Purpose:

Stereotactic ablative radiotherapy (SABR) has demonstrated clinical benefit in oligometastatic prostate cancer. 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 patients will benefit from SABR alone versus combination SABR and systemic agents. Herein, we provide the first proof-of-concept of circulating prostate cancer-specific extracellular vesicles (PCEVs) as a non-invasive predictor of outcomes in oligometastatic castration-resistant prostate cancer (omCRPC) treated with SABR.

Materials and methods:

We analyzed the levels and kinetics of PCEVs in the peripheral blood of 79 omCRPC patients at baseline and days 1, 7, and 14 post-SABR using nanoscale flow cytometry and compared with baseline values from localized and widely metastatic prostate cancer cohorts. Association of omCRPC PCEV levels with oncological outcomes was determined with Cox regression models.

Results:

PCEV were highest in mCRPC followed by omCRPC and lowest in localized prostate cancer. High PCEV levels at baseline predicted shorter median time to distant recurrence (3.5 vs 6.6 months, p=0.0087). Following SABR, PCEV peaked on day 7 and median overall survival was significantly longer in patients with elevated PCEV levels (32.7 vs 27.6 months, p=0.003). This suggests that pre-treatment PCEV levels reflect tumor burden while early PCEV changes post-treatment predict response to SABR. In contrast, radiomic features of ¹¹C-choline PET/CT before and after SABR were not predictive of clinical outcomes. Interestingly, PCEV levels and peripheral tumor-reactive CD8 T cells (T_TR; CD8⁺ CD11a^high) were correlated.

Conclusion:

This original study demonstrates that circulating PCEVs can serve as prognostic and predictive marker to SABR in order to identify “true” omCRPC 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.