Benchmarking progression-free survival ratio as primary endpoint in precision oncology clinical trials
Progression Free Survival Ratio (PFSratio), as defined as the ratio between PFS on investigational treatment (PFS2) and PFS on the last prior therapy (PFS1), is a popular endpoint in precision oncology (PO) studies. In this work, five methodologies for PFSratio-based trial analysis (count-based, Kaplan Meier, Kernel-based Kaplan Meier, parametric and midrank) and two for trial design (GBVE and Weibull) are benchmarked. The Kernel-based Kaplan Meier analysis is most recommended, as it handles informative censoring and does not require PFS1/PFS2 distribution assumptions. Sample size and power calculation methods perform best when applied to settings with expected high PFS1/PFS2 correlation and median ratio. Analysis of five clinical trials (MOSCATO 01, WINTHER, MASTER, SHIVA and POG570) from >800 patients revealed an overall weak PFS1/PFS2 correlation (Kendall's τ range 0.17-0.35), and an asymptotically unbiased median S<sub>PFSratio</sub>(δ=1.3) = 33% by means of the Kernel-based analysis, while other methods considerably deviated in studies with censoring rate>10%. This methodology is implemented in the PROPHETS R package and Shiny app.
Authors
- Daniel Hübschmann (ORCID: https://orcid.org/0000-0002-6041-7049)
- Simone Rota (ORCID: https://orcid.org/0009-0006-9172-7003)
- Stefan Fröhling (ORCID: https://orcid.org/0000-0001-7907-4595)
- Filippo de Braud (ORCID: https://orcid.org/0000-0003-0103-730X)
- Erin Pleasance (ORCID: https://orcid.org/0000-0002-5104-042X)
- Luca Agnelli (ORCID: https://orcid.org/0000-0003-0582-6170)
- Dominic Edelmann (ORCID: https://orcid.org/0000-0001-7467-6343)
- Pauline du Rusquec (ORCID: https://orcid.org/0000-0001-5803-4850)
- Peter Horak (ORCID: https://orcid.org/0000-0003-4536-9306)
- Monica Niger
- Gabriele Tinè (ORCID: https://orcid.org/0000-0003-1762-1375)
- Christophe Le Tourneau (ORCID: https://orcid.org/0000-0001-9772-4686)
- Paolo Ambrosini
- Andreas Möck (ORCID: https://orcid.org/0000-0002-3332-9166)
- Federico Nichetti (ORCID: https://orcid.org/0000-0001-8044-4207)
- Giancarlo Pruneri (ORCID: https://orcid.org/0000-0002-7963-7172)
- Jennifer Hüllein
- Janessa Laskin (ORCID: https://orcid.org/0000-0002-0161-9329)
- Luigi Mariani (ORCID: https://orcid.org/0000-0001-6208-4084)
- Chi Wang (ORCID: https://orcid.org/0000-0001-8984-4995)
- Li Chen (ORCID: https://orcid.org/0000-0002-9478-6432)
Institutions
- University of Kentucky (US)
- Inserm (FR)
- German Cancer Research Center (DE)
- University of Milan (IT)
- Heidelberg University (DE)
- Université Paris-Saclay (FR)
- Markey Cancer Center (US)
- Istituto Oncologico Veneto (IT)
- National Center for Tumor Diseases (DE)
- Canada's Michael Smith Genome Sciences Centre (CA)
- Heidelberg Institute for Stem Cell Technology and Experimental Medicine (DE)
- Istituti di Ricovero e Cura a Carattere Scientifico (IT)
- Fondazione IRCCS Istituto Nazionale dei Tumori (IT)
- Deutsches Konsortium für Translationale Krebsforschung (DE)
- Institut Curie (FR)
- Ludwig-Maximilians-Universität München (DE)
Publication Details
- Journal
- npj Precision Oncology
- Published
- 2025-12-15
- DOI
- https://doi.org/10.1038/s41698-025-01231-x
- Citations
- 1
- Primary Topic
- Statistical Methods in Clinical Trials
- Type
- article
- Field-Weighted Citation Impact
- 2.63