Integrating aggressive variant prostate cancer–associated tumor suppressor genes (AVPC-TSG) status to refine prognosis and predict androgen-receptor pathway inhibitors (ARPI) response in metastatic hormone-sensitive prostate cancer (mHSPC).

243 Background: Alterations in AVPC-TSG (TP53, RB1, PTEN) are related with androgen insensitivity and aggressive disease. However, their role in mHSPC prognosis and treatment guidance is unclear. This retrospective study assesses the value of AVPC-TSG alterations in refining prognosis and predicting ARPI benefit in mHSPC. Methods: We included 158 mHSPC patients with available genomic tumor sequencing analysis undergoing treatment between 2013 and 2023. We compared patients with AVPC-TSGalt tumors (defined by ≥1 alterations in the TP53 gene, RB1 gene, or PTEN/PI3K/AKT pathway genes) to those without (AVPC-TSGwt tumors). 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 univariate and multivariate (MV) analyses (MV PFS: HR 0.58, p=0.012; MV OS: HR 0.48, p=0.025). AVPC-TSGalt mHSPC patients seemed to derive no PFS benefit (PFS: HR 1.13, p=0.721) from the addition of an ARPI to ADT, while AVPC-TSGwt mHSPC patients did (PFS: HR 0.51, p=0.029). Integrating AVPC-TSG status with CHAARTED volume criteria enhanced prognostic and predictive discrimination in mHSPC. Three distinct subgroups were identified: "good-risk" (AVPC-TSGwt and low-volume), "intermediate-risk" (either AVPC-TSGalt or high-volume), and "poor-risk" (AVPC-TSGalt and high-volume) with median PFS of 46.8, 28.2, and 15.7 months, respectively. Among them, only the "intermediate-risk" subgroup seemed to derive PFS benefit (HR 0.36, p=0.002) from addition of an ARPI. Conclusions: Integrating AVPC-TSG status with clinical prognostic variables refines prognostication and may predict PFS benefits from the addition of an ARPI in patients with mHSPC. Patients with AVPC-TSGalt mHSPC should be considered for clinical trials exploring alternative treatments, as they may not benefit from current standard approaches. Patient characteristics. AVPC-TSGaltn=63(39.9%) AVPC-TSGwtn=95(60.1%) p-value mHSPC treatmentADT aloneADT+ARPIADT+DocetaxelADT+ARPI+Docetaxel 23(36.5%)28(44.5%)8(12.7%)4(6.3%) 32(33.6%)49(51.6%)7(7.4%)7(7.4%) p=0.64 1 De Novo disease 43(68.3%) 57 (60%) p=0.29 1 CHAARTED High Volume 36(57.1%) 52(54.7%) p=0.77 1 AVPC-TSG 1 altAVPC-TSG 2-3 alt 56(88.9%)7(11.1%) 00 p<0.012 1 median PFS (months)median OS (months) 20.568.2 39.6NR p=0.010 2 1 Pearson, 2 Log-rank test.