PSMA-Positive Extracellular Vesicles Predict Disease Recurrence in Oligometastatic Castration-Sensitive Prostate Cancer Treated with Stereotactic Ablative Radiotherapy: Analysis of the ORIOLE trial

Abstract

Stereotactic ablative radiation therapy (SABR) can prolong progression free survival in oligometastatic prostate cancer (omPC) patients. However, predictive tools to identify those who will benefit from SABR are necessary. Our group was the first to demonstrate that plasma levels of prostate cancer-derived extracellular vesicles (ProstEVs) correlate with tumor burden and predict disease progression in omPC after SABR. Herein, we conducted a blinded validation study using plasma samples from the ORIOLE randomized phase 2 clinical trial in castration-sensitive patients. Plasma samples from 46 omPC patients from the Baltimore ORIOLE trial: a 2:1 ratio randomization to SABR vs observation (NCT02680587). Baseline PSMA+ ProstEV levels were measured by standardized and calibrated nanoscale flow cytometry using fluorescent PSMA antibodies. Median ProstEV levels was used as cut-off for low and high levels. Kaplan-Meier curves and Cox regression models were used to determine the association of ProstEV levels with clinical outcomes [PSA progression-free survival (psaPFS) and radiographic distant progression free survival (rPFS)]. No association was observed between number of metastatic lesions or baseline PSA and plasma ProstEV levels. The rPFS for patients treated with SABR was 29.6 months. The rPFS for patients treated with SABR with high and low ProstEV levels were 11.1 months and 36 months, respectively (Hazard Ratio: 2.85; 95% CI, 1.01-7.48; P = 0.02). The psaPFS for patients treated with SABR was 11.9 months. The psaPFS for patients with high and low ProstEV levels were 5.9 months and 24.3 months, respectively (HR: 2.44; 95% CI, 1.00-5.94; P = 0.03). ProstEVs is the first blood biomarker of tumor burden that can prognosticate the risk of disease recurrence in omPC patients treated with SABR. While biomarker-guided trials are warranted, our validation study strengthens the clinical value of ProstEVs for personalized radiation therapy.