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AbstractPurpose: In preclinical models, glucocorticoid receptor (GR) signaling drives resistance to taxane chemotherapy in multiple solid tumors via upregulation of antiapoptotic pathways. ORIC-101 is a potent and selective GR antagonist that was investigated in combination with taxane chemotherapy as an anticancer regimen preclinically and in a phase 1 clinical trial.Patients and Methods: The ability of ORIC-101 to reverse taxane resistance was assessed in cell lines and xenograft models, and a phase 1 study (NCT03928314) was conducted in patients with advanced solid tumors to determine the dose, safety, and antitumor activity of ORIC-101 with nab-paclitaxel.Results: ORIC-101 reversed chemoprotection induced by glucocorticoids in vitro and achieved tumor regressions when combined with paclitaxel in both taxane-naïve and -resistant xenograft models. In the phase 1 study, 21 patients were treated in dose escalation and 62 patients were treated in dose expansion. All patients in dose expansion had previously progressed on a taxane-based regimen. In dose escalation, five objective responses were observed. A preplanned futility analysis in dose expansion showed a 3.2% (95% confidence interval, 0.4–11.2) objective response rate with a median progression-free survival of 2 months (95% confidence interval, 1.8–2.8) across all four cohorts, leading to study termination. Pharmacodynamic analysis of tissue and plasma showed GR pathway downregulation in most patients in cycle 1.Conclusions: ORIC-101 with nab-paclitaxel showed limited clinical activity in taxane-resistant solid tumors. Despite clear inhibition of GR pathway signaling, the insufficient clinical signal underscores the challenges of targeting a single resistance pathway when multiple mechanisms of resistance may be in play.Significance: Glucocorticoid receptor (GR) upregulation is a mechanism of resistance to taxane chemotherapy in preclinical cancer models. ORIC-101 is a small molecule GR inhibitor. In this phase 1 study, ORIC-101 plus nab-paclitaxel did not show meaningful clinical benefit in patients who previously progressed on taxanes despite successful GR pathway downregulation.
Chen et al. (Fri,) studied this question.