Genomic alterations and associated outcomes in patients with PSMA-positive metastatic castration-resistant prostate cancer treated with 177Lu-PSMA-617. Oncologist 2025 Nov 11;30(11)
Date
10/22/2025Pubmed ID
41124032Pubmed Central ID
PMC12622373DOI
10.1093/oncolo/oyaf358Scopus ID
2-s2.0-105022010503 (requires institutional sign-in at Scopus site) 2 CitationsAbstract
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.
MATERIALS AND 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 3. 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 = .03 for NF1; 100% vs 47%, P = .03 for FOXA1). Among CRPC sequenced tumors (n = 119), androgen receptor (AR) alterations (n = 58) were associated with lower PSA50 (38% vs 60%, P = .03). While any tumor suppressor genes (TSG) (PTEN, TP53, RB1) (n = 109) or TP53 (n = 83) alteration were associated with lower PSA90 (P = .02 for both), NF1 (n = 8), and FOXA1 alterations were associated with higher PSA90 (P = .03 and P = .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.
Author List
Panian J, Henderson NC, Herchenhorn D, Barata PC, Bilen MA, Graham L, Heath E, Hwang C, Supernois A, Kilari D, Thapa B, Koshkin VS, Jindal T, Nauseef JT, Sokolova A, Amery T, Zakharia Y, Schweizer MT, Raychaudhuri R, Reichert ZR, Dorff T, Armstrong AJ, Wang J, Alva A, McKay RRAuthor
Deepak Kilari MD Associate Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AgedAged, 80 and over
Dipeptides
Genomics
Glutamate Carboxypeptidase II
Heterocyclic Compounds, 1-Ring
Humans
Lutetium
Male
Middle Aged
Neoplasm Metastasis
Prostate-Specific Antigen
Prostatic Neoplasms, Castration-Resistant
Radioisotopes
