Incidence and co-occurrence of targetable key genomic alterations (GenAlt) in metastatic prostate cancer (mPC): Preliminary results from the prostate cancer cohort of the FPG500 program.

249 Background: PC is the most common male malignancy worldwide, associated with significant morbidity and mortality. GenAlt in some genes are critical drivers of tumor progression and dissemination. Emerging evidence are suggesting as some of these GenAlt can be used as predictive factors for response to therapies such as hormone therapy (SPOP), PARPi (BRCA and HRR), PTEN/AKT inhibitors (capivasertib) or highlight aggressive tumor phenotype (p53, Rb, TMPSRR-ERG), that deserve chemotherapy. In this study, we aim to describe the incidence and co-occurrence of key GenAlt in mPC. Methods: All tumor tissue samples of male patients affected by mPC, enrolled in the FPG500 program (NCT06020625), active at our institution, were included. Tumor tissue was analyzed using the TruSight Oncology 500 High Throughput (TSO500HT) assay. This analysis reported the incidence of pathogenic alterations in selected genes (BRCA1/2, ERG, p53, PTEN, Rb, SPOP, TMPSRR), as well as their co-occurrence. Results: Between January 2022 and May 2025, a total of 262 patients with mPC were enrolled in the FPG500 program and underwent comprehensive genomic profiling (CGP). In 115 cases (44%), sequencing was incomplete due to insufficient tumor material or DNA/RNA degradation. Among the 147 pts with complete CGP data, 128 (87%) harbored at least one genomic alteration. Clinically significant alterations (TIER I–II) were absent in 19 cases (13%). Baseline characteristics of the pts were: median age 73; mPC at the diagnosis in 80% of patients; high volume disease in 57% of cases; presence of bone metastases in 88% of cases. Among the evaluated population, 63% had at least one among the selected gene alterations. The incidence for each of these was BRCA1 in 1%, BRCA2 in 10%, ERG in 5%, p53 in 30%, PTEN in 18%, Rb1 in 1%, SPOP in 1% and TMPSRR in 20% of patients. The co-occurrence of GenAlt was found in 29% of patients and reported in the table below. Conclusions: Extensive genomic profiling can allow to identify targetable genes in over 60% of patients affected by mPC. This approach can facilitate access to personalized and potentially more effective treatment options. Future studies are warranted to elucidate the clinical implication of coexisting mutations in mPC. Clinical trial information: NCT06020625 . Frequency and co-occurrence of driven genetic alterations in treatment-naïve metastatic prostate cancer. Genetic Correlations (147 pts) BRCA 1(n°) BRCA 2 PTEN TP53 TMPRSS ERG SPOP Rb1 % (n°) 1% (2) 10% (15) 18% (26) 30% (44) 20% (29) 5% (7) 13% (19) 1% (2) BRCA 1 (n°) // 0 1 1 1 0 0 0 BRCA 2 0 // 2 4 1 0 1 0 PTEN 1 2 // 8 7 0 3 0 TP53 1 4 8 // 15 2 0 0 TMPRSS 1 1 7 15 <jats:t