Efficacy of 177 Lu-PSMA-617 in neuroendocrine prostate cancer.

80 Background: The approval of Lutetium vipivotide tetraxetan ( 177 Lu-PSMA-617) for metastatic castrate resistant prostate cancer has greatly benefited patients both before and after docetaxel. However, conventional wisdom holds that 177 Lu-PSMA-617 is ineffective and thus rarely used in neuroendocrine prostate cancer (NEPC) due to the assumption that NEPC cells lack expression of PSMA. For patients with NEPC treated with 177 Lu-PSMA-617 at a single center, we correlated PSMA expression on tumors by PET with PSA response. Methods: We utilized our institutional IRB approved database and retrospectively identified patients treated with 177 Lu-PSMA-617 from 2022 to 2025. NEPC was defined based on histology showing small cell differentiation or IHC staining for synaptophysin/chromogranin. FDA-approved MIM software (version 7.4.2) was used to perform whole-body tumor quantification on PSMA-PET scans. This software automates the segmentation of tumors through an AI-based model. Whole-body tumor PET metrics included SUV mean , SUV max , volume, and TLA (SUV mean *volume). The Pearson correlation coefficient and p-values were calculated using R version 4.5.1. Results: A total of 58 patients were treated with 177 Lu-PSMA-617 during this period and 6 met the inclusion criteria. The median age was 71 (range: 68-79) years. 5 (83.3%) patients presented with transformation to NEPC from adenocarcinoma prior to therapy and 1 patient presented with de novo NEPC (16.7%) prior to therapy. The median number of cycles was 3 (range 2-6). At baseline, the average whole body SUV max of patients was 46.79 (10.3-72.8) and average SUV mean was 8.1 (4.5-12.7). Median baseline PSA was 34.63 (0.154-88.24). PSA decline >50% occurred in 5 patients (83.3%). Whole body SUV mean was correlated with best PSA % response and we noted a weak negative correlation between the two (R = -0.28) though this did not reach statistical significant (p = 0.593). Conclusions: Although our study is limited by small sample size, we observed that NEPC does have the potential to express levels of PSMA that may be effectively targeted by 177 Lu-PSMA-617. In addition, we observed a weak but notable correlation that NEPC patients with higher PSMA expression had better response to 177 Lu-PSMA-617, like in the VISION trial. Our findings challenge the current assumption that 177 Lu-PSMA-617 is ineffective in NEPC and further exploration of PET selection criteria for this population of patients is warranted.