Prior work from the Intermediate Clinical Endpoints in Cancer of the Prostate (ICECaP) consortium (ICECaP-1) demonstrated that metastasis-free survival (MFS) is a valid surrogate for overall survival (OS) in localized prostate cancer (PCa). This was based on data from patients treated predominantly before 2004, prior to docetaxel being available for the treatment of metastatic castrate-resistant prostate cancer (mCRPC). We sought to validate surrogacy in a more contemporary era (ICECaP-2) with greater availability of docetaxel and other systemic therapies for mCRPC.
Eligible trials for ICECaP-2 were those providing individual patient data (IPD) after publication of ICECaP-1 and evaluating adjuvant/salvage therapy for localized PCa, and which collected MFS and OS data. MFS was defined as distant metastases or death from any cause, and OS defined as death from any cause. Surrogacy was evaluated using a meta-analytic two-stage validation model, with an R2 ≥0.7 defined a priori as clinically relevant.
15,164 IPD from 14 trials were included in ICECaP-2, with 70% of patients treated after 2004. Median follow-up was 8.3 years and median post-metastasis survival was 3.1 years in ICECaP-2, compared to 1.9 years in ICECaP-1. For surrogacy condition 1, Kendall's tau was 0.92 for MFS with OS at the patient-level, and R2 from weighted linear regression (WLR) of 8-yr OS on 5-yr MFS was 0.73 (95% CI 0.53-0.82) at the trial level. For condition 2, R2 was 0.83 (0.64-0.89) from WLR of log(HR)-OS on log(HR)-MFS. The surrogate threshold effect on OS was an HR(MFS) of 0.81.
MFS remained a valid surrogate for OS in a more contemporary era, where patients had greater access to docetaxel and other systemic therapies for mCRPC. This supports the use of MFS as the primary outcome measure for ongoing adjuvant trials in localized PCa.
Annals of oncology : official journal of the European Society for Medical Oncology. 2023 Dec 05 [Epub ahead of print]
W Xie, P Ravi, M Buyse, S Halabi, P Kantoff, O Sartor, H Soule, N Clarke, J Dignam, N James, K Fizazi, S Gillessen, N Mottet, L Murphy, W Parulekar, H Sandler, B Tombal, S Williams, C J Sweeney
Dana-Farber Cancer Institute, Boston, MA, USA., International Drug Development Institute, Louvain-la-Neuve, Belgium; I-BioStat, Hasselt University, Hasselt, Belgium., Duke University, Durham, NC, USA., Convergent Therapeutics, Cambridge, MA, USA., Mayo Clinic, Rochester, MN, USA., Prostate Cancer Foundation, Santa Monica, CA, USA., The Christie NHS Foundation Trust, Manchester, UK., University of Chicago, Chicago, IL, USA., The Institute of Cancer Research & The Royal Marsden NHS Foundation Trust, London, UK., Institut Gustave Roussy, University of Paris Saclay, Villejuif, France., Oncology Institute of Southern Switzerland, EOC, Bellinzona, Switzerland; Università della Svizzera Italiana, Lugano, Switzerland., 4Mutualite Francoise Loire, St Etienne, France., Medical Research Council at UCL, London, United Kingdom., Queens University, Kingston, Ontario, Canada., Cedars-Sinai Medical Center, Los Angeles, CA, USA., Cliniques Universitaires Saint-Luc, Brussels, Belgium., Peter Maccallum Cancer Centre, Melbourne, Australia., South Australian Immunogenomics Cancer Institute, University of Adelaide, Adelaide, Australia. Electronic address: .