Biomarker-Driven Treatments for Ovarian Cancer: Moving Beyond HRD?
Liz Joseph1, Michael Flynn1, Jonathan A Ledermann2
1NIHR Clinical Research Facility, University College Hospital, London, UK.
Abstract:
Ovarian cancer is a biologically heterogeneous disease, yet for more than two decades its standard treatment of surgery and platinum-taxane chemotherapy changed little. Only a modest additional benefit was seen with the addition of bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor A (VEGF-A) in selected patients. The recognition that BRCA1/2 mutations impair the repair of DNA double-strand breaks by homologous recombination, and that inhibitors of PARP are highly active in this setting, established the first widely adopted biomarker-driven treatment in this disease. Homologous recombination deficiency (HRD) therefore remains the established predictive biomarker for first-line maintenance therapy, but it is imperfect: benefit is not confined to HRD-positive tumours, assays report historical genomic scars, and most patients ultimately relapse with platinum-resistant disease. This review examines how biomarker-driven treatment in ovarian cancer is developing beyond HRD. We appraise the evidence for strategies that are already clinically established, principally PARP inhibitors, the folate receptor α-directed antibody-drug conjugate mirvetuximab soravtansine, and, more recently, PD-L1-selected immune checkpoint inhibition in platinum-resistant disease and distinguish these from approaches that remain investigational, including antibody-drug conjugates directed at HER2, TROP2, CLDN6, B7-H3/H4 and CDH6, and agents exploiting cell cycle dysregulation and replication stress such as CCNE1-associated, WEE1 and ATR-directed therapies. We also consider the practical obstacles to implementation: tumour heterogeneity and evolution, the complementary roles of tissue and liquid biopsy, when molecular profiling should be repeated, assay standardisation and access, and the limitations of basket trial designs. Progress will depend on expanding the development of practical frameworks for biomarker testing, treatment selection and sequencing.
