Metastasis-directed therapy and standard of care versus standard of care for oligometastatic prostate cancer (WOLVERINE): a systematic review and individual patient data meta-analysis from the X-MET collaboration.

BACKGROUND

Oligometastatic disease represents the proximal end of a metastatic spectrum. Metastasis-directed therapy (MDT) is increasingly used to treat oligometastatic disease despite the absence of level 1 evidence. We amalgamated individual patient data across trials to evaluate the effectiveness of MDT for oligometastatic prostate cancer.

METHODS

We conducted a systematic review and individual patient data meta-analysis. We systematically searched Embase, PubMed, CENTRAL, MEDLINE, and ClinicalTrials.gov to identify randomised trials of MDT enrolling patients with oligometastatic prostate cancer. Inclusion criteria were published randomised prospective trials enrolling patients with oligometastatic (up to five metastases) prostate cancer, in which investigators recorded sufficient data to evaluate progression-free survival and overall survival. This systematic review was conducted from database creation to Nov 3, 2023, and was updated on May 4, 2025. Data appraisal was conducted using Covidence with two investigators (CT and ADS) performing independent screens. Studies were evaluated using the Cochrane Collaboration's risk-of-bias assessment (version 2.0). Individual patient data were provided by investigators. Coprimary endpoints were progression-free survival and overall survival. Secondary endpoints were radiographic progression-free survival and castration resistance-free survival. The primary analysis was conducted in the subset of studies in which patients were randomly assigned to MDT plus standard of care (SOC) versus SOC. The primary analysis included a trial-level analysis using a random effects model and a patient-level analysis stratifying by trial. This meta-analysis is registered with PROSPERO (CRD42023479078).

FINDINGS: Of 2975 studies identified for screening, seven phase 2 studies randomly assigning 574 men were included. Six trials randomly assigning 472 patients to MDT plus SOC (n=248) versus SOC (n=224) were used to evaluate MDT and had a median follow-up time of 40·7 months (IQR 25·6-53·7). MDT was associated with improved progression-free survival (trial-level hazard ratio [HR] 0·44, [95% CI 0·35-0·56], p<0·0001; patient-level HR 0·45 [0·35-0·57], p<0·0001), radiographic progression-free survival (trial-level HR 0·60 [0·42-0·85], p=0·0039; patient-level HR 0·59 [0·46-0·76], p<0·0001), and castration resistance-free survival (trial-level HR 0·58 [95% CI 0·37-0·92], p=0·019; patient-level HR 0·58 [95% CI 0·37-0·91], p=0·017). The association between MDT and overall survival showed an HR of 0·63 (95% CI 0·39-1·00, p=0·051) in trial-level analyses and 0·64 (95% CI 0·40-1·01, p=0·057) in patient-level analyses.

INTERPRETATION: WOLVERINE showed a benefit with MDT for oligometastatic prostate cancer in progression-free survival, radiological progression-free survival, and castration resistance-free survival. Overall survival benefit was not significant and further research is needed.

FUNDING: Philanthropic gift and National Cancer Institute.