Circulating Tumor-Derived Extracellular Vesicles Predict Clinical Outcomes in 11C Choline-identified Oligometastatic Castration-Refractory Prostate Cancer Treated with Stereotactic Ablative Radiotherapy

Stereotactic ablative radiotherapy (SABR) has demonstrated clinical benefit in oligometastatic prostate cancer patients. However, the risk of developing new distant metastatic lesions remains high and only a minority of patients experience durable progression-free response. Therefore, there is a critical need to identify which subset of oligometastatic patients will benefit from SABR alone versus combination SABR and systemic agents. Herein, we provide the first proof-of-concept for the clinical value of circulating prostate cancer-specific extracellular vesicles (PCEVs) as non-invasive predictor of oncological outcomes in oligometastatic castration-refractory prostate cancer (oCRPC) patients treated with SABR. We have defined PCEVs and analyzed their kinetics in the peripheral blood of 79 oCRPC patients with nanoscale flow cytometry at baseline and days 1, 7, and 14 post-SABR. High PCEV levels at baseline was predictive of shorter time to distant recurrence (3.5 vs 6.6 months, p=0.0087). Following SABR, PCEV levels reached a peak at day 7 and median overall survival was significantly longer in patients with higher PCEV levels (32.7 vs 27.6 months, p=0.003). This suggests that pre-treatment PCEV levels can be a biomarker of tumor burden while early changes post-treatment can predict response to SABR. In contrast, radiomic analyses of 11C-choline PET/CT before and after SABR was not predictive of clinical outcomes. Interestingly, a correlation was noted between PCEV levels and peripheral tumor-reactive CD8 T cells (TTR; CD8+ CD11ahigh). This original study demonstrates that circulating PCEVs can serve as prognostic and predictive marker to SABR in order to identify true oCRPC patients. In addition, we provide novel insights in the global crosstalk mediated by PCEVs between tumors and immune cells which leads to systemic suppression of immunity against CRPC. This work lays the foundation for future studies that investigate the underpinnings of metastatic progression and providing new therapeutic targets (e.g PCEVs) to improve SABR efficacy and clinical outcomes in treatment resistant CRPC.