PRIMARY OBJECTIVE:
I. To determine proportion of patients with biochemical and/or clinical disease failure @ 1 year (BCDF1) after completion of RT.
SECONDARY OBJECTIVES:
I. To determine proportion of patients with biochemical and/or clinical disease failure @ 2.0-2.5 yrs. (BCDF2) after completion of all treatment (all treatment includes both RT and ADT, whichever is longer).
II. To assess acute toxicity.
III. To assess late toxicity.
EXPLORATORY OBJECTIVES:
I. To assess biochemical failure-free interval (BFFI).
II. To assess biochemical failure-free Survival (BFFS).
III. To assess failure-free interval (FFI).
IV. To assess failure-free survival (FFS).
V. To determine proportion of patients with pathology-determined complete response (PathCR).
VI. To assess failure rate (FR). 
VII. To assess progression-free survival (PFS).
VIII. To assess overall survival (OS).
IX. To assess pretreatment, post-treatment, and longitudinal health-related quality of life (HRQoL).
X. To draw and store tumor and benign prostate tissue, urine, serum, plasma, and buffy coat from pretreatment and at different post-treatment intervals for future studies.
XI. To assess the ability of a software application “HRS6” to identify clinically significant prostate cancer both at the time of prostate biopsy and in the radiotherapy planning process.
OUTLINE: Patients with very low risk to favorable intermediate risk clinical genomic (CG) score are assigned to Cohort 1. Patients with unfavorable intermediate to very high-risk CG score are assigned to Cohort 2. Patients are randomized to 1 of 2 arms within each cohort. Patients randomized to Arm B and Arm D are further randomized to 1 of 2 arms.
COHORT 1 (FTLEAD):
ARM A (LEAD RT ALONE): Patients undergo mpMRI guided FTLEAD RT on day 1. Additionally, patients undergo digital rectal exam (DRE), blood sample collection, prostate specific membrane antigen (PSMA) positron emission tomography (PET)/computed tomography (CT), mpMRI, and prostate biopsy throughout the study. Patients may also undergo DRE at screening and bone scan at screening and at progression.
ARM B1 (LEAD RT + uSTAS): Patients undergo mpMRI guided FTLEAD RT on day 1. Patients also receive darolutamide orally (PO) twice daily (BID) on days -14 to 14 in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo DRE, blood sample collection, PSMA PET/CT, mpMRI, and prostate biopsy throughout the study. Patients may also undergo DRE at screening and bone scan at screening and at progression.
ARM B2 (LEAD RT + uSTAS): Patients undergo mpMRI guided FTLEAD RT on day 1. Patients also receive darolutamide PO BID on days -28 to 0 in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo DRE, blood sample collection, PSMA PET/CT, mpMRI, and prostate biopsy throughout the study. Patients may also undergo DRE at screening and bone scan at screening and at progression.
COHORT 2 (HypoLEAD):
ARM C (HypoLEAD): Patients undergo mpMRI guided FTLEAD RT on day 1. Beginning 4 weeks later, patients undergo HypoLEAD RT over 15 minutes QD on Monday-Friday for up to 25 fractions over 5 weeks. Patients may also receive ADT post-uSTAS at the discretion of the treating physician. Additionally, patients undergo DRE, blood sample collection, PSMA PET/CT, mpMRI, and prostate biopsy throughout the study. Patients may also undergo DRE at screening and bone scan at screening and at progression.
ARM D1 (HypoLEAD + uSTAS): Patients undergo mpMRI guided FTLEAD RT on day 1. Beginning 4 weeks later, patients undergo HypoLEAD RT over 15 minutes QD on Monday-Friday for up to 25 fractions over 5 weeks. Patients also receive darolutamide PO BID on days -14 to 14 in the absence of disease progression or unacceptable toxicity. Patients may also receive ADT post-uSTAS at the discretion of the treating physician. Additionally, patients undergo DRE, blood sample collection, PSMA PET/CT, mpMRI, and prostate biopsy throughout the study. Patients may also undergo DRE at screening and bone scan at screening and at progression.
ARM D2 (HypoLEAD + uSTAS): Patients undergo mpMRI guided FTLEAD RT on day 1. Beginning 4 weeks later, patients undergo HypoLEAD RT over 15 minutes QD on Monday-Friday for up to 25 fractions over 5 weeks. Patients also receive darolutamide PO BID on days -28 to 0 in the absence of disease progression or unacceptable toxicity. Patients may also receive ADT post-uSTAS at the discretion of the treating physician. Additionally, patients undergo DRE, blood sample collection, PSMA PET/CT, mpMRI, and prostate biopsy throughout the study. Patients may also undergo DRE at screening and bone scan at screening and at progression.
After completion of study treatment, patients are followed up at 6 weeks, and months 3, 9, 12, 27 then every 6 months until month 60.