Platinum-resistant ovarian cancer presents a significant therapeutic challenge, with most patients experiencing recurrence and developing resistance to standard chemotherapy. The phase 3 ROSELLA trial (NCT05257408) is investigating relacorilant, an oral, selective glucocorticoid receptor (GR) modulator, to overcome chemoresistance in this setting. By antagonizing the GR pathway, relacorilant aims to block cortisol's antiapoptotic effects in GR-overexpressing solid tumors, offering a novel approach to enhance chemotherapy efficacy.
The Rationale Behind Targeting the GR Pathway
Activation of the GR pathway, driven by cortisol binding, has been implicated in the development of chemoresistance. High GR expression is common in ovarian tumors and has been associated with poorer patient prognosis. Preclinical and early clinical evidence suggests that GR overexpression contributes to chemoresistance and epithelial-mesenchymal transition, leading to a more chemoresistant and worse prognostic phenotype.
Preclinical and Early Clinical Evidence
In vitro studies have demonstrated that adding relacorilant to paclitaxel reverses the deleterious effects of glucocorticoids on paclitaxel's efficacy (P < .001) in OVCAR5 cells. Furthermore, relacorilant plus paclitaxel decreased tumor growth and slowed time to progression in xenograft models compared to paclitaxel alone (both P < .0001).
A phase 1 dose escalation study (NCT02762981) evaluating relacorilant plus nab-paclitaxel in heavily pretreated patients with advanced or metastatic solid tumors showed that 33% of response-evaluable patients (n = 57) achieved durable disease control of 16 weeks or greater. Notably, 28.6% of patients (n = 42) experienced longer duration of benefit than they did on a prior taxane.
Phase 2 Trial Results
Data from a phase 2 trial (NCT03776812) indicated that intermittent dosing of relacorilant plus nab-paclitaxel (n = 60) improved progression-free survival (PFS) and duration of response (DOR), with a trend towards superior overall survival (OS), compared with nab-paclitaxel alone (n = 60) in patients with platinum-resistant/refractory ovarian cancer treated with no more than 4 prior chemotherapeutic lines.
At a median follow-up of 11.1 months, intermittent relacorilant plus nab-paclitaxel resulted in a median PFS of 5.6 months vs 3.8 months with nab-paclitaxel alone (HR, 0.66; 95% CI, 0.44-0.98; P = .038). The median DOR was 5.55 months (95% CI, 3.75-5.88) and 3.65 (95% CI, 2.89-5.09) in the intermittent vs monotherapy arms, respectively (HR, 0.36; 95% CI, 0.16-0.77; P = .006).
In the preplanned OS analysis, at a median follow-up of 22.5 months, the median OS was 13.9 months (95% CI, 11.1-18.4) vs 12.2 months (95% CI, 7.7-15.3) in the intermittent vs monotherapy arms, respectively (HR, 0.67; 95% CI, 0.43-1.03; P = .066).
ROSELLA Trial Design and Objectives
The ROSELLA study is a randomized, 2-arm, open-label, multicenter, global trial designed to confirm the phase 2 findings in a larger patient population. The study enrolled patients with confirmed high-grade serous epithelial ovarian, primary peritoneal, or fallopian tube cancers who have platinum-resistant disease.
Patients are randomized 1:1 to receive either 150 mg of oral relacorilant the day before, day of, and day after infusion with 80 mg/m2 of nab-paclitaxel, administered on days 1, 8, and 15 of each 28-day cycle, or 100 mg/m2 of nab-paclitaxel monotherapy on days 1, 8, and 15 of each 28-day cycle.
The primary end point of the study is PFS by blinded independent central review (BICR) per RECIST v1.1. Key secondary end points include OS per RECIST v1.1, investigator-assessed PFS, ORR by BICR, and DOR. The study was initiated in June 2022, with a planned enrollment of approximately 360 patients, and completed recruitment as of April 8, 2024. The trial is being conducted at 117 locations across North America and Europe.
