2710 - Surrogacy of Progression Free Survival to Overall Survival in Metastasis-Directed Therapies for Oligometastatic Cancer
Presenter(s)
D. Chen1, E. Khoshkish1, S. Lee1, N. N. Sanford2, D. A. Palma3, X. Y. Ye4, Z. Liu5, G. Boldt6, P. Wong7, and S. Raman7; 1University of Toronto, Toronto, ON, Canada, 2Harvard Radiation Oncology Program, Boston, MA, 3Division of Radiation Oncology, London Health Sciences Centre, London, ON, Canada, 4Department of Biostatistics, University Health Network, Toronto, ON, Canada, 5Department of Biostatistics, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada, 6Western University, London, ON, Canada, 7Department of Radiation Oncology, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada
Purpose/Objective(s): The oligometastatic state is characterized by limited metastatic burden for which metastasis-directed therapy (MDT) may provide durable control. Clinical endpoints selected for clinical trials of MDT interventions remain poorly standardized and may be prone to bias in endpoint selection that does not reflect long-term clinical benefit or patient priorities. We systematically reviewed clinical endpoints in prospective MDT trials and trial registrations to inform a phase-appropriate, patient-centred framework to the design of clinical trials assessing MDT in oligometastatic cancer.
Materials/Methods: We searched Ovid MEDLINE, Embase, CENTRAL, and ClinicalTrials.gov from inception to June 19 2025. We included prospective studies that enrolled exclusively oligometastatic populations and evaluated MDT. Two reviewers independently screened and extracted study design, disease state, interventions, and endpoints. Data were summarized descriptively and stratified by trial phase. Surrogacy of PFS to OS was conducted using weighted least squares meta-regression to determine surrogate threshold effect (STE) HR and Pearson correlation coefficient.
Results: This review included 235 trials, comprising 29 randomized trials, 35 non-randomized trials, and 171 prospective trial registrations. Among randomized trials, PFS was the most frequent primary endpoint (n=20, 67%), followed by OS(n=4, 13%). Among non-randomized studies, PFS similarly remained the most common primary endpoint (n=14, 45%), followed closely by local control (n=13, 42%). Among trial registrations, the most common primary endpoints included PFS (n=83, 47%), toxicity (n=23, 13%), and local control (n=11, 6%). To assess the surrogacy of the most prevalent primary clinical endpoint, PFS, with the gold standard endpoint of OS, we conducted a surrogacy meta-analysis of 18 randomized trials reporting both PFS and OS hazard ratios that demonstrated a moderate correlation (r=0.80, 95% CI 0.64–0.91) and a HR of 0.79 (95% CI 0.71–0.87) as the surrogate threshold effect of PFS to OS.
Conclusion: MDT trials in oligometastatic cancer predominantly use progression-based primary endpoints, with infrequent selection of OS and patient-reported outcomes. PFS demonstrates moderate validity as a surrogate endpoint for OS in trials evaluating MDT for oligometastatic cancer. We recommend phase-appropriate, patient-centered endpoint strategies where early-phase trials should pair standardized PFS and lesion-level control with QoL or systemic-therapy-free survival, while later-phase trials should also target OS or validated surrogates where durable benefit is expected. Harmonized endpoint definitions, fixed imaging frameworks, independent review, and lesion-level transparency are essential to advance consistent and patient-aligned evaluation of MDT efficacy.