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.

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.

While GnRH antagonists like relugolix show a potential cardiovascular advantage, this benefit may disappear when patients receive intensive, proactive cardiovascular management. A trial comparing degarelix to Lupron showed no difference in CV toxicity when all patients underwent rigorous CV assessment and optimization, suggesting proactive care is the most critical factor.

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 HERO trial found the GnRH antagonist relugolix reduced major adverse cardiovascular events (MACE) by 54% compared to the agonist leuprolide. While absolute rates were low (2.8% vs 5.6%), this suggests a significant safety advantage for antagonists in patients with cardiovascular risk.

While high glucocorticoid receptor (GR) expression is linked to chemoresistance and worse outcomes in ovarian cancer, clinical data found no correlation between GR levels and patient benefit from the GR antagonist relacorilant. This finding means no predictive biomarker test is required to select patients for this therapy.

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 HERO trial demonstrated that the ADT antagonist relugolix has a 54% lower risk of major adverse cardiovascular events compared to the agonist leuprolide. This makes antagonists a safer choice for prostate cancer patients with pre-existing cardiovascular disease.

A drug-drug interaction study found that apalutamide induces an enzyme (CYP3A4) that lowers relagolix concentrations, leading to suboptimal hormonal suppression. To maintain efficacy when used in combination, the standard dose of the oral GnRH antagonist relagolix must be doubled.