BACKGROUND: Prostate-specific membrane antigen (PSMA)-directed radioligand therapy (PRLT) with Lutetium-177 ([ METHODS: This retrospective study included 36 patients from two centers achieving extreme response after [¹⁷⁷Lu]Lu-PSMA PRLT. The primary outcomes were the duration of maintained response in months (MR) and improvement post-therapy-clinically, serologically, and on molecular (PET/CT) imaging. We examined several variables, including pathology, gene sequencing, baseline PSA, Gleason score, prior therapies, number of PRLT cycles, and pattern of disease, to identify potential factors that may influence the extreme response. RESULTS: Between 2018 and mid-September 2024, 36 men with mCRPC received a mean of three cycles of [ CONCLUSIONS: We propose there may be intrinsic mechanisms suggesting the immunomodulatory enhancement of ionizing radiation, primarily driving extreme responses.