Lutetium-177-PSMA-617 ( ¹⁷⁷ Lu-PSMA-617) in neuroendocrine prostate cancer (NEPC).

e17046 Background: Lutetium-177–PSMA-617 (¹⁷⁷Lu-PSMA-617) improves survival in PSMA-positive metastatic castration-resistant prostate cancer (mCRPC). Although neuroendocrine prostate cancer (NEPC) is often associated with low PSMA expression, tumor heterogeneity exists, and some cases—particularly those with mixed adenocarcinoma–neuroendocrine features—can retain PSMA avidity on imaging. Clinical outcomes with ¹⁷⁷Lu-PSMA-617 in NEPC are poorly characterized. Methods: We performed a retrospective, single-institution analysis of patients with histologic or pathologic evidence of NEPC who demonstrated PSMA-avid disease on PET/CT and received ≥1 cycle of ¹⁷⁷Lu-PSMA-617 monotherapy. Outcomes included PSA decline ≥50% (PSA50), investigator-assessed radiographic response, time to progression (TTP; radiographic or clinical), and overall survival (OS). Time-to-event outcomes were estimated using Kaplan–Meier methods and reported as medians with two-sided 95% confidence interval (CI). Results: Ten patients initiated ¹⁷⁷Lu-PSMA-617 between July 2022 and October 2024. At time of data cutoff on 1/20/26, median follow-up was 38 months with most events occurring during the first year. Median age was 70 years (range: 64–78); 8 (80%) had ECOG performance status 0–1, and median baseline PSA was 16.7 ng/mL (range: < 0.02–335). Sites of metastasis included lymph node in 8 (80%), bone in 8 (80%), and liver in 5 (50%) pts. All patients had prior exposure to androgen receptor pathway inhibitor (ARPI) and taxane chemotherapy; 6 (60%) had received prior platinum-based therapy. Treatment-emergent NEPC was present in all cases, including adenocarcinoma with neuroendocrine differentiation (n = 7, 70%) and pure high-grade neuroendocrine or small cell carcinoma (n = 3, 30%). Tumor genomic profiling was available for all patients, with 7 (70%) harboring alterations in RB1, TP53, and/or PTEN. The median number of ¹⁷⁷Lu-PSMA-617 cycles was 3 (range: 1–6). Among 8 evaluable patients with detectable baseline PSA, 5 (63%) achieved PSA50. Best radiographic response by conventional or PSMA PET/CT imaging included 1 complete response CR, 1 partial response, 1 stable disease, 2 mixed responses, and 5 cases of progressive disease. Median TTP was 3 months (95% CI, < 1–9, 9/10 events) and median OS was 7 months (95% CI, 2–not reached, 7/10 events). Notably, one patient achieved an ongoing durable complete response lasting > 2 years following 177 Lu-PSMA-617 had completed neoadjuvant platinum-based chemotherapy and surgical resection with no residual NEPC identified. Conclusions: Selected patients with NEPC and PSMA-avid disease may derive clinical benefit from ¹⁷⁷Lu-PSMA-617, although presentation is heterogeneous and overall prognosis is poor. Benefit appears greatest in patients with limited neuroendocrine differentiation and prior sensitivity to NEPC-directed therapy. Prospective evaluation in larger cohorts is warranted.