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purposeLutetium-177-labelled radioligand therapy targeting prostate-specific membrane antigen ([¹⁷⁷Lu]Lu-PSMA-RLT) is an established third-line treatment for metastatic castration-resistant prostate cancer (mCRPC). We evaluated the therapeutic effectiveness of [¹⁷⁷Lu]Lu-PSMA-RLT in systemic therapy-naïve patients with metastatic hormone-sensitive prostate cancer (mHSPC). PATIENTS AND

methodsThis retrospective analysis included mHSPC patients without prior systemic hormone therapy or chemotherapy who received [¹⁷⁷Lu]Lu-PSMA-RLT between September 2015 and February 2025. The primary outcomes were prostate-specific antigen (PSA) response one month after the final cycle and PSA progression-free survival (PFS). Hematological and biochemical laboratory parameters were monitored to assess toxicity. Baseline PSMA PET imaging parameters (maximum standardized uptake value (SUVmax), mean SUV, peak SUV, and total tumor volume (TTV)) were collected. Uni- and multivariable analyses, together with Kaplan-Meier survival analysis, were performed to identify predictors of PSA-PFS, androgen deprivation therapy (ADT)-free survival, and any-therapy-free survival.

resultsTwenty-four patients were identified. Median PSA declined significantly from 6.4 ng/mL (range 0.49–3149) at baseline to 2.3 ng/mL (range 0.00-1731) one month after last [¹⁷⁷Lu]Lu-PSMA-RLT cycle (p = 0.002). All patients received ≥ 3 cycles of [177Lu]Lu-PSMA-RLT. Overall, 15 of 24 patients (62.5%) achieved a PSA decline ≥ 50%, including 10 patients (41.7%) with a decline ≥ 80%. Median PSA-PFS was 24.6 months in patients with a PSA decline ≥ 50%, versus 5.2 months in those with a decline < 50% (p < 0.0001). In the Kaplan-Meier analysis, baseline TTV, the presence of bone metastases, and age < 66.3 years were significant predictors of shorter ADT-free and any-therapy-free survival (all p < 0.05). In contrast, baseline SUV-values of metastatic lesions showed no predictive value in distinguishing responders from non-responders. No severe treatment-related adverse events occured. One patient (4.2%) died 10.3 months after initiation of [¹⁷⁷Lu]Lu-PSMA-RLT.

conclusionThis study evaluated [¹⁷⁷Lu]Lu-PSMA-RLT in early-stage PCa, demonstrating strong PSA decline, prolonged PCa progression-free period, and good tolerability. Baseline TTV and metastatic extent were independent predictors of ADT-free and any-therapy-free survival. The absence of differences in PSMA PET-derived SUV-parameters between responders and non-responders suggests a more homogeneous tumor biology in treatment-naïve mHSPC patients. Prospective studies are needed to define the clinical benefit and predictors of response to [¹⁷⁷Lu]Lu-PSMA-RLT in this setting.