Eur Urol. 2026 Mar 11:S0302-2838(26)02002-6. doi: 10.1016/j.eururo.2026.02.011. Online ahead of print.
ABSTRACT
BACKGROUND AND OBJECTIVE: Studies reported to date indicate that local therapy may improve outcomes in men with de novo metastatic (M1) prostate cancer (PCa). The aim of this study was to evaluate the effect of local therapy to the primary tumor on progression-free survival (PFS) in men with M1 PCa.
METHODS: In a multicenter, randomized phase 2 trial, men with de novo M1 PCa, after receiving 6 mo of best systemic therapy (BST), were randomly assigned (1:1) to continue BST alone (arm 1) or BST with the addition of either radiotherapy or surgery to their primary tumor (arm 2). The primary endpoint was PFS, defined as the time from randomization to progression (Prostate Cancer Working Group 2) by prostate-specific antigen, radiographic or symptomatic progression, or the time to change systemic therapy as per physician discretion and/or clinical decision, or death, whichever occurred first. Immunohistochemistry for the tumor suppressors p53, RB1, and PTEN was performed on available prostate biopsies at baseline and 6 mo. The aggressive variant PCa molecular signature (AVPC-MS) was assigned if two or more of these tumor suppressors were abnormal. In the current intent-to-treat analysis, the Kaplan-Meier product-limit method was used to estimate the median PFS.
KEY FINDINGS AND LIMITATIONS: Between March 2013 and April 2018, 119 patients were randomized (arm 1: 59 and arm 2: 60). The median follow-up for patients who survived was 66 mo (64 mo for BST alone and 67 mo for BST plus local therapy groups). BST included androgen deprivation therapy (n = 119), with docetaxel (n = 37) or with androgen receptor pathway inhibitor agents (n = 9). Local therapy included surgery (n = 45), radiation (n = 13), or none (n = 2). At data analysis, 88 patients met Prostate Cancer Working Group 2 progression, and 53 patients had died. The median PFS was 17.9 mo (95% confidence interval [CI] 11.7-36.4) in arm 1 and 14.8 mo (95% CI 11.4-42.9) in arm 2 (hazard ratio [HR] 0.89, 95% CI 0.59-1.34, p = 0.6). Toxicity was limited in both arms, with grade 3 toxicities in four patients (6.7%) in arm 2 and zero patients in arm 1. Three patients required palliative intervention for symptomatic local progression in arm 1, while an additional six patients crossed over to receive local therapy after meeting castration-resistant PCa progression criteria. Predictors of worse overall survival (OS) for all comers included CHAARTED high-volume (HR 1.84, 95% CI 1.06-3.19) and clinical cT3b/T4 (HR 1.97, 95% CI 0.88-4.41) disease. Having the AVPC molecular profile (AVPC-MS) at baseline or 6 mo was significantly associated with worse PFS (HR 1.74, 95% CI 1.02-2.98, p = 0.04). However, there was no statistically significant association with OS (HR 1.83, 95% CI 0.94-3.56, p = 0.08).
CONCLUSIONS AND CLINICAL IMPLICATIONS: This phase 2 randomized study failed to demonstrate improved PFS in men with de novo M1 PCa treated with BST with the addition of local therapy to their primary tumor. Its effect on OS is being tested in an ongoing phase 3 trial (SWOG 1802). We identified biomarkers of potential prognostic value (CHAARTED volume status, cT3b/cT4 disease, and the AVPC-MS) that may serve to optimize therapy selection and stratification in this population, but these require further evaluation.
PMID:41833492 | DOI:10.1016/j.eururo.2026.02.011
