Oligometastatic prostate cancer (omPC) is characterized by limited metastases. We hypothesized that metastasis-directed therapy (MDT) to all sites of omPC combined with androgen deprivation therapy (ADT) would improve clinical outcomes.
In the multicenter phase 2 EXTEND trial, patients with omPC were randomized 1:1 to ADT versus MDT + ADT in two independently powered and randomized baskets, one using intermittent ADT and one using continuous ADT. The primary endpoint was progression-free survival (PFS). The secondary endpoints included radiologic PFS (rPFS) and castration resistance-free survival (CRFS). Here, the primary results of the continuous ADT basket, the combined analysis of both baskets, and translational immune correlatives are reported.
From September 2018 through August 2022, 174 patients were randomized and were eligible for the primary analysis. In the continuous ADT basket (N = 87), the median PFS was 47 mo with MDT + ADT versus 22 mo with ADT (hazard ratio [HR], 0.50; one-sided p = 0.036). In the combined analysis, the median PFS was 36 mo with MDT + ADT versus 17 mo with ADT (HR, 0.45; p < 0.001). Radiologic PFS and CRFS were also superior with MDT + ADT. Durable clinical responses after MDT + ADT were associated with systemic Th1-polarizing cytokine upregulation and CD8+ T-cell proliferation. Compared with ADT, MDT + ADT induced greater systemic immune activation, including T-cell receptor expansion/contraction, which we also observed in the independent ORIOLE trial of MDT. The greatest PFS benefit after MDT + ADT was observed in patients with systemic T-cell receptor expansion/contraction.
MDT + ADT improves PFS compared with ADT in omPC patients, meriting phase 3 confirmation. Hypothesis-generating immune responses warrant mechanistic validation and future trials with T-cell-targeted immunotherapies.
European urology. 2025 Jul 31 [Epub ahead of print]
Alexander D Sherry, Bilal A Siddiqui, Cara Haymaker, Bryan M Fellman, Marina N Medina-Rosales, Tharakeswara K Bathala, Shuqi Wang, Suyu Liu, Aaron Seo, Kieko Hara, Hsinyi Lu, Patricia Troncoso, Stephen G Chun, Chul S Ha, Lauren L Mayo, Henry Mok, Ryan J Park, Brian F Chapin, Ryan M Phillips, Matthew P Deek, Craig A Kovitz, Ana Aparicio, Amado J Zurita, Patrick G Pilie, Lorenzo Cohen, Seungtaek L Choi, Alexandre Reuben, Phuoc T Tran, Paul G Corn, Sumit K Subudhi, Chad Tang
Department of Radiation Oncology, Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Radiation Oncology, The Mayo Clinic, Rochester, MN, USA., Department of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Department of Translational Molecular Pathology, Division of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Department of Abdominal Imaging, Division of Diagnostic Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Department of Radiation Oncology, Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Department of Pathology, Division of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Department of Radiation Oncology, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA., Department of Genitourinary Radiation Oncology, Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Department of Urology, Division of Surgical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Department of Radiation Oncology, The Mayo Clinic, Rochester, MN, USA., Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, USA., Department of General Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Department of Palliative, Rehabilitation, and Integrative Medicine, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Behavioral Science, Division of Cancer Prevention and Population Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Department of Thoracic/Head & Neck Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD, USA., Department of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: ., Department of Translational Molecular Pathology, Division of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Genitourinary Radiation Oncology, Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: .