Bayesian Reappraisal of the Safety of [177Lu]Lu-PSMA Radioligand Therapy Across Clinical Settings

Abstract

Abstract Objective: To evaluate adverse-event incidence and uncertainty with lutetium-177 prostate-specific membrane antigen (PSMA) radioligand therapy across clinically distinct treatment settings. Methods: Eight published trials and cohorts were evaluated, including taxane-naive and post-taxane populations, an expanded-access cohort, and cohorts with diffuse bone marrow involvement, impaired baseline renal function, or long-term renal follow-up. For each cohort and safety outcome, event counts were analyzed separately using Bayesian binomial models with weakly informative priors on the logit scale. Exploratory posterior comparisons were performed between selected clinically relevant cohorts. Results: Grade 3 or higher anemia and thrombocytopenia varied across clinical settings, whereas grade 3 or higher neutropenia remained uncommon. Higher estimates were observed in several later-line or marrow-compromised cohorts. The posterior probabilities that PSMAfore had lower incidences than VISION were 99.8% for anemia, 99.9% for thrombocytopenia, and 94.6% for neutropenia. Exploratory comparisons of the Japanese phase II subgroups with the corresponding pivotal-trial cohorts showed no uniform directional pattern and remained uncertain because of the small sample sizes. Severe acute renal events were uncommon, whereas long-term follow-up suggested measurable estimated glomerular filtration rate declines in a subset of patients. Conclusions: With [¹⁷⁷Lu]Lu-PSMA radioligand therapy, grade 3 or higher anemia and thrombocytopenia varied across clinical settings, whereas severe neutropenia was generally uncommon. Higher estimates were observed in several heavily pretreated or marrow-compromised cohorts. Severe acute renal toxicity was uncommon, but short-term safety assessments may not fully capture delayed changes in renal function.