Background: ENZARAD investigates the addition of enzalutamide or conventional nonsteroidal anti-androgens (NSAA) to radiation therapy (RT) and ADT for high-risk localized PCa. DASL-HiCaP investigates the addition of darolutamide or placebo to RT and androgen deprivation therapy (ADT) using Luteinizing hormone releasing hormone analog (LHRHA) for very-high-risk localized PCa as either primary definitive therapy, or as early salvage treatment after prostatectomy where PSA has persisted or become detectable within 12 months. Methods: The eligibility of DASL-HiCaP differed from ENZARAD by excluding patients solely based on PSA > 20ng/mL and also allowing a very-high risk patient population suitable for salvage radiation post prostatectomy. Participants in DASL-HiCaP were randomized 1:1 to darolutamide 600mg twice daily or placebo plus LHRHA for 96 weeks; all received external beam radiotherapy including mandated pelvic radiation. Participants in ENZARAD were randomized 1:1 to enzalutamide 160mg daily for 24 months or conventional NSAA for 6 months, plus LHRHA for 24 months, and EBRT. Brachytherapy boost was allowed in both trials and pelvic nodal radiation was at investigator’s discretion in ENZARAD. The primary end point for both trials is metastasis-free survival (MFS) (time from randomization to first evidence of metastasis or death from any cause). MFS events are based on conventional imaging with ^99mTc bone scan and CT, and/or MRI. Lesions evident only on PSMA PET are not counted as MFS events. Results: The median age for both trials was 71-years. Complete baseline characteristics are summarised in the Table. ENZARAD randomized 802 participants across 8 countries. Half had Gleason score 9 (52%), 45% had cT3 PCa, 42% had cT2, and 11% were cN1. Gleason score 7 was present in up to 11% of ENZARAD population. DASL-HiCaP randomized 1,107 participants across 6 countries. Most had Gleason score 9 (69%), 41% had cT3 PCa, 32% had cT2, and 28% were cN1. Gleason score 7 was present in <5% of the DASL-HiCaP population. Conclusions: ENZARAD and DASL-HiCaP will define the efficacy of more potent hormonal therapy in the adjuvant setting of patients with both high- and very-high-risk disease and in both primary and salvage radiation settings. Clinical trial information: NCT02446444 and NCT04136353.