Integrating Aggressive Variant Prostate Cancer-Associated Tumor Suppressor Gene Status to Refine Prognosis and Predict Androgen-Receptor Pathway Inhibitors Response in Metastatic Hormone-Sensitive Prostate Cancer

Purpose: Alterations in Aggressive Variant Prostate Cancer-Associated Tumor Suppressor Genes (AVPC-TSG: TP53, RB1, PTEN) are related with androgen insensitivity and aggres-sive disease. However, their prognostic and predictive role in metastatic hor-mone-sensitive prostate cancer (mHSPC) is unclear. This single-center retrospective study assesses the value of AVPC-TSG alterations in re-fining prognosis and predicting the response to androgen-receptor pathway inhibitors (ARPI) in mHSPC. Patients and Methods: We included 158 patients with genomic tumor sequencing under-going treatment for mHSPC between 2013 and 2023. We compared patients with AVPC-TSGalt tumors (≥1 alteration in TP53, RB1, or PTEN/PI3K/AKT pathway genes) to those with AVPC-TSGwt tumors (i.e. without alterations in AVPC-TSG). Cox analyses were performed for progression-free survival (PFS) and overall survival (OS). Results: AVPC-TSGwt status was associated with improved PFS and OS in both univari-ate and multivariate (MV) analyses (MV PFS: HR 0.58, 95%CI:0.38-0.89, p=0.012; MV OS: HR 0.48, 95%CI:0.26- 0.91, p=0.025). AVPC-TSGalt mHSPC patients seemed to derive no PFS benefit from ARPI addition (PFS: HR 1.13, 95%CI: (0.58-2.19), p=0.721), while AVPC-TSGwt mHSPC patients did (PFS: HR 0.51, 95%CI: 0.28-0.93 p=0.029). Integrating AVPC-TSG status with CHAARTED volume criteria we identified three distinct sub-groups: "good-risk" (AVPC-TSGwt low-volume), "intermediate-risk" (either AVPC-TSGalt low-volume or AVPC-TSGwt high-volume), and "poor-risk" (AVPC-TSGalt high-volume) with median PFS of 46.8, 28.2, and 15.7 months, respectively. Only the "intermediate-risk" subgroup seemed to derive PFS benefit from ARPI addition (HR 0.36, 95%CI:0.19-0.70, p=0.002). Conclusions: AVPC-TSG status assessment refines prognosis and may predict PFS bene-fits from ARPI in mHSPC. AVPC-TSGalt mHSPC patients should be considered for clini-cal trials as they may not benefit from current standard approaches.