Bevacizumab in ovarian cancer: Clinical data and predictive and prognostic biomarkers

Abstract

Angiogenesis, driven by the vascular endothelial growth factor (VEGF)/VEGFR signalling axis under hypoxic conditions, is one of the hallmarks of ovarian cancer (OC), contributing to tumour progression, metastatic dissemination and immune evasion. Hypoxia-induced angiogenic signalling sustains tumour growth and shapes an immunosuppressive tumour microenvironment, while homologous recombination deficiency (HRD) has been associated with increased tumour hypoxia and pro-angiogenic signalling. Conversely, VEGF pathway inhibition may exacerbate DNA damage and modulate immune cell trafficking, providing a strong biological rationale for synergy between anti-angiogenic agents, PARP inhibitors (PARPi), and immune checkpoint inhibitors. Bevacizumab, a humanised monoclonal antibody targeting VEGF-A, represents a pivotal therapeutic agent in OC management by inhibiting tumour angiogenesis and inducing transient vascular normalisation. Its clinical efficacy has been demonstrated as maintenance therapy in the first-line setting, alone or in combination with PARPi for HRD-positive disease, and in the recurrent setting both in platinum-sensitive and platinum-resistant disease. Despite these benefits, variability in patient response highlights the unmet need for validated predictive biomarkers. Circulating, tissue-based and molecular biomarkers have been investigated, including angiogenic factors (Tie2/Ang1 axis, interleukin-6 [IL-6] and chitinase-3-like protein [YKL-40]), VEGF-A isoforms, microvessel density, EGFR/ADAM17 signalling, angiomiRs and transcriptional subtypes with mesenchymal and proliferative phenotypes showing greater sensitivity to anti-angiogenic strategies. Although HRD status holds prognostic relevance and selected microRNAs show emerging potential, no biomarker has yet been validated to predict benefit from bevacizumab in clinical practice. Translational analyses from the MITO16A/MaNGO OV-2 program, highlight challenges such as assay standardisation, multiplicity correction and external validation, while identifying tumour immune infiltration patterns, TP53 mutation classes and composite HRD assessments as areas of further investigation. In conclusion, bevacizumab remains an integral component of OC treatment. Future progress will depend on biomarker-driven, prospectively designed clinical trials and the integration of multi-omic data and machine learning approaches to enable precision application of anti-angiogenic strategies, maximising clinical benefit while minimising toxicity.

Keywords: PARP inhibitors; VEGF; angiogenesis; bevacizumab; homologous recombination deficiency (HRD); ovarian cancer; predictive biomarkers; prognostic biomarkers.