Validation of metastasis-free survival as a surrogate endpoint for overall survival in localized prostate cancer in the era of docetaxel for castration resistant prostate cancer
Xie, W. Ravi, P. Buyse, M. Halabi, S. Kantoff, P. Sartor, O. Soule, H. Clarke, Noel Dignam, J. James, N.
Xie, W.
Ravi, P.
Buyse, M.
Halabi, S.
Kantoff, P.
Sartor, O.
Soule, H.
Clarke, Noel
Dignam, J.
James, N.
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Abstract
BACKGROUND: 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. PATIENTS & METHODS: 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 R(2) ≥0.7 defined a priori as clinically relevant. RESULTS: 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 R(2) 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, R(2) 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. CONCLUSION: 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.
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Date
2023
Publisher
Collections
Keywords
Type
Article
Citation
Xie W, Ravi P, Buyse M, Halabi S, Kantoff P, Sartor O, et al. VALIDATION OF METASTASIS-FREE SURVIVAL AS A SURROGATE ENDPOINT FOR OVERALL SURVIVAL IN LOCALIZED PROSTATE CANCER IN THE ERA OF DOCETAXEL FOR CASTRATION RESISTANT PROSTATE CANCER. Annals of oncology : official journal of the European Society for Medical Oncology. 2023 Dec 5. PubMed PMID: 38061427. Epub 2023/12/08. eng.