Simple SummaryThe response of high-grade serous ovarian cancer (HGSOC) to DNA-damaging agents largely depends on tumor genomic instability (GI), a phenomenon that affects the entire genome. Nowadays, surrogate biomarkers of this phenomenon, such asBRCA-gene mutations, are used in clinical practice to identify patients harboring this characteristic. However, these approaches do not capture the entire picture of GI, mainly due to the lack of information on non-BRCAmutation causes and hence, leading to the misclassification of patients. Thus, considering the great interest in studying GI from a comprehensive perspective, this study aims to establish an integrative response-predictive classifier (Scarface Score) for DNA-damaging agents in the context of HGSOC. The Scarface score will support clinical decision-making by correctly selecting the subpopulation of patients with better responses and avoiding overtreatment of those with a low Scarface Score.AbstractGenomic Instability (GI) is a transversal phenomenon shared by several tumor types that provide both prognostic and predictive information. In the context of high-grade serous ovarian cancer (HGSOC), response to DNA-damaging agents such as platinum-based and poly(ADP-ribose) polymerase inhibitors (PARPi) has been closely linked to deficiencies in the DNA repair machinery by homologous recombination repair (HRR) and GI. In this study, we have developed the Scarface score, an integrative algorithm based on genomic and transcriptomic data obtained from the NGS analysis of a prospective GEICO cohort of 190 formalin-fixed paraffin-embedded (FFPE) tumor samples from patients diagnosed with HGSOC with a median follow up of 31.03 months (5.87–159.27 months). In the first step, three single-source models, including the SNP-based model (accuracy = 0.8077), analyzing 8 SNPs distributed along the genome; the GI-based model (accuracy = 0.9038) interrogating 28 parameters of GI; and the HTG-based model (accuracy = 0.8077), evaluating the expression of 7 genes related with tumor biology; were proved to predict response. Then, an ensemble model called the Scarface score was found to predict response to DNA-damaging agents with an accuracy of 0.9615 and a kappa index of 0.9128 (p< 0.0001). The Scarface Score approaches the routine establishment of GI in the clinical setting, enabling its incorporation as a predictive and prognostic tool in the management of HGSOC.