Targeting glucocorticoid receptor signaling in platinum-resistant ovarian cancer: translational rationale and clinical advances following the ROSELLA trial.

Platinum-resistant ovarian cancer (PROC) remains a major clinical challenge, with limited effective treatment options and poor survival outcomes. Aberrant activation of the glucocorticoid receptor (GR) signaling pathway promotes tumor progression, chemoresistance, and immune evasion, providing a strong rationale for therapeutic targeting. Selective GR antagonists (SGRAs) represent an emerging novel strategy aimed at blocking this pro-tumorigenic pathway while minimizing off-target effects. Preclinical studies demonstrated that GR blockade restores chemosensitivity, particularly to taxane-based therapies, and may modulate the tumor microenvironment. These findings have translated into clinical evaluation, culminating in the phase 3 ROSELLA trial, which reported that the addition of relacorilant, a SGRA, to nab-paclitaxel significantly improved progression-free and overall survival in patients with recurrent PROC. These results, presented in March 2026, establish GR antagonism as a promising therapeutic strategy and a potential new treatment paradigm in this setting. In this evidence-based review, we summarize the biological basis of GR signaling in ovarian cancer, evaluate the clinical evidence supporting SGRAs, and discuss key challenges for implementation, including biomarker development, safety considerations, and rational combination strategies with chemotherapy, PARP inhibitors, and immunotherapy. We also highlight critical considerations for future clinical trial design to optimize the integration of GR-targeted therapies into the management of ovarian cancer.