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The initial choice of nab-paclitaxel was to avoid corticosteroids typically given with paclitaxel, which would contradict relacorilant's mechanism. However, current practice often omits steroids with weekly paclitaxel, suggesting the combination might be feasible, broadening its potential application.
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The efficacy of relacorilant, a glucocorticoid antagonist, has raised concerns that routine steroid use with chemotherapy may induce resistance. This has led clinicians to reduce steroid doses, questioning a long-standing practice and its potential to blunt the therapeutic effects of chemotherapy.
Subgroup analysis of the ROSELLA trial shows a consistent overall survival benefit for the relacorilant-nab-paclitaxel combination, even in patients with a short interval (<6 months) since their last taxane exposure. This crucial finding supports using the regimen as a taxane re-challenge without concern for diminished efficacy.
The persistent separation of survival curves in the ROSELLA trial suggests relacorilant's benefit extends beyond sensitizing tumors to chemotherapy. By acting as a glucocorticoid receptor antagonist and blocking immunosuppressive cortisol, it may also have a favorable immune-modulatory effect.
The ROSELLA trial's success in boosting chemotherapy with a glucocorticoid receptor antagonist is thought-provoking. It suggests that routinely used steroids for managing side effects like nausea might inadvertently be diminishing chemotherapy's effectiveness across various cancers.
The novel drug relacorilant overcomes taxane resistance in ovarian cancer by targeting glucocorticoid receptors. It blocks stress-induced steroid signaling that promotes anti-apoptotic proteins, effectively re-sensitizing tumors to chemotherapy. This represents a completely new mechanism of action for this patient population.
The decision between new regimens in platinum-resistant ovarian cancer—relicorolant/nab-paclitaxel vs. pembrolizumab/paclitaxel—hinges on the patient's need for bevacizumab. If bevacizumab is required for symptomatic disease, the relicorolant combination is off the table.
The glucocorticoid receptor antagonist relacorilant does not require biomarker testing for patient selection. Its target is ubiquitously expressed in over 95% of ovarian cancer tissues, making it a broadly applicable therapy without the need for additional screening.
The success of the KEYNOTE-B96 trial highlights weekly paclitaxel as a uniquely effective partner for immunotherapy in platinum-resistant ovarian cancer. Its metronomic dosing modulates the tumor microenvironment, enhances immunogenicity, and reduces immunosuppression, making it superior to other chemotherapies in this combination.
High cortisol, a stress hormone, is linked to worse outcomes in ovarian cancer. Relacorilant, by blocking its receptor, appears to overcome chemo resistance by allowing the body's own immune system to help fight the cancer.
With multiple new effective options in platinum-resistant disease (relacorilant, pembrolizumab, ADCs), the key clinical question is shifting from choosing one superior drug to determining the optimal sequence. Biomarkers can guide initial choices, but sequencing multiple regimens, including re-using weekly paclitaxel backbones, is now a viable strategy.