Real-world evaluation of [<sup>177</sup>Lu]Lu-PSMA-617 RLT in post-taxane mCRPC: feasibility and safety of individualized treatment in a challenging cohort.

Abstract

PurposeEvaluating efficacy and safety of individualized [177Lu]Lu‑PSMA‑617 radioligand therapy in heavily pretreated post-taxane patients with metastatic castration‑resistant prostate cancer (mCRPC), and to present a comparison with outcomes of non-individualized regimens.MethodsPer‑cycle activities of [177Lu]Lu-PSMA-617 were individualized by normalizing to body surface area and adjusting for renal clearance, hematopoietic function, and tumor burden and progression parameters. 227 post-taxane mCRPC patients with intense PSMA expression on PET/CT were enrolled in the prospective registry (REALITY; NCT04833517) and retrospectively analyzed. PSA progression-free survival (PSA-PFS) and overall survival (OS) according to Kaplan-Meier analysis, Cox proportional‑hazards models with backward elimination for identification of outcome predictors, safety assessment according to CTCAE v5.0.ResultsMedian administered activity was 7.1 GBq per cycle (range 2.7-11.6 GBq) and cumulative activity 22.3 GBq (range 2.7-77.8 GBq), while patients received a median of 3 cycles within a 6-week interval. After a median follow‑up of 15.9 months (95%CI: 11.2-20.5 months), median PSA‑PFS was 5.1 months (95% CI: 4.0-6.2 months), and median OS 14.5 months (95% CI: 11.4-17.7 months). PSA declined after the first cycle in 63.9% of patients; PSA reduction ≥ 50% occurred in 51.5%. Shortened PSA‑PFS was associated with visceral metastasis (p = 0.001) and ALP ≥ 220 U/L (p = 0.004). Shortened OS was associated with visceral metastasis (p = 0.009), ALP ≥ 220 U/L (p = 0.001), age ≤ 65 years (p = 0.034), hemoglobin ConclusionIn conclusion, the retrospective real-world analysis suggests that individualized, dose-adapted 177Lu based PSMA RLT regimens may provide an opportunity to successfully extend applicability of RLT to more challenging clinical scenarios and a broader patient population without compromising safety and survival outcomes.