Despite major increases in the longevity of men with metastatic hormone-sensitive prostate cancer (mHSPC), most men still die of prostate cancer. Phase III trials assessing new therapies in mHSPC with overall survival (OS) as the primary end point will take approximately a decade to complete. We investigated whether radiographic progression-free survival (rPFS) and clinical PFS (cPFS) are valid surrogates for OS in men with mHSPC and could potentially be used to expedite future phase III clinical trials.
We obtained individual patient data (IPD) from 9 eligible randomized trials comparing treatment regimens (different androgen deprivation therapy [ADT] strategies or ADT plus docetaxel in the control or research arms) in mHSPC. rPFS was defined as the time from random assignment to radiographic progression or death from any cause whichever occurred first; cPFS was defined as the time from random assignment to the date of radiographic progression, symptoms, initiation of new treatment, or death, whichever occurred first. We implemented a two-stage meta-analytic validation model where conditions of patient-level and trial-level surrogacy had to be met. We then computed the surrogate threshold effect (STE).
IPD from 6,390 patients randomly assigned from 1994 to 2012 from 13 units were pooled for a stratified analysis. The median OS, rPFS, and cPFS were 4.3 (95% CI, 4.2 to 4.5), 2.4 (95% CI, 2.3 to 2.5), and 2.3 years (95% CI, 2.2 to 2.4), respectively. The STEs were 0.80 and 0.81 for rPFS and cPFS end points, respectively.
Both rPFS and cPFS appear to be promising surrogate end points for OS. The STE of 0.80 or higher makes it viable for either rPFS or cPFS to be used as the primary end point that is surrogate for OS in phase III mHSPC trials with testosterone suppression alone as the backbone therapy and would expedite trial conduct.
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2024 Jan 05 [Epub ahead of print]
Susan Halabi, Akash Roy, Larysa Rydzewska, Siyuan Guo, Peter Godolphin, Maha Hussain, Catherine Tangen, Ian Thompson, Wanling Xie, Michael A Carducci, Matthew R Smith, Michael J Morris, Gwenaelle Gravis, David P Dearnaley, Paul Verhagen, Takayuki Goto, Nick James, Marc E Buyse, Jayne F Tierney, Christopher Sweeney, STOPCAP/ICECaP Collaboration
Duke University Medical Center, Duke University, Durham, NC., Medical Research Council Clinical Trials Unit at University College London, London, United Kingdom., Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL., Fred Hutchinson Cancer Research Center, Seattle, WA., Christus Health, San Antonio, TX., Dana-Farber Cancer Institute, Boston, MA., Sidney Kimmel Cancer Center, Johns Hopkins University, Baltimore, MD., Massachusetts General Hospital Cancer Center, Boston, MA., Division of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, NY., Institut Paoli-Calmettes Aix-Mareseille Université, Marseille, France., Institute of Cancer Research, The Royal Marsden NHS Foundation Trust, London, United Kingdom., Erasmus Medical Center, Rotterdam, the Netherlands., Department of Urology, Graduate School of Medicine, Kyoto University, Kyoto, Japan., International Drug Development Institute, Louvain-La-Neuve, Belgium., University of Adelaide, Adelaide, Australia.