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

Alterations in aggressive-variant prostate cancer-associated tumor suppressor genes (AVPC-TSG: <i>TP53</i>, <i>RB1</i>, <i>PTEN</i>) are related with androgen insensitivity and aggressive disease. However, their prognostic and predictive role in metastatic hormone-sensitive prostate cancer (mHSPC) is unclear. This single-center retrospective study assesses the value of AVPC-TSG alterations in refining prognosis and predicting the response to androgen receptor pathway inhibitors (ARPIs) in mHSPC. We included 158 patients with genomic tumor sequencing undergoing treatment for mHSPC between 2013 and 2023. We compared patients with AVPC-TSGalt tumors (≥1 alteration in <i>TP53</i>, <i>RB1</i>, or <i>PTEN</i>/<i>PI3K</i>/<i>AKT</i> 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). AVPC-TSGwt status was associated with improved PFS and OS in both univariate and multivariate (MV) analyses (MV PFS: HR 0.58, 95%CI: 0.38-0.89, <i>p</i> = 0.012; MV OS: HR 0.48, 95%CI: 0.26-0.91, <i>p</i> = 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, <i>p</i> = 0.721), while AVPC-TSGwt mHSPC patients did (PFS: HR 0.51, 95%CI: 0.28-0.93 <i>p</i> = 0.029). Integrating AVPC-TSG status with CHAARTED volume criteria, we identified three distinct subgroups: "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, <i>p</i> = 0.002). AVPC-TSG status assessment refines prognosis and may predict PFS benefits of ARPIs in mHSPC. AVPC-TSGalt mHSPC patients should be considered for clinical trials as they may not benefit from current standard approaches.