Immuno-molecular features associated with exceptional recurrence-free survivorship from Ovarian Cancer in the pre-PARP era.

High-grade serous ovarian cancer (HGSOC) remains a leading cause of gynecological cancer mortality, with only <15% of patients achieving long-term, relapse-free survival. Using data from the VIVROVAIRE (NCT03418844) and CHIVA (NCT03418844) clinical trials, this study investigated the molecular and immunophenotypic characteristics of long-term recurrence-free survivors (LTS) compared with short-term survivors (STS). Tumor samples from 37 LTS (recurrence-free ≥3 years) and 105 STS were analyzed using next-generation sequencing, BRCA1/RAD51C promoter methylation assays, shallow whole genome and multiplex immunofluorescence. Homologous recombination deficiency (HRD) was defined by BRCA1/2 or RAD51C/D alterations, and genomic instability scores (GIS). Immune profiling included quantification of CD4+, CD8+, CD20+, and FOXP3+ cells. LTS were younger and had a lower prevalence of FIGO stage IV disease. Molecularly, LTS showed fewer TP53 mutations, enrichment of BRCA2 mutations and BRCA1 and RAD51C promoter methylation, and a strong association between RB1 loss co-occurring with a BRCA alteration. Conversely, CCNE1 amplification was underrepresented in LTS. Immune profiling demonstrated increased stromal and intraepithelial CD8+ T-cell infiltration and reduced FOXP3+ regulatory T cells in LTS. Overall, exceptional survival in HGSOC is associated with younger age, enrichment of BRCA2 mutations and BRCA1/RAD51C methylation, reduced CCNE1 amplification, and a competent antitumor immune response. These findings highlight potential biomarkers for refining risk stratification and guiding personalized therapeutic strategies in ovarian cancer management.