Genomic and transcriptomic correlates of deep prostate-specific antigen response in patients with metastatic androgen pathway modulation-sensitive prostate cancer.

Abstract

Background: Despite advances in metastatic androgen pathway modulation-sensitive prostate cancer (mAPMS) treatment, outcomes remain heterogeneous. Achieving a post-treatment undetectable prostate-specific antigen (PSA) is a strong prognostic marker. We aimed to identify genomic and transcriptomic determinants of PSA response in a real-world clinical-genomic cohort.

Patients and methods: Patients with mAPMS who underwent DNA (Tempus xT) and, in a subset, RNA (Tempus xR) sequencing were identified from the Tempus Lens database. Inclusion required stage IV disease within 90 days of sample collection and obtained within 12 months before or 3 months after treatment initiation. Patients with PSA at 6 months (n = 525) were classified as PSA-Low (<0.1 ng/mL, n = 240) or PSA-High (≥0.1 ng/mL, n = 285). Overall survival (OS) was assessed by 6-month landmark analysis with delayed-entry adjustment. Logistic and Cox models were adjusted for clinical variables. Sensitivity analyses used a relative definition of >95% PSA decline from baseline.

Results: Baseline PSA was lower in PSA-Low versus PSA-High patients (24 vs 36 ng/mL, P = .01). SPOP (17% vs 11%) and ZFHX3 (2.5% vs 6%) alterations differed between groups, but neither persisted after adjustment. Using the relative definition, ZMYM3 and JAK1 alterations were independently associated with failure to achieve a deep PSA response. Expression of PSMA, TROP2, B7-H3, and STEAP1 did not differ between groups. PSA-Low status was independently associated with improved OS, as was deep relative response.

Conclusion: Deep PSA response at 6 months correlates with improved OS in mAPMS. Integrating molecular markers with PSA response may inform treatment intensification or de-escalation strategies.