Association of ATM Alterations with Outcomes After ¹⁷⁷Lu-PSMA-617 Treatment in Patients with Metastatic...

Treatment with ¹⁷⁷Lu-PSMA-617 improves survival in some patients with metastatic castration-resistant prostate cancer, yet marked heterogeneity in treatment response underscores the need for robust biomarkers. Homologous recombination repair (HRR) gene alterations are frequently analyzed in composite, potentially obscuring gene-level predictive signals. Methods: We conducted a retrospective genomic study of 205 patients with metastatic castration-resistant prostate cancer who received ¹⁷⁷Lu-PSMA-617 at the University of Minnesota between 2022 and 2026 and for whom next-generation DNA sequencing results were available. Clinical endpoints included a prostate-specific antigen (PSA) response (a reduction of at least 50% from baseline [PSA₅₀]), progression-free survival (PFS), and overall survival (OS). A random-effects pooled analysis of published studies reporting OS hazard ratios according to ATM, TP53, CDK12, SPOP, and AR alteration status was also performed. Results: ATM alterations (12.7%) were independently associated with improved PSA₅₀ response (odds ratio, 2.91; P = 0.009), longer PFS (hazard ratio [HR], 0.40; P = 0.002), and longer OS (HR, 0.39; P = 0.003). BRCA2 alterations were not associated with clinical outcomes. CDK12 alterations represented the strongest adverse genomic factor, conferring significantly shorter PFS (HR, 2.76; P = 0.013) and OS (HR, 2.58; P = 0.016). In the pooled analysis, ATM alterations remained significantly associated with improved OS (pooled HR, 0.36), whereas TP53 (pooled HR, 1.49) and AR (pooled HR, 1.57) were associated with significantly worse OS. Conclusion: ATM alterations were independently associated with improved outcomes after treatment with ¹⁷⁷Lu-PSMA-617 and validated across a pooled analysis. Marked heterogeneity among individual HRR genes was observed, supporting gene-level rather than composite HRR analysis for precision oncology in radiopharmaceutical therapy.