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.
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.
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).
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.
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2025 May 07 [Epub ahead of print]
Jarey H Wang, Alexander D Sherry, Soha Bazyar, Philip Sutera, Noura Radwan, Ryan M Phillips, Matthew P Deek, Jiayun Lu, Shirl Dipasquale, Curtiland Deville, Theodore L DeWeese, Daniel Y Song, Hao Wang, Robert F Hobbs, Reem Malek, Sara A Dudley, Stephen C Greco, Emmanuel S Antonarakis, Catherine H Marshall, Samuel Denmeade, Channing J Paller, Michael A Carducci, Kenneth J Pienta, Orhan K Oz, Matthew Ramotar, James L Leenstra, Sean S Park, Matthew C Abramowitz, Neil Desai, Alejandro Berlin, Bradley J Stish, Chad Tang, Phuoc T Tran, Ana P Kiess
Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD., Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX., Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD., Department of Radiation Oncology, Mayo Clinic, Rochester, MN., Department of Radiation Oncology, Rutgers Cancer Institute, New Brunswick, NJ., Department of Oncology, Division of Quantitative Sciences, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD., Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD., Department of Radiation Oncology, University of Miami Miller School of Medicine, Miami, FL., Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX., Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, ON, Canada.