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We investigated the longitudinal changes in multiparametric MRI (mpMRI) (T2-weighted, Apparent Diffusion Coefficient (ADC), and Dynamic Contrast Enhanced (DCE-)MRI) of prostate cancer patients receiving Lattice Extreme Ablative Dose (LEAD) radiotherapy (RT) and the capability of their imaging features to predict RT outcome based on endpoint biopsies. Ninety-five mpMRI exams from 25 patients, acquired pre-RT and at 3-, 9-, and 24-months post-RT were analyzed. MRI/Ultrasound-fused biopsies were acquired pre- and at two-years post-RT (endpoint). Five regions of interest (ROIs) were analyzed: Gross tumor volume (GTV), normally-appearing tissue (NAT) and peritumoral volume in both peripheral (PZ) and transition (TZ) zones. Diffusion and perfusion radiomics features were extracted from mpMRI and compared before and after RT using two-tailed Student t-tests. Selected features at the four scan points and their differences (Δ radiomics) were used in multivariate logistic regression models to predict the endpoint biopsy positivity. Baseline ADC values were significantly different between GTV, NAT-PZ, and NAT-TZ (p-values < 0.005). Pharmaco-kinetic features changed significantly in the GTV at 3-month post-RT compared to baseline. Several radiomics features at baseline and three-months post-RT were significantly associated with endpoint biopsy positivity and were used to build models with high predictive power of this endpoint (AUC = 0.98 and 0.89, respectively). Our study characterized the RT-induced changes in perfusion and diffusion. Quantitative imaging features from mpMRI show promise as being predictive of endpoint biopsy positivity.