Despite the efficacy of Lutetium-177 (Lu)-PSMA-617 in Metastatic Castration-Resistant Prostate Cancer (mCRPC), high discontinuation rates limit its therapeutic potential. This study aimed to characterize discontinuation reasons, timing, predictive factors, and survival impact in a real-world cohort.

We retrospectively analyzed 208 mCRPC patients treated with ¹⁷⁷Lu-PSMA-617 between 2017 and 2024. Discontinuation was defined as cessation before 6 cycles. Reasons were categorized as disease progression, serious adverse events, patient-related factors, physician decision, death, or miscellaneous. Early discontinuation was defined as < 3 cycles. Logistic regression and Cox models identified predictors of discontinuation and overall survival (OS).

Median cycles received were 3 (IQR 2-5); 169 patients (81.2%) discontinued, with 92 (44.2%) early discontinuation. Disease progression (43.8%) and serious adverse events (21.9%) were leading causes. Multivariate analysis revealed baseline creatinine (OR 5.50, P = .050) and ALP (per 100 U/L; OR 1.12, P = .032) predicted overall discontinuation, while Gleason score (OR 2.11, P = .009), hemoglobin (OR 0.62, P < .001), and platelet counts (OR 0.54, P = .004) predicted early discontinuation. Median OS was 13 months overall, 11 months in discontinuers versus 22 months in completers (P < .001), and 5 vs. 20 months in early vs. nonearly groups (P < .001). Treatment discontinuation (HR 1.95, P = .001) and hemoglobin (HR 0.68, P < .001) independently predicted OS.

Over 80% of mCRPC patients discontinued ¹⁷⁷Lu-PSMA-617, driven by progression and toxicity, with early discontinuation linked to aggressive disease and poor hematologic reserve. Discontinuation independently worsens survival, emphasizing the need for careful selection and supportive interventions to improve adherence and outcomes.