Phase I Study of ORIC-101, a Glucocorticoid Receptor Antagonist, in Combination with Enzalutamide in Patients with Metastatic Castration-resistant Prostate Cancer Progressing on Enzalutamide

Authors

Wassim Abida
Andrew W Hahn
Neal Shore
Neeraj Agarwal
Paul Sieber
Matthew R Smith
Tanya Dorff
Paul Monk
Matthew Rettig
Rupal Patel
Anne Page
Maureen Duff
Rongda Xu
Jian Wang
Shravani Barkund
Aleksandr Pankov
Amber Wang
Melissa R Junttila
Pratik S Multani
Anneleen Daemen
Edna Chow Maneval
Christopher J Logothetis
Michael J Morris

Publication Date

3-15-2024

Journal

Clinical Cancer Research

DOI

10.1158/1078-0432.CCR-23-3508

PMID

38226958

PMCID

PMC10947849

PubMedCentral® Posted Date

3-15-2024

PubMedCentral® Full Text Version

Post-print

Abstract

Purpose: Increased glucocorticoid receptor (GR) signaling is a proposed compensatory mechanism of resistance to androgen receptor (AR) inhibition in metastatic castration-resistant prostate cancer (mCRPC). ORIC-101 is a potent and selective orally-bioavailable GR antagonist.

Patients and methods: Safety, pharmacokinetic/pharmacodynamic, and antitumor activity of ORIC-101 in combination with enzalutamide were studied in patients with mCRPC progressing on enzalutamide. ORIC-101 doses ranging from 80 to 240 mg once daily were tested in combination with enzalutamide 160 mg once daily. Pharmacokinetics/pharmacodynamics was assessed after a single dose and at steady state. Disease control rate (DCR) at 12 weeks was evaluated at the recommended phase 2 dose (RP2D).

Results: A total of 41 patients were enrolled. There were no dose-limiting toxicities and the RP2D was selected as 240 mg of ORIC-101 and 160 mg of enzalutamide daily. At the RP2D, the most common treatment-related adverse events were fatigue (38.7%), nausea (29.0%), decreased appetite (19.4%), and constipation (12.9%). Pharmacokinetic/pharmacodynamic data confirmed ORIC-101 achieved exposures necessary for GR target engagement. Overall, for 31 patients treated at the RP2D, there was insufficient clinical benefit based on DCR (25.8%; 80% confidence interval: 15.65-38.52) which did not meet the prespecified target rate, leading to termination of the study. Exploratory subgroup analyses based on baseline GR expression, presence of AR resistance variants, and molecular features of aggressive variant prostate cancer suggested possible benefit in patients with high GR expression and no other resistance markers, although this would require confirmation.

Conclusions: Although the combination of ORIC-101 and enzalutamide demonstrated an acceptable tolerability profile, GR target inhibition with ORIC-101 did not produce clinical benefit in men with metastatic prostate cancer resistant to enzalutamide.

Keywords

Male, Humans, Prostatic Neoplasms, Castration-Resistant, Receptors, Glucocorticoid, Phenylthiohydantoin, Benzamides, Nitriles, Antineoplastic Agents, Hormonal

Comments

Trial registration: ClinicalTrials.gov NCT04033328.

Published Open-Access

yes

Recommended Citation

Abida, Wassim; Hahn, Andrew W; Shore, Neal; et al., "Phase I Study of ORIC-101, a Glucocorticoid Receptor Antagonist, in Combination with Enzalutamide in Patients with Metastatic Castration-resistant Prostate Cancer Progressing on Enzalutamide" (2024). Faculty, Staff and Student Publications. 5124.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/5124