Highlights
- Relacorilant, a selective glucocorticoid receptor antagonist, combined with nab-paclitaxel, demonstrated statistically significant improvements in both progression-free survival (PFS) and overall survival (OS) in patients with platinum-resistant ovarian cancer in the phase 3 ROSELLA trial.
- The combination maintained a manageable safety profile, with adverse events comparable to nab-paclitaxel alone when adjusted for drug exposure.
- Findings support relacorilant plus nab-paclitaxel as a potential new standard of care for this challenging patient population.
Study Background and Disease Burden
Ovarian cancer remains the most lethal gynecologic malignancy worldwide, with high-grade serous subtypes predominating. Platinum-resistant disease, defined as recurrence within six months of completing platinum-based chemotherapy, represents a critical therapeutic challenge. These patients have limited treatment options and poor prognoses, with typical median OS ranging from 12 to 15 months. Nab-paclitaxel, a nanoparticle albumin-bound formulation of paclitaxel, is commonly used in this setting but offers modest benefit. New approaches to enhance chemosensitivity and prolong survival are urgently needed.
Glucocorticoid signaling, mediated via the glucocorticoid receptor (GR), has been implicated in tumor resistance to chemotherapy. Relacorilant is a first-in-class, selective GR antagonist designed to counteract cortisol-driven chemoresistance and potentially restore tumor sensitivity to cytotoxic agents.
Study Design
The pivotal ROSELLA (GOG-3073/ENGOT-ov72) phase 3 trial was an open-label, randomized, controlled study conducted at 117 centers across 14 countries. Eligible participants were women aged 18 years or older with platinum-resistant, high-grade serous, endometrioid, or carcinosarcoma (≥30% epithelial component) ovarian, primary peritoneal, or fallopian tube cancer. All had measurable disease, good performance status (ECOG 0–1), and adequate organ function, with up to three prior lines of therapy and prior bevacizumab exposure.
Patients were randomized 1:1 to receive either:
- Relacorilant (150 mg orally the day before, of, and after nab-paclitaxel infusion) plus nab-paclitaxel (80 mg/m2 IV days 1, 8, 15 of a 28-day cycle), or
- Nab-paclitaxel monotherapy (100 mg/m2 IV days 1, 8, 15 of a 28-day cycle).
Dual primary endpoints were PFS (as assessed by blinded independent central review per RECIST v1.1) and OS. Secondary endpoints included objective response rate (ORR), duration of response (DOR), and safety. The intention-to-treat population comprised all randomized patients; the safety population included all who received at least one dose.
Supporting phase II data (NCT03776812) further explored dosing strategies, comparing intermittent and continuous relacorilant schedules combined with nab-paclitaxel versus nab-paclitaxel alone in a similar patient population.
Key Findings
Phase 3 ROSELLA Trial Results
A total of 381 women were randomized: 188 to the combination and 193 to nab-paclitaxel monotherapy. Key efficacy and safety outcomes:
- Progression-Free Survival (PFS): Median PFS was 6.54 months (95% CI 5.55–7.43) for relacorilant plus nab-paclitaxel versus 5.52 months (3.94–5.88) for nab-paclitaxel alone (hazard ratio [HR] 0.70, 95% CI 0.54–0.91; p=0.0076), indicating a 30% reduction in the risk of progression or death.
- Overall Survival (OS): Interim analysis showed median OS of 15.97 months (95% CI 13.47–not reached) for the combination versus 11.50 months (10.02–13.57) for monotherapy (HR 0.69, 95% CI 0.52–0.92; p=0.0121), reflecting a clinically meaningful survival improvement.
- Safety: Adverse event profiles were similar across arms when adjusted for nab-paclitaxel exposure; common grade ≥3 events included neutropenia, anemia, peripheral neuropathy, and fatigue. No new safety signals emerged.
Phase II Study Results
In the phase II trial (n=178), patients were randomized to:
- Nab-paclitaxel + intermittent relacorilant (150 mg the day before, of, and after nab-paclitaxel)
- Nab-paclitaxel + continuous relacorilant (100 mg daily)
- Nab-paclitaxel monotherapy
Key findings included:
- Intermittent relacorilant plus nab-paclitaxel improved PFS (HR 0.66, p=0.038) and DOR (HR 0.36, p=0.006) versus monotherapy, with similar ORR.
- OS favored the intermittent combination (HR 0.67, p=0.066), though not statistically significant at final analysis.
- Safety was comparable across arms, with no unexpected toxicities.
| Endpoint | Phase 3 Combination | Phase 3 Monotherapy | Phase 2 Intermittent Combo | Phase 2 Monotherapy |
|---|---|---|---|---|
| Median PFS (months) | 6.54 | 5.52 | 7.6 | 3.7 |
| Median OS (months) | 15.97 | 11.50 | 13.3 | 9.2 |
| HR for PFS | 0.70 | – | 0.66 | – |
| Common Gr ≥3 AEs | Neutropenia, anemia, neuropathy, fatigue (all arms) | |||
Expert Commentary
The ROSELLA trial delivers compelling evidence that relacorilant, by antagonizing GR-mediated chemoresistance, can meaningfully extend both PFS and OS when added to nab-paclitaxel for platinum-resistant ovarian cancer. The magnitude of benefit, especially in OS, is notable given the refractory nature of this population. The phase II study further supports intermittent dosing as the optimal strategy, with the greatest efficacy and no excess toxicity.
Expert opinion emphasizes the innovation of targeting stress hormone signaling in cancer therapy. However, some limitations remain: subgroup analyses by histology, molecular profile, or prior therapies were not fully presented, and longer-term OS data are awaited. The open-label design and international multicenter execution strengthen the real-world relevance, though regional practice patterns may influence generalizability.
Conclusion
The addition of relacorilant to nab-paclitaxel offers a clinically meaningful advance in the management of platinum-resistant ovarian cancer, with significant gains in both PFS and OS and an acceptable safety profile. These results support adoption of this regimen as a new standard of care, pending full regulatory review and guideline endorsement. Further research should focus on biomarker-driven patient selection and combination strategies with emerging targeted therapies.
References
Olawaiye AB, Gladieff L, O’Malley DM, Kim JW, Garbaos G, Salutari V, et al. Relacorilant and nab-paclitaxel in patients with platinum-resistant ovarian cancer (ROSELLA): an open-label, randomised, controlled, phase 3 trial. Lancet. 2025 Jun 21;405(10496):2205-2216. doi: 10.1016/S0140-6736(25)01040-2.
Colombo N, Van Gorp T, Matulonis UA, Oaknin A, Grisham RN, Fleming GF, et al. Relacorilant + Nab-Paclitaxel in Patients With Recurrent, Platinum-Resistant Ovarian Cancer: A Three-Arm, Randomized, Controlled, Open-Label Phase II Study. J Clin Oncol. 2023 Oct 20;41(30):4779-4789. doi: 10.1200/JCO.22.02624.