Genomic Alterations and Associated Outcomes in Patients with PSMA-Positive Metastatic Castration-Resistant Prostate Cancer treated with 177Lu-PSMA-617.
Academic Article
Overview
abstract
BACKGROUND: 177Lu-PSMA-617 is approved for patients with metastatic castration-resistant prostate cancer (mCRPC). Although treatment is associated with improved outcomes, not all patients benefit and response is heterogeneous. We aim to characterize genomic alterations associated with benefit to 177Lu-PSMA-617. METHODS: This study used the Prostate Cancer Precision Medicine Multi-Institutional Collaborative Effort (PROMISE) clinical-genomic database (n = 2445). The primary endpoint was ≥50% PSA decline (PSA50) from baseline with 177Lu-PSMA-617 in molecular subgroups. Secondary endpoints included 90% PSA decline (PSA90). Associations were assessed using Fisher's exact test and Cox regression in multivariable analysis. RESULTS: We identified 183 mCRPC patients treated with 177Lu-PSMA-617. Median number of prior lines of mCRPC therapy was three. Overall, PSA50 was 49%, median progression-free survival was 7.6 months, and median overall survival was 13.9 months. NF1 (n = 8) and FOXA1 alterations (n = 5) were associated with increased PSA50 (88% vs. 47%, p = 0.03 for NF1; 100% vs. 47%, p = 0.03 for FOXA1). Among CRPC sequenced tumors (n = 119), androgen receptor (AR) alterations (n = 58) were associated with lower PSA50 (38% vs. 60%, p = 0.03). While any tumor suppressor genes (TSG) (PTEN, TP53, RB1) (n = 109) or TP53 (n = 83) alteration were associated with lower PSA90 (p = 0.02 for both), NF1 (n = 8) and FOXA1 alterations were associated with higher PSA90 (p = 0.03 and p = 0.003, respectively). CONCLUSIONS: This analysis identifies potential genomic predictors of response to 177Lu-PSMA-617, with NF1 and FOXA1 alterations associated with favorable outcomes and AR and TSG alterations with diminished response. These hypothesis-generating findings suggest genomic profiling may inform selection for PSMA-targeted therapy and warrant prospective validation in larger cohorts. IMPLICATIONS OF PRACTICE: In this study, we evaluate the use of genetic markers to predict response to treatment with 177Lu-PSMA-617 in patients with metastatic prostate cancer. We identified that alterations in the androgen receptor (AR) and tumor suppressor genes (TSG) were associated with a worse response to 177Lu-PSMA-617, which FOXA1 and NF1 alterations were associated with improved outcomes. These data are hypothesis generating and warrant validation in larger studies. Identifying predictive markers to 177Lu-PSMA-617 can better optimize treatment selection for this therapy.
