Continuous Androgen Deprivation Therapy with or Without Metastasis-directed Therapy for Oligometastatic Prostate Cancer: The Multicenter Phase 2 Randomized EXTEND Trial

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.