Prognostic Value of Imaging and Genomic Biomarkers in Systemic Therapy-Naïve Metastatic Androgen Pathway Modulator-Naïve Prostate Cancer Undergoing Radioligand Therapy

BACKGROUND: [177Lu]Lu-prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) has demonstrated clinical efficacy in metastatic androgen pathway modulator-naïve (mAPMN) and metastatic castration-resistant prostate cancer (mCRPC), however treatment responses remain heterogeneous. PURPOSE: To evaluate the prognostic value of PSMA PET-derived imaging biomarkers and genomic alterations in relation to biochemical response and clinical outcomes in systemic therapy-naïve patients with mAPMN PCa receiving [177Lu]Lu-PSMA RLT as first-line systemic therapy. METHODS: Systemic therapy-naïve patients with mAPMN PCa treated exclusively with [177Lu]Lu-PSMA-RLT were retrospectively analyzed. Standardized uptake value (SUV) parameters (SUVmax, SUVmean, SUVpeak) and PSMA total tumor volume (PSMA-TTV) were derived from baseline and post-treatment [68Ga]Ga-PSMA-11 PET scans, with imaging response defined as a ≥30% reduction. Prostate-specific antigen (PSA) response, PSA-PFS and androgen deprivation therapy (ADT)-free survival were assessed. Available germline and somatic genomic alterations were analyzed for associations with outcomes. RESULTS: 26 patients were analyzed. Reductions ≥30% in SUVmax and PSMA-TTV were associated with prolonged PSA-PFS (27.1 vs. 9.4 months, p=0.01; 27.1 vs. 5.5 months, p< 0.001, respectively) and ADT-free survival (39.0 vs. 19.9 months, p=0.03; 23.9 vs. 13.8 months, p=0.028, respectively). In multivariable analysis, ΔPSMA-TTV ≥30% was independently associated with prolonged PSA-PFS (HR 0.23, 95% CI 0.08-0.68; p=0.008). Of 17 genomically profiled patients, nine had somatic alterations, most frequently involving TP53, MYC, NF1. Patients with altered DNA damage repair (DDR) pathway had lower baseline PSA (0.78 vs. 12.3 ng/mL; p=0.03) and SUVpeak (7.9 vs. 16.7; p=0.03). No other associations with genetic alteration status were observed. CONCLUSIONS: In systemic therapy-naïve patients with mAPMN PCa, reductions of ≥30% in SUVmax and PSMA-TTV following PSMA-RLT were associated with favorable outcomes, with ΔPSMA-TTV independently associated with prolonged PSA-PFS. PSMA PET-derived parameters may support treatment response assessment, whereas no prognostic association with genomic alterations was identified in this cohort.