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Genomic Alterations and Associated Outcomes in Patients with PSMA-Positive Metastatic Castration-Resistant Prostate Cancer treated with 177Lu-PSMA-617
Journal article   Open access   Peer reviewed

Genomic Alterations and Associated Outcomes in Patients with PSMA-Positive Metastatic Castration-Resistant Prostate Cancer treated with 177Lu-PSMA-617

Justine Panian, Nicholas C Henderson, Daniel Herchenhorn, Pedro C Barata, Mehmet Asim Bilen, Laura Graham, Elisabeth Heath, Clara Hwang, Avery Supernois, Deepak Kilari, …
The oncologist (Dayton, Ohio), Vol.30(11), oyaf358
11/2025
DOI: 10.1093/oncolo/oyaf358
PMCID: PMC12622373
PMID: 41124032
url
https://doi.org/10.1093/oncolo/oyaf358View
Published (Version of record) Open Access

Abstract

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. 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. 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). 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. 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.
 Genomics 177Lu-PSMA-617 prostate metastatic

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