Comprehensive genomic PROfiling to iMprove accEss to targeted Therapies in High Grade Serous Carcinoma: a rEal-world stUdy (PROMETHEUS).

The PROMETHEUS study describes the real-world implementation of a comprehensive diagnostic test for homologous recombination deficiency in high-grade serous carcinoma. Comprehensive genomic profiling was performed at Istituto Nazionale Tumori (INT) using the TruSight Oncology 500 HRD assay, providing assessment of genomic instability score on Illumina next-generation sequencing platforms. Genomic data were evaluated by the institutional Molecular Tumor Board to guide therapeutic recommendations. Over 26 months, 295 consecutive patients were enrolled, including 163 treated at INT and 132 referred from regional public hospitals. Comprehensive genomic profiling was successfully carried out in 285 cases (96.6%), identifying pathogenic BRCA1 and BRCA2 mutations in 41 (14.4%) and 25 patients (8.8%), respectively. Genomic instability score was evaluable in 276 cases (93.6%), with a score ≥42 in 133 (46.7%). Genomic profiling identified additional potentially actionable alterations, mainly amplifications, including CCNE1, in 44 patients (15.4%). Results were discussed by the molecular tumor board in 169 cases (59.3%): on-label and off-label therapies were recommended in 93 (54.0%) and 33 patients (19.4%), respectively. Fifty-five of 116 patients with follow-up data (47.4%) received biomarker-based maintenance therapy with poly(ADP-ribose) polymerase inhibitors. Patients with high genomic instability score showed significantly better event-free and overall survival. Forty-six patients (39.7%) were referred to genetic counseling, and 32 (69.7%) carried pathogenic germline variants. These findings demonstrate the feasibility and clinical utility of comprehensive genomic profiling.