Outcomes of Radium-223 and Stereotactic Ablative Radiotherapy Versus Stereotactic Ablative Radiotherapy for Oligometastatic Prostate Cancers: The RAVENS Phase II Randomized Trial
Abstract
PURPOSE Randomized clinical trials (RCTs) have shown progression-free survival (PFS) benefits of metastasis-directed therapy (MDT) without androgen deprivation therapy for oligometastatic castration-sensitive prostate cancer (omCSPC). Most patients with bone metastatic (BM) omCSPC recur with additional bone disease after MDT. We hypothesized the BM-targeting alpha-emitter radium-223 dichloride (Ra223) could target subclinical bone disease and delay progression. METHODS This is an investigator-initiated, multicenter, open-label phase II RCT. Eligible men with recurrent omCSPC with ≥one bone metastasis (≤three on conventional imaging and/or ≤five on molecular imaging) were randomly assigned (1:1) to stereotactic ablative radiation (SABR) MDT alone or SABR MDT with Ra223 (six cycles). Primary end point was composite PFS. RESULTS From August 9, 2019, to March 2, 2023, 64 patients were randomly assigned, 33 to SABR MDT and 31 to SABR MDT/Ra223 balancing for key covariates. Most SABR MDT/Ra223 patients (87%) received six cycles of Ra223. The median PFS was 11.8 months with SABR MDT and 10.5 months with SABR MDT/Ra223 (adjusted hazard ratio [aHR], 1.42 [95% CI, 0.79 to 2.56]; P = .24). Seven patients (11%) experienced grade 3 treatment-related adverse events (no grade 4 or 5), 2 of 33 (6%) with SABR and 5 of 30 (17%) with SABR MDT/Ra223. Patients with high-risk (HiRi) pathogenic mutations in ATM , BRCA1/2 , RB1 , or TP53 had worse PFS (HR, 5.95 [95% CI, 1.83 to 19.3]; P = .003). Greater T-cell receptor (TCR) unique productive rearrangements were prognostic for improved PFS independent of the treatment arm (aHR, 0.45 [95% CI, 0.21 to 0.96]; P = .04). CONCLUSION Adding Ra223 to SABR MDT in BM omCSPC does not delay progression of disease. We provide evidence for an HiRi mutational signature and TCR repertoire as prognostic biomarkers in omCSPC treated with SABR MDT, highlighting the importance of collecting biological correlates in RCTs for omCSPC.
Article Details
Journal Info
Journal of Clinical Oncology
Lippincott Williams & Wilkins
Authors (34)
Jarey H. Wang
Phuoc T. Tran, MD, PhD, Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD; Phuoc T. Tran, MD, PhD, Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD; Chad Tang, MD, Department of GU Radiation Oncology, MD Anderson Cancer Center, Houston, TX; and Ana P. Kiess, MD, PhD, Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD
Alexander D. Sherry
Noah S. Meimoun, BA, Division of Radiation Oncology, Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX; Alexander D. Sherry, MD, Department of Radiation Oncology, The Mayo Clinic, Rochester, MN; Ethan B. Ludmir, MD, Division of Radiation Oncology, Department of Gastrointestinal Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX; and Timothy A. Lin, MD, MBA, Division of Radiation Oncology, Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
Soha Bazyar
Philip Sutera
Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD
Noura Radwan
Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD
Ryan M. Phillips
Department of Radiation Oncology, Mayo Clinic, Rochester, MN
Matthew P. Deek
Department of Radiation Oncology, Rutgers Cancer Institute, New Brunswick, NJ
Jiayun Lu
Shirl Dipasquale
Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD
Curtiland Deville
Theodore L. DeWeese
Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD
Daniel Y. Song
Johns Hopkins University, Baltimore, MD
Hao Wang
Division of Quantitative Sciences, Department of Oncology Johns Hopkins University School of Medicine Baltimore Maryland USA
Robert F. Hobbs
Reem Malek
Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD
Sara A. Dudley
Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD
Stephen C. Greco
Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD
Emmanuel S. Antonarakis
Masonic Cancer Center, University of Minnesota
Catherine H. Marshall
Samuel Denmeade
Johns Hopkins University
Channing J. Paller
Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD
Michael A. Carducci
Johns Hopkins, Baltimore, MD
Kenneth J. Pienta
Urology, Oncology, Pharmacology and Molecular Sciences, and Chemical and Biomolecular Engineering Cancer Ecology Center at the Brady Urological Institute Johns Hopkins University Baltimore Maryland USA
Orhan K. Oz
Department of Radiation Oncology, University of Miami Miller School of Medicine, Miami, FL
Matthew Ramotar
Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX
James L. Leenstra
Department of Radiation Oncology, Mayo Clinic, Rochester, MN
Sean S. Park
Matthew C. Abramowitz
Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, ON, Canada
Neil Desai
UT Southwestern Medical Center, Dallas, TX
Alejandro Berlin
Bradley J. Stish
Mayo Clinic Department of Radiation Oncology, Rochester, MN
Chad Tang
Department of Genitourinary Medical Oncology The University of Texas MD Anderson Cancer Center Houston Texas USA
Phuoc T. Tran
Ana P. Kiess