Prognostic nomogram for progression-free survival in patients with BRCA mutations and platinum-sensitive recurrent ovarian cancer on maintenance olaparib therapy following response to chemotherapy

Angelina Tjokrowidjaja; Michael Friedlander; Sarah J Lord; Rebecca Asher; Manuel Rodrigues; Jonathan A Ledermann; Ursula A Matulonis; Amit M Oza; Ilan Bruchim; Tomasz Huzarski; Charlie Gourley; Philipp Harter; Ignace Vergote; Clare L Scott; Werner Meier; Ronnie Shapira-Frommer; Tsveta Milenkova; Eric Pujade-Lauraine; Val Gebski; Chee K Lee

doi:10.1016/j.ejca.2021.06.024

Prognostic nomogram for progression-free survival in patients with BRCA mutations and platinum-sensitive recurrent ovarian cancer on maintenance olaparib therapy following response to chemotherapy

Eur J Cancer. 2021 Sep:154:190-200. doi: 10.1016/j.ejca.2021.06.024. Epub 2021 Jul 19.

Authors

Angelina Tjokrowidjaja¹, Michael Friedlander², Sarah J Lord³, Rebecca Asher⁴, Manuel Rodrigues⁵, Jonathan A Ledermann⁶, Ursula A Matulonis⁷, Amit M Oza⁸, Ilan Bruchim⁹, Tomasz Huzarski¹⁰, Charlie Gourley¹¹, Philipp Harter¹², Ignace Vergote¹³, Clare L Scott¹⁴, Werner Meier¹⁵, Ronnie Shapira-Frommer¹⁶, Tsveta Milenkova¹⁷, Eric Pujade-Lauraine¹⁸, Val Gebski⁴, Chee K Lee¹⁹

Affiliations

¹ National Health and Medical Research Council Clinical Trials Centre, The University of Sydney, Sydney, NSW 2050, Australia; Department of Medical Oncology, St George Hospital, Kogarah, NSW 2217, Australia; Australia New Zealand Gynecological Oncology Group, Camperdown, New South Wales, Australia. Electronic address: [email protected].
² Australia New Zealand Gynecological Oncology Group, Camperdown, New South Wales, Australia; Department of Medical Oncology, Prince of Wales Hospital, Randwick, NSW 2031, Australia.
³ National Health and Medical Research Council Clinical Trials Centre, The University of Sydney, Sydney, NSW 2050, Australia; School of Medicine, The University of Notre Dame, Sydney, NSW 2007, Australia.
⁴ National Health and Medical Research Council Clinical Trials Centre, The University of Sydney, Sydney, NSW 2050, Australia.
⁵ INSERM U830, DNA Repair and Uveal Melanoma (D.R.U.M.), Equipe Labellisée Par La Ligue Nationale Contre le Cancer, Paris, France; Department of Medical Oncology, Institut Curie, PSL Research University, Paris, France.
⁶ UCL Cancer Institute, University College London, London WC1E 6DD, Great Britain, UK.
⁷ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
⁸ Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON M5G 2C1, Canada.
⁹ Gynecologic Oncology Division, Hillel Yaffe Medical Center, Technion Institute of Technology, Haifa, Israel.
¹⁰ Department of Genetics and Pathology, Pomeranian Medical University, 70-204 Szczecin, Poland.
¹¹ Nicola Murray Centre for Ovarian Cancer Research, Cancer Research UK Edinburgh Centre, MRC IGMM, University of Edinburgh, Western General Hospital, Edinburgh, UK.
¹² Department of Gynecology and Gynecologic Oncology, Kliniken Essen-Mitte, Essen, Germany.
¹³ Department of Oncology, KU Leuven - University of Leuven, B-3000 Leuven, Belgium; Division of Gynaecological Oncology, University Hospitals Leuven, B-3000 Leuven, Belgium.
¹⁴ Walter and Eliza Hall Institute of Medical Research, Stem Cells, and Cancer, University of Melbourne, Melbourne, Victoria, Australia.
¹⁵ Department of Gynaecology and Obstetrics, Evangelisches Krankenhaus Düsseldorf, Germany; University Hospital Düsseldorf, Düsseldorf, Germany.
¹⁶ Sheba Medical Center, Ramat-Gan, Israel.
¹⁷ AstraZeneca, Cambridge, United Kingdom.
¹⁸ Université Paris Descartes, Paris, France; ARCAGY-GINECO, Australia.
¹⁹ National Health and Medical Research Council Clinical Trials Centre, The University of Sydney, Sydney, NSW 2050, Australia; Department of Medical Oncology, St George Hospital, Kogarah, NSW 2217, Australia; Australia New Zealand Gynecological Oncology Group, Camperdown, New South Wales, Australia.

PMID: 34293664
DOI: 10.1016/j.ejca.2021.06.024

Abstract

Background: The impact of maintenance therapy with PARP inhibitors (PARPi) on progression-free survival (PFS) in patients with BRCA mutations and platinum-sensitive recurrent ovarian cancer (PSROC) varies widely. Individual prognostic factors do not reliably distinguish patients who progress early from those who have durable benefit. We developed and validated a prognostic nomogram to predict PFS in these patients.

Methods: The nomogram was developed using data from a training patient cohort with BRCA mutations and high-grade serous PSROC on the placebo arm of two maintenance therapy trials, Study 19 and SOLO2/ENGOT-ov21. We performed multivariable Cox regression analysis based on pre-treatment characteristics to develop a nomogram that predicts PFS. We assessed the discrimination and validation of the nomogram in independent validation patient cohorts treated with maintenance olaparib.

Results: The nomogram includes four PFS predictors: CA-125 at randomisation, platinum-free interval, presence of measurable disease and number of prior lines of platinum therapy. In the training (placebo) cohort (internal validation C-index 0.64), median PFS in the model-predicted good, intermediate and poor-risk groups was: 7.7 (95% CI 5.3-11.3), 5.4 (4.8-5.8) and 2.9 (2.8-4.4) months, respectively. In the validation (olaparib) cohort (C-index 0.71), median PFS in the model-predicted good, intermediate and poor-risk groups was: not reached, 16.6 (13.1-22.4) and 8.3 (7.1-10.8) months, respectively. The nomogram showed good calibration in the validation cohort (calibration plot).

Conclusions: This nomogram can be used to predict PFS and counsel patients with BRCA mutations and PSROC prior to maintenance olaparib and for stratification of patients in trials of maintenance therapies.

Keywords: BRCA mutation; Nomogram; Olaparib; Ovarian cancer; Poly(ADP-ribose) polymerase inhibitors; Prognosis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Aged, 80 and over
Female
Genes, BRCA1*
Genes, BRCA2*
Humans
Middle Aged
Mutation*
Neoplasm Recurrence, Local / drug therapy*
Nomograms*
Ovarian Neoplasms / drug therapy*
Ovarian Neoplasms / genetics
Ovarian Neoplasms / mortality
Phthalazines / toxicity*
Piperazines / toxicity*
Prognosis
Progression-Free Survival

Substances

Phthalazines
Piperazines
olaparib