e17055 Background: 177 Lu-PSMA-617 ( 177 Lu) radioligand therapy (RLT) is a standard treatment for mCRPC after progression on androgen receptor (AR) pathway inhibitors, with or without prior taxane chemotherapy. Clinical outcomes remain heterogeneous, and predictive genomic biomarkers are lacking. SPOP-mutant prostate cancers exhibit relative genomic stability and preserved AR signaling, which may confer differential sensitivity to PSMA-targeted RLT. We aimed to evaluate the association between SPOP mutations status and treatment outcomes following 177 Lu RLT. Methods: We performed a retrospective analysis of mCRPC patients treated with 177 Lu at a single academic center (2023-2025). Clinical and genomic data were extracted from the EMR. Genomic profiling focused on DNA damage repair (DDR) genes, tumor suppressor genes (TSGs: TP53, RB1, PTEN), and SPOP mutation status. Overall survival (OS) and radiographic progression-free survival (rPFS) were assessed using Kaplan-Meier and Cox proportional hazards models. Results: Among 43 evaluable patients (median age 67 years; 69% Gleason 8-10, 84% received prior taxane therapy), 6 (13.9%) were SPOP-mutant and 37 were wild-type (WT). SPOP mutation was associated with a trend toward improved outcomes, with hazard ratio (HR) 0.20 for OS (p = 0.1) and 0.47 for rPFS (p = 0.1). Identified SPOP mutations clustered within the substrate-binding MATH (Meprin and TRAF Homology) domain, most commonly at known hotspot residues Y87 (n = 3), F102 (n = 1), and F133 (n = 1). Median OS was not reached in SPOP-mutant patients compared with 13.6 months in SPOP-WT patients (log-rank p = 0.09), while median rPFS was 9.0 vs. 5.1 months, respectively (log-rank p = 0.1). SPOP mutation was not significantly associated with baseline clinical, metastatic, genomic, or treatment-related characteristics. In exploratory Cox models with limited adjustment for key clinical variables, the association between SPOP mutation and improved OS (HR range 0.16-0.22) and rPFS (HR range 0.38-0.50) remained directionally consistent. Conclusions: In this real-world cohort of mCRPC patients, SPOP mutation was associated with a consistent trend toward improved survival following 177 Lu therapy. Despite limited numbers of SPOP-mutant cases, these findings suggest that SPOP-mutant mCRPC may represent a biologically distinct subgroup with enhanced sensitivity to PSMA-targeted RLT that is not readily explained by baseline disease burden or treatment history, supporting further investigation in larger, prospective biomarker-driven studies.
Koh et al. (Thu,) studied this question.