乌鸦传媒

A combination of relacorilant, a drug that modulates the glucocorticoid receptor, and nab-paclitaxel shows promise for patients with recurrent, platinum-resistant ovarian cancer.

Although ovarian cancer patients usually initially respond to platinum-based chemotherapy, most unfortunately have disease relapse within the first 3 years and may then eventually die of treatment-resistant disease.

As Nicoletta Colombo, MD, of the European Institute of Oncology in Milan, and colleagues explained in their recent study in the , one mechanism of chemotherapy resistance may be driven by glucocorticoids. via suppression of the apoptotic pathways used by cytotoxic agents. Cortisol may activate the glucocorticoid receptor, leading to upregulation of target genes and suppression of apoptosis pathways. High glucocorticoid receptor expression in ovarian cancer correlates with shorter progression-free survival (PFS).

Relacorilant is an investigational, orally administered, selective glucocorticoid receptor modulator that restores chemosensitivity and enhances chemotherapy efficacy by competitively antagonizing the anti-apoptotic effects of cortisol. Nab-paclitaxel is a solvent-free, albumin-bound nanoparticle form of paclitaxel that was developed to avoid numerous toxicities, including hypersensitivity reactions. Nab-paclitaxel has shown in a phase II study of patients with platinum-resistant ovarian cancer. A combination of relacorilant plus nab-paclitaxel has shown a good safety profile and no need for corticosteroid premedication.

The randomized, controlled, open-label, international phase II study by Colombo's group evaluated the efficacy, safety, pharmacokinetics, and pharmacodynamics of relacorilant plus nab-paclitaxel in patients with platinum-resistant/refractory ovarian cancer compared with nab-paclitaxel monotherapy.

In the following interview, co-author Ursula A. Matulonis, MD, chief of the Division of Gynecologic Oncology at Dana-Farber Cancer Institute in Boston, elaborates on the findings.

What does the study add to the literature?

Matulonis: This phase II study looked at nab-paclitaxel itself or with relacorilant administered continuously or intermittently. The results show that patients who received relacorilant intermittently plus nab-paclitaxel improved PFS and overall survival (OS). This is intriguing data about the concept of adding a drug that modulates glucocorticoid receptor to restore cancer cell sensitivity to chemotherapy. These phase II results have paved the way for a confirmatory ongoing phase III trial.

A total of 178 women were randomly assigned to nab-paclitaxel 80 mg/m² plus intermittent relacorilant 150 mg the day before, of, and after nab-paclitaxel; nab-paclitaxel 80 mg/m² plus continuous relacorilant 100 mg once daily; or nab-paclitaxel monotherapy 100 mg/m². Nab-paclitaxel was administered on days 1, 8, and 15 of each 28-day cycle.

Intermittent relacorilant plus nab-paclitaxel showed improved PFS vs nab-paclitaxel alone. Continuous relacorilant plus nab-paclitaxel showed numerically improved median PFS, but did not result in significant improvement over nab-paclitaxel monotherapy.

The overall response rate was similar across all three arms. Median OS was better for intermittent (13.9 months) vs continuous (11.3 months) relacorilant and nab-paclitaxel alone (12.2 months).

What are some of the unique features of recurrent platinum-resistant ovarian cancer?

Matulonis: Platinum-resistant ovarian cancer does not have as many driver mutations as other cancers or genetic underpinnings to target. Bevacizumab and PARP inhibitors have been used as standard therapies. For the first time in 10 years, we have a new drug, mirvetuximab [Elahere], which received accelerated FDA approval in November 2022 for adult patients with folate receptor alpha positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer, who have received one to three prior systemic treatment regimens.

Relacorilant has a novel mechanism of action and has shown strong preclinical data and may add to the armamentarium.

How is high glucocorticoid receptor expression a factor in treating these patients?

Matulonis: High glucocorticoid receptor expression was previously reported in ovarian tumors. High glucocorticoid receptor expression was also an independent predictor of PFS and was associated with decreased OS in patients with ovarian cancer, independent of BRCA mutation status.

How would you characterize the safety profile?

Matulonis: Overall, intermittent relacorilant plus nab-paclitaxel was tolerated better than the continuous regimen and showed an adverse events profile comparable to nab-paclitaxel monotherapy. Some observed adverse events, such as fatigue, may overlap with glucocorticoid receptor modulation and were numerically higher in the relacorilant-treated arms.

One reason continuous relacorilant had less activity than intermittent administration is that there may be more side effects with continuous dosing. Intermittent administration is not an issue, and the safety profile seems similar to nab-paclitaxel alone.

We know that nab-paclitaxel causes bone marrow suppression. I prefer to use weekly paclitaxel, not nab-paclitaxel. If the phase III trial shows promising results, then I would use nab-paclitaxel. Outside of a clinical trial, clinicians should use weekly paclitaxel for now.

What is your main message for practicing oncologists?

Matulonis: Relacorilant has an intriguing, novel mechanism of action, binding to the glucocorticoid receptor with the potential to allow nab-paclitaxel to work better. We need to wait for phase III results for any change in clinical practice.

Read the study here and expert commentary about it here.