Relacorilant is emerging as one of the most innovative agents in the glucocorticoid receptor (GR) pathway, developed to counteract chemotherapy resistance in ovarian cancer and other GR-driven solid tumors. As a selective glucocorticoid receptor modulator (SGRM), relacorilant suppresses tumor-promoting GR signaling while avoiding the endocrine, electrolyte, and adrenal toxicities historically associated with first-generation GR inhibitors such as mifepristone. The drug’s mechanistic specificity, supported by promising late-phase clinical data, positions relacorilant as a potentially practice-changing therapy in platinum-resistant ovarian cancer.
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Scientific Rationale: Targeting GR-Driven Chemoresistance
Glucocorticoids are routinely used in oncology to prevent nausea and reduce inflammation, but a growing body of translational and clinical evidence shows that they can also activate tumor-protective programs. Through GR activation, cancer cells acquire resistance to apoptosis, increase DNA repair capacity, and upregulate anti-apoptotic pathways involving BCL-XL and SGK1 (Greenwood et al., 2020; West et al., 2021). These effects are especially pronounced in ovarian cancer, where GR activation is associated with shorter survival and reduced chemotherapy responsiveness (O’Connor et al., 2021).
Relacorilant was designed to interrupt these pathways by blocking cortisol-mediated GR signaling. Importantly, it does so without interfering with progesterone receptors or inducing adrenal insufficiency, allowing continuous dosing without the burden of hormonal destabilization—a limitation that prevented broader use of earlier GR antagonists (Fleseriu et al., 2019).
Mechanism of Action: Selective Blockade Without Systemic Hormonal Disruption
Relacorilant binds GR with high affinity and prevents activation of GR-regulated gene expression. Because it does not stimulate progesterone or mineralocorticoid receptors, relacorilant avoids complications such as electrolyte imbalance, endometrial thickening, or cortisol withdrawal. This selectivity permits sustained suppression of tumor-protective GR signaling while maintaining physiological glucocorticoid responses elsewhere in the body. As a result, the drug is particularly suited for combination with cytotoxic chemotherapy.
Clinical Development in Oncology
The most clinically advanced program for relacorilant involves its combination with nab-paclitaxel in platinum-resistant ovarian cancer. The scientific rationale is straightforward: GR activation induces resistance to taxanes, and blocking GR restores chemotherapy sensitivity.
The ROSELLA Phase III Trial
The global ROSELLA Phase III trial evaluated relacorilant combined with nab-paclitaxel versus nab-paclitaxel alone in women with platinum-resistant epithelial ovarian cancer. The study met its primary endpoint, showing an improvement in progression-free survival, along with a greater rate of tumor response and more durable disease control. Early disclosures reported that the drug conferred benefit even in heavily pretreated patients and those previously exposed to glucocorticoids—two populations known to exhibit profound chemoresistance.
These results have generated significant optimism because ROSELLA is one of the few Phase III trials in recent years to demonstrate meaningful benefit in platinum-resistant disease. Safety findings were also encouraging: relacorilant did not add neurotoxicity or exacerbate taxane-related effects, making long-term dosing more tolerable.
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Phase II Evidence Supporting the Strategy
Prior Phase II results further validated the drug’s potential. Relacorilant combined with nab-paclitaxel nearly doubled the objective response rate compared with nab-paclitaxel alone and extended median progression-free survival from 3.8 to 5.6 months (Weinberg et al., 2022). Patients who avoided dexamethasone premedication experienced the strongest benefit, underscoring the biologic dependence of the tumor on GR signaling.
Safety Profile
Relacorilant’s safety is one of its strongest attributes. Across trials, adverse events were largely related to the chemotherapy backbone rather than the SGRM itself.
Common events include:
- Fatigue
- Nausea
- Alopecia (taxane-related)
- Neutropenia (manageable and expected with taxanes)
Notably absent are:
- Adrenal insufficiency
- Electrolyte disturbance
- Progesterone-related effects
This differentiates relacorilant significantly from mifepristone and other nonspecific GR inhibitors.
Why Relacorilant Matters
Platinum-resistant ovarian cancer remains an area of dire unmet need, with historically poor outcomes and minimal therapeutic innovation. Relacorilant introduces a mechanistically rational approach—reversing chemotherapy resistance by disabling a survival pathway that tumors exploit.
The drug’s importance lies in its ability to target a biologic vulnerability rather than purely suppressing cell proliferation. If full Phase III results confirm the early findings, relacorilant could become the first GR-modulating therapy to significantly improve outcomes in this setting. Its selective mechanism, favorable tolerability, and compatibility with chemotherapy also open opportunities for exploration in other GR-driven tumors such as pancreatic, breast, and adrenal cancers.
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Future Directions
Relacorilant continues to be evaluated in multiple oncology programs, including studies designed to identify biomarkers of response based on GR activity. Emerging research is exploring whether GR signaling signatures can predict which tumors are most likely to benefit from SGRM therapy. Corcept Therapeutics is also developing combination approaches, particularly in cancers where stress-hormone signaling is known to promote progression.
Conclusion
Relacorilant represents a sophisticated and biologically grounded approach to overcoming chemotherapy resistance. By selectively inhibiting GR signaling, the drug offers a pathway to restore cytotoxic sensitivity in platinum-resistant ovarian cancer—a field that has struggled to achieve meaningful advances. With encouraging Phase III findings and a mechanistic rationale supported by decades of translational research, relacorilant stands as one of the most promising targeted agents now advancing in gynecologic oncology.
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Written by Armen Gevorgyan, MD