Survival and hospitalizations with lutetium (Lu)-177 vipivotide tetraxetan in veterans with underlying genomic alterations.

5068 Background: Lutetium-Lu 177 vipivotide tetraxetan ( 177 Lu-PSMA-617) is a radioligand therapy used to treat metastatic castration resistant prostate cancer (mCRPC) with limited real-world survival data outside of large academic centers. Emerging data suggests outcomes are associated with somatic tumor genomic profiles, such as status of tumor suppressor gene (TSG) alterations, including TP53, PTEN, or RB1. We utilized a nationwide retrospective cohort within the Veterans Health Affairs (VHA) to evaluate overall survival of patients treated with 177 Lu-PSMA-617 and considered tumor suppressor gene alteration status, which could serve as a biomarker for personalized treatment. Methods: Veterans with mCRPC treated in the VHA who received at least one dose of 177 Lu-PSMA-617 through November 2024 were included. The National Precision Oncology Program (NPOP) was used to identify patients who underwent tumor sequencing and had TSG alterations. Age, Charlson comorbidity index (CCI), and number of hospitalizations were collected. The Kaplan-Meier method was used to estimate overall survival (OS), logistic regression for risk of hospitalization, and Cox proportional hazards models to estimate mortality. Results: A total of 228 Veterans who had received at least one dose of 177 Lu-PSMA-617 were identified. Mean age was 76.5 years (SD 7.6) with median CCI of 2 (IQR 1-4). Median OS was 11.4 months (95% CI 8.6-14.2) in the entire cohort and 29.8% of Veterans (68/228) were hospitalized in the year after first dose. Age was not associated with mortality or hospitalization, however CCI was associated with mortality (HR 1.12, 95% CI 1.01-1.24) and any hospitalization (OR 1.21, 95% CI 1.05-1.41). There were no differences in OS based on receipt of NPOP testing (HR 0.97, 95% CI 0.62-1.5). In 108 patients with NPOP testing, 44% (48/108) were found to have at least one TSG alteration. Median OS was shorter in patients with TSG alterations (5.8 vs. 18.0 months, p=0.001, HR 2.8, 95% CI 1.5-5.3) compared to patients without TSG alterations. When accounting for age and CCI, risk of death was increased in Veterans with TSG alterations (aHR 3.0, 95% CI 1.6-5.9). Conclusions: In US Veterans treated with 177 Lu-PSMA-617, median OS was 11.4 months, shorter than observed in other cohorts, although the mean age was higher. Comorbidities were prognostic for mortality and hospitalization while age was not. Veterans who had TSG alterations had significantly shorter OS in unadjusted and adjusted analyses, suggesting that patients with TSG alterations are less likely to benefit from 177 Lu-PSMA-617 and could consider different treatment modalities. Prospective studies are needed to identify additional clinical outcomes over time.