Background High-grade serous ovarian carcinoma (HGSOC) remains one of the most lethal gynecologic malignancies due to its aggressive nature, frequent late-stage diagnosis, and the development of treatment resistance. Although platinum-based chemotherapy remains the cornerstone of therapy, the underlying genomic heterogeneity complicates the prediction of treatment response and the development of effective therapies. Results We performed comprehensive genomic profiling of 523 cancer-associated genes using the TruSight Oncology 500 HT panel in a retrospective cohort of 42 HGSOC patients, including 22 platinum-sensitive (Pt-S) and 20 primary platinum-resistant (Pt-R) cases. In 14 cases, paired tumor samples collected before and after recurrence or neoadjuvant chemotherapy were analyzed to assess the changes in clinically relevant and actionable alterations. Genomic profiling revealed significant heterogeneity in molecular alterations between Pt-S and Pt-R tumors, with CCNE1 amplification confirmed as more frequent in Pt-R cases. Actionable findings ranked in ESCAT tiers I-III were identified in 54.5% and 55% of Pt-S and Pt-R patients, respectively. A total of 18% and 20% of patients harbored tier III hypothetical targets, highlighting opportunities for future targeted therapies in HGSOC. Analysis of paired samples demonstrated dynamic genomic changes, with 60% of Pt-S and 44% of Pt-R patients exhibiting shifts that could affect therapeutic actionability. Conclusions Our findings highlight the importance of comprehensive genomic profiling in HGSOC management. While platinum-based chemotherapy remains central to treating newly diagnosed and recurrent disease, its molecular complexity might require more personalized strategies. Beyond established markers such as BRCA1/2, additional genomic changes present opportunities to expand therapeutic options. The evolving tumor genomic landscape further underscores the need for repeated biopsies or alternative methods to assess tumor evolution, enabling more adaptive and individualized treatment approaches.