Faculty, Staff and Student Publications

Language

English

Publication Date

11-1-2025

Journal

European Urology

DOI

10.1016/j.eururo.2025.07.006

PMID

40750497

PMCID

PMC12921538

PubMedCentral® Posted Date

2-21-2026

PubMedCentral® Full Text Version

Author MSS

Abstract

Background and objective: 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.

Methods: 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.

Key findings and limitations: 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.

Conclusions and clinical implications: 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.

Keywords

Humans, Male, Androgen Antagonists, Prostatic Neoplasms, Aged, Neoplasm Metastasis, Middle Aged, Local consolidative therapy, Oligometastasis, Stereotactic ablative radiation, therapy, Prostate adenocarcinoma, Metastasis-directed therapy

Published Open-Access

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