Individual Patient Level Meta-Analysis of Prospective Trials Studying Metastasis-Directed Therapy for Metachronous Oligometastatic Prostate Cancer

Abstract

Emerging data suggest that metastasis is a spectrum of disease burden rather than part of a binary state. Metastasis-directed therapy (MDT) such as radiation might improve outcomes in individuals with oligometastatic disease. Prospective data of MDT for metachronous oligometastatic or oligorecurrent prostate cancer (PCa) have been limited to single arm or small phase 2 randomized studies. We report an individual patient data meta-analysis to characterize the safety and clinical benefit of MDT in oligorecurrent PCa.Individual patient data was submitted from trials published or in conference proceedings by January 2020. Included were single- or multi-arm prospective trials including only patients with recurrent prostate cancer and ≤5 sites of extracranial disease undergoing MDT (surgery or radiotherapy). We hypothesized that MDT improves ADT-free survival. ADT-free survival was analyzed as the primary outcome and biochemical relapse-free survival as secondary outcome. If hazard ratios (HR) were not constant across the different trials, we calculated standardized survival curves, analyzing the trials separately and pooling the adjusted log HR weighted by sample size. The following covariates were examined with the interaction test: PSA doubling time and localization of disease (nodal vs extra-nodal).We identified 4 trials with published results, 2 single arm and 2 randomized trials, representing in total 174 patients (MDT: 72%, active surveillance (AS): 28%). Patient characteristics differed with respect to imaging at inclusion (conventional vs molecular imaging), PSA doubling time and localization of disease (nodal vs extra-nodal). Non-proportional hazards were detected for ADT-free survival but not for biochemical relapse-free survival. ADT-free survival is improved with MDT over AS (HR: 0.56, 95% CI 0.34 - 0.94, P = 0.03) across all covariates, as well as biochemical relapse-free survival (HR: 0.44, 95% CI 0.29 - 0.67, P < 0.01). Grade 2 and 3 toxicity were observed in 3% and 2%, respectively, of patients treated with MDT.MDT improves both biochemical relapse-free and ADT-free survival as compared to active surveillance with low rates of grade 2 or higher toxicity.