Relacorilant, a selective glucocorticoid receptor modulator, in combination with nab-paclitaxel (Abraxane), has shown promising results in patients with recurrent, platinum-resistant ovarian cancer. A phase 2 trial (NCT03776812) indicated that the combination could restore chemosensitivity and improve the efficacy of nab-paclitaxel in this patient population, characterized by elevated endogenous cortisol levels associated with tumor progression.
Phase 2 Trial Results
The phase 2 trial compared nab-paclitaxel alone with nab-paclitaxel combined with relacorilant, administered either intermittently or continuously. According to Domenica Lorusso, MD, PhD, the intermittent-dosing arm demonstrated significant improvements in progression-free survival (PFS), overall survival, overall response rate, and duration of response (DOR) compared to nab-paclitaxel monotherapy. Specifically, the median PFS was 5.6 months with the combination (n = 56) versus 3.8 months with nab-paclitaxel alone (n = 53; HR, 0.66; 95% CI, 0.44-0.98; P = .038). The median DORs were 5.55 months (95% CI, 3.75-5.88) and 3.65 months (95% CI, 2.89-5.09) in the respective arms.
ROSELLA Phase 3 Trial
These phase 2 results led to the initiation of the ongoing, randomized, phase 3 ROSELLA trial (EudraCT 2022-000662-18). This trial compares nab-paclitaxel alone with nab-paclitaxel combined with intermittent relacorilant in patients with platinum-resistant ovarian cancer who have received no more than three prior lines of therapy and have already been treated with bevacizumab (Avastin). The phase 2 exploratory analysis suggested that this specific population experienced the greatest benefit from the combination therapy.
Mechanism of Action and Rationale
Preclinical research suggests that glucocorticoid receptors are overexpressed in several solid tumors, leading to a worse prognosis and involvement in chemoresistance. Relacorilant targets these receptors, potentially blocking the cortisol pathway implicated in chemoresistance and epithelial-mesenchymal transition. Nab-paclitaxel was chosen as the companion drug because it does not require corticosteroid premedication, which could impair the efficacy of relacorilant.
Managing Toxicities
While the phase 2 trial mandated prophylaxis to reduce the incidence of grade 3 or greater hematologic toxicities, the phase 3 ROSELLA trial allows investigators more discretion in determining the necessity of prophylaxis. Lorusso noted that, in her experience, the hematologic toxicities associated with relacorilant plus nab-paclitaxel have been manageable without the routine use of granulocyte colony-stimulating factor.
Future Implications
The final outcomes of the ROSELLA trial will determine whether this combination can become a new therapeutic option for patients with platinum-resistant ovarian cancer. Lorusso emphasized the potential of blocking the cortisol pathway to improve patient outcomes by reducing chemoresistance.
