Epithelial ovarian cancer (OC) remains a lethal gynecologic malignancy, with approximately 70 % of patients relapsing within three years of frontline treatment. A clinically useful framework is to view advanced-stage ovarian cancer (ads-OC) as “two diseases” rather than a single uniform entity: one reflecting the classic course guided by the platinum-free interval (PF–I), and the second highlighting biologically defined subgroups where repeated relapses occur across multiple lines. This framework implies that optimal management should not be determined by PF-I alone but should be individualized using integrated disease biology and treatment context. Within these pathways, immunotherapy (IOT) has transitioned from ineffective monotherapy toward rational combination strategies designed to modulate the tumor microenvironment (TME) and overcome dominant immunosuppressive forces, such as regulatory T cells (Tregs) and tumor-associated macrophages (TAMs). Recent clinical evidence from the phase III ENGOT-ov65/KEYNOTE-B96 trial represents a historic milestone, demonstrating that the addition of pembrolizumab to weekly paclitaxel, with or without investigator-choice bevacizumab, significantly improves overall survival (OS) in patients with platinum-resistant rOC (PR-rOC) with PD-L1–expressing tumors, with OS benefit also observed in the intention-to-treat (ITT) population. These findings validate the potential of immune checkpoint inhibitor (ICI)-based regimens to reshape the therapeutic landscape in populations with substantial unmet need. Furthermore, biomarker development is moving toward a more structured framework, as proposed by SITC and NCI, emphasizing the need for standardized reporting and the exploration of emergent indicators. Institutional research further highlights that IOT-relevant biomarkers, such as PD-L1, are not fixed baseline characteristics but are dynamically upregulated by cytotoxic stress and cisplatin exposure, reflecting a compensatory immune-evasive state linked to platinum resistance. Ultimately, the management of rOC is evolving into a biologically informed, line-specific strategy that prioritizes the integration of IOT within established systemic backbones. The success of contemporary combination approaches underscores the necessity of interpreting biomarkers within a dynamic, treatment-contextualized framework. Future progress will depend on a bidirectional lab-to-trial paradigm, where mechanistic insights into treatment-induced immune modulation guide the design of precise clinical trials, ensuring that therapeutic strategies are tailored to the evolving immune context of each patient throughout the disease continuum. Beyond ICI, immune-relevant strategies targeting treatment-induced resistance pathways, exemplified by glucocorticoid receptor (GR) antagonism in the ROSELLA trial, suggest that indirect TME modulation may also yield clinically meaningful benefit in PR-rOC.
Chang et al. (Sun,) studied this question.