ORIC-101, a Glucocorticoid Receptor Antagonist, in Combination with Nab-Paclitaxel in Patients with Advanced Solid Tumors

Authors

Christopher T Chen
Vishesh Khanna
Shivaani Kummar
Raghad M Abdul-Karim
David Sommerhalder
Anthony W Tolcher
Naoto T Ueno
Sarah Lindsey Davis
Douglas W Orr
Erika Hamilton
Manish R Patel
Alexander I Spira
Shekeab Jauhari
Vaia Florou
Maureen Duff
Rongda Xu
Jian Wang
Shravani R Barkund
Haiying Zhou
Aleksandr Pankov
Wayne Kong
Nadine S Jahchan
Erica L Jackson
Jessica D Sun
Melissa R Junttila
Pratik S Multani
Anneleen Daemen
Edna Chow Maneval
Pamela N Munster

Publication Date

9-1-2024

Journal

Cancer Research Communications

DOI

10.1158/2767-9764.CRC-24-0115

PMID

39177285

PMCID

PMC11396014

PubMedCentral® Posted Date

9-13-2024

PubMedCentral® Full Text Version

Post-print

Abstract

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.

Keywords

Humans, Paclitaxel, Female, Neoplasms, Receptors, Glucocorticoid, Male, Middle Aged, Antineoplastic Combined Chemotherapy Protocols, Aged, Albumins, Animals, Adult, Mice, Xenograft Model Antitumor Assays, Drug Resistance, Neoplasm, Cell Line, Tumor

Published Open-Access

yes

Recommended Citation

Chen, Christopher T; Khanna, Vishesh; Kummar, Shivaani; et al., "ORIC-101, a Glucocorticoid Receptor Antagonist, in Combination with Nab-Paclitaxel in Patients with Advanced Solid Tumors" (2024). Faculty, Staff and Student Publications. 5122.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/5122