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Updated: Jun 15, 2025
High-Throughput In Vitro Assay using Patient-Derived Tumor Organoids
Published on: June 14, 2021
ORIC-101, a Glucocorticoid Receptor Antagonist, in Combination with Nab-Paclitaxel in Patients with Advanced Solid
Christopher T Chen1, Vishesh Khanna1, Shivaani Kummar1,2
1Division of Oncology, Department of Medicine, Stanford University School of Medicine, Palo Alto, California.
Purpose:
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.
Insights
Glucocorticoid receptor (GR) inhibition with ORIC-101 did not overcome taxane resistance in advanced solid tumors. The combination therapy showed limited clinical activity and did not provide meaningful benefit to patients previously treated with taxanes.
Area of Science:
- Oncology
- Pharmacology
Background:
- Glucocorticoid receptor (GR) signaling promotes taxane chemotherapy resistance in solid tumors by upregulating antiapoptotic pathways.
- ORIC-101 is a selective GR antagonist developed to counteract this resistance mechanism.
Purpose of the Study:
- To evaluate the efficacy and safety of ORIC-101 in combination with nab-paclitaxel in patients with advanced solid tumors.
- To assess ORIC-101's ability to reverse taxane resistance in preclinical models and a Phase 1 clinical trial.
Main Methods:
- Preclinical assessment in cell lines and xenograft models to evaluate taxane resistance reversal.
- A Phase 1 clinical trial (NCT03928314) involving dose escalation and expansion in patients with advanced solid tumors, including those with prior taxane progression.
- Pharmacodynamic analysis of tumor and plasma to assess GR pathway inhibition.
Main Results:
- ORIC-101 demonstrated reversal of glucocorticoid-induced chemoprotection in vitro and tumor regressions in preclinical models.
- In the Phase 1 trial, limited antitumor activity was observed, with an objective response rate of 3.2% and median progression-free survival of 2 months in the dose expansion cohorts.
- Pharmacodynamic analyses confirmed GR pathway downregulation in most patients during the first cycle of treatment.
Conclusions:
- The combination of ORIC-101 and nab-paclitaxel exhibited limited clinical activity in taxane-resistant solid tumors.
- Despite successful GR pathway inhibition, the lack of significant clinical benefit highlights the complexity of targeting single resistance pathways in cancer therapy.
