Dr Thaker on the Role of the Glucocorticoid Pathway in Platinum-Resistant Ovarian Cancer

"A selective glucocorticoid receptor modulator is important because we know that cortisol [plays a role] in hypothalamic pituitary access, which is critical for how we respond to stress. Cancer is a big stressor, and we know that patients [with ovarian cancer] who have high cortisol levels tend to have worse [outcomes] than patients who have lower levels. Trying to modulate that is really important."

Premal Thaker, MD, MS, surgeon, David G. and Lynn Mutch Professor of Obstetrics, director of gynecology, clinical research chief, Gynecological Oncology, Division of Gynecologic Oncology, Siteman Cancer Center, discusses the role of the glucocorticoid receptor (GR) pathway in the development of cortisol-related chemoresistance in ovarian cancer, as well as efforts to target this pathway through the development of selective GR modulators.

The development of a selective GR modulator is critical for managing the physiological impact of cortisol dysregulation, especially within the context of cancer, Thaker begins. Cortisol plays a pivotal role in the hypothalamic-pituitary axis, influencing how the body responds to stress, she explains. Cancer, as a significant stressor, often disrupts this pathway, leading to elevated cortisol levels. Notably, research has shown that patients with ovarian cancer with higher cortisol levels, particularly when measured at night, tend to have worse outcomes than those with lower levels. By mitigating these cortisol spikes, a selective GR modulator could play an important role in treatment, Thaker asserts.

The oral selective GR modulator relacorilant (CORT125134), which is currently in development, could address this cortisol-related resistance in ovarian cancer, Thaker continues. Relacorilant may provide a novel approach to overcoming chemoresistance by blocking cortisol’s antiapoptotic effects in GR-overexpressing tumors, she states. This approach is especially relevant for platinum-resistant ovarian cancer, a setting where effective treatment options are limited, Thaker emphasizes. The phase 3 ROSELLA study (NCT05257408) has been launched to validate and expand previous findings indicating that relacorilant can improve responses when combined with nab-paclitaxel (Abraxane) in this population.

Glucocorticoids are traditionally studied in the context of non-cancerous conditions like Cushing syndrome; however, exploring their modulation in cancer patients offers a new frontier, she says. By targeting cortisol’s effects, relacorilant could provide a promising strategy for enhancing responses and addressing resistance in difficult-to-treat cancers, Thaker concludes.