The surrogacy of biochemical recurrence (BCR) for overall survival (OS) in localized prostate cancer remains controversial. Herein, we evaluate the surrogacy of BCR using different surrogacy analytic methods.
Individual patient data from 11 trials evaluating radiotherapy dose escalation, androgen deprivation therapy (ADT) use, and ADT prolongation were obtained. Surrogate candidacy was assessed using the Prentice criteria (including landmark analyses) and the two-stage meta-analytic approach (estimating Kendall's tau and the R2). Biochemical recurrence-free survival (BCRFS, time from random assignment to BCR or any death) and time to BCR (TTBCR, time from random assignment to BCR or cancer-specific deaths censoring for noncancer-related deaths) were assessed.
Overall, 10,741 patients were included. Dose escalation, addition of short-term ADT, and prolongation of ADT duration significantly improved BCR (hazard ratio [HR], 0.71 [95% CI, 0.63 to 0.79]; HR, 0.53 [95% CI, 0.48 to 0.59]; and HR, 0.54 [95% CI, 0.48 to 0.61], respectively). Adding short-term ADT (HR, 0.91 [95% CI, 0.84 to 0.99]) and prolonging ADT (HR, 0.86 [95% CI, 0.78 to 0.94]) significantly improved OS, whereas dose escalation did not (HR, 0.98 [95% CI, 0.87 to 1.11]). BCR at 48 months was associated with inferior OS in all three groups (HR, 2.46 [95% CI, 2.08 to 2.92]; HR, 1.51 [95% CI, 1.35 to 1.70]; and HR, 2.31 [95% CI, 2.04 to 2.61], respectively). However, after adjusting for BCR at 48 months, there was no significant treatment effect on OS (HR, 1.10 [95% CI, 0.96 to 1.27]; HR, 0.96 [95% CI, 0.87 to 1.06] and 1.00 [95% CI, 0.90 to 1.12], respectively). The patient-level correlation (Kendall's tau) for BCRFS and OS ranged between 0.59 and 0.69, and that for TTBCR and OS ranged between 0.23 and 0.41. The R2 values for trial-level correlation of the treatment effect on BCRFS and TTBCR with that on OS were 0.563 and 0.160, respectively.
BCRFS and TTBCR are prognostic but failed to satisfy all surrogacy criteria. Strength of correlation was greater when noncancer-related deaths were considered events.
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2023 Aug 28 [Epub ahead of print]
Soumyajit Roy, Tahmineh Romero, Jeff M Michalski, Felix Y Feng, Jason A Efstathiou, Colleen A F Lawton, Michel Bolla, Philippe Maingon, Theo de Reijke, David Joseph, Wee Loon Ong, Matthew R Sydes, David P Dearnaley, Alison C Tree, Nathalie Carrier, Abdenour Nabid, Luis Souhami, Luca Incrocci, Wilma D Heemsbergen, Floris J Pos, Almudena Zapatero, Araceli Guerrero, Ana Alvarez, Carmen Gonzalez San-Segundo, Xavier Maldonado, Robert E Reiter, Matthew B Rettig, Nicholas G Nickols, Michael L Steinberg, Luca F Valle, T Martin Ma, Matthew J Farrell, Beth K Neilsen, Jesus E Juarez, Jie Deng, Sitaram Vangala, Norbert Avril, Angela Y Jia, Nicholas G Zaorsky, Yilun Sun, Daniel Spratt, Amar U Kishan, Meta-Analysis of Randomized Trials in Cancer of the Prostate (MARCAP) Consortium Investigators
Department of Radiation Oncology, Rush University Medical Center, Chicago, IL., Department of Medicine Statistics Core, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA., Department of Radiation Oncology, Washington University, St Louis, MO., Department of Radiation Oncology, University of California San Francisco, San Francisco, CA., Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA., Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, WI., Radiotherapy Department, University Hospital, Grenoble, France., Department of Oncology, Hematology, and Supportive Care, Sorbonne University, Paris, France., Department of Urology, Prostate Cancer Network in the Netherlands, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands., Department of Medicine and Surgery, University of Western Australia, Perth, WA, Australia., Alfred Health Radiation Oncology, Monash University, Melbourne, VIC, Australia., MRC Clinical Trials Unit at UCL, Institute of Clinical Trials and Methodology, University College London, London, United Kingdom., Division of Radiotherapy and Imaging, The Institute of Cancer Research and Department of Urology, The Royal Marsden NHS Foundation Trust, London, United Kingdom., Department of Radiation Oncology, University of Washington, Seattle, WA., Clinical Research Center, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, QC, Canada., Department of Radiation Oncology, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, QC, Canada., Department of Radiation Oncology, McGill University Health Centre, Montréal, QC, Canada., Department of Radiation Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands., Department of Radiation Oncology, Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands., Hospital Universitario de la Princesa, Madrid, Spain., Hospital Son Espases, Palma de Mallorca, Spain., Hospital General Universitario Gregorio Marañón, Madrid, Spain., Hospital Universitari Vall d'Hebron, Barcelona, Spain., Department of Urology, University of California Los Angeles, Los Angeles, CA., Department of Medical Oncology, University of California Los Angeles, Los Angeles, CA., Department of Radiation Oncology, University of California Los Angeles, Los Angeles, CA., Department of Radiology, Division of Nuclear Medicine, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH., Department of Radiation Oncology, University Hospitals Seidman Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH.