneca, Tesaro and Genomic Health. All remaining authors have declared no conflicts of interest.

  • Patient consent for publication Not required.

  • Ethics approval The trial conformed to the Declaration of Helsinki and Good Clinical Practice guidelines and was approved by the ethics committee of each participating site.

  • Provenance and peer review Not commissioned; externally peer reviewed.