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Clinical Trial
. 2024 Mar 15;30(6):1111-1120.
doi: 10.1158/1078-0432.CCR-23-3508.

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

Wassim Abida  1 , Andrew W Hahn  2 , Neal Shore  3 , Neeraj Agarwal  4 , Paul Sieber  5 , Matthew R Smith  6 , Tanya Dorff  7 , Paul Monk  8 , Matthew Rettig  9 , Rupal Patel  10 , Anne Page  10 , Maureen Duff  10 , Rongda Xu  10 , Jian Wang  10 , Shravani Barkund  10 , Aleksandr Pankov  10 , Amber Wang  10 , Melissa R Junttila  10 , Pratik S Multani  10 , Anneleen Daemen  10 , Edna Chow Maneval  10 , Christopher J Logothetis  2 , Michael J Morris  1
Affiliations
Clinical Trial

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

Wassim Abida et al. Clin Cancer Res. .

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.

Trial registration: ClinicalTrials.gov NCT04033328.

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Conflict of interest statement

Conflicts of Interest:

WA: Speaking honoraria from Roche, Pfizer, Medscape, Aptitude Health, Clinical Education Alliance, touchIME and Onclive/MJH Life Sciences, consulting fees from Clovis Oncology, Janssen, ORIC Pharmaceuticals (prior to opening of the study in this publication), Daiichi Sankyo and AstraZeneca, and Research Funding (to his institution) from AstraZeneca, Zenith Epigenetics, Clovis Oncology, ORIC Pharmaceuticals, Epizyme, and Nuvation Bio.

AWH: Advisory board consulting: Janssen, Intellisphere; Honoraria: Medscape; Travel support: Dava Oncology.

NS: Consulting: Abbvie, Accord, Alessa Therapeutics, Amgen, Antev, Arquer, Asieris, Astellas, Astra Zeneca, Aura Biosciences, Bayer, Bioprotect, Bristol Myers Squibb, Boston Scientific, CG Oncology, Clarity, Cold Genesys, Dendreon, Exact Imaging, Genentech Roche, Ferring, Fize Medical, Foundation Medicine, Genesis Care, Immunity Bio, Incyte, Invitae, Janssen, Lantheus, Lilly, MDXHEALTH, Merck, Minomic, Myovant, Myriad, Nonagen, Novartis, Nymox, Palette Life, PlatformQ, Pacific Edge, Pfizer, Preview, Profound Medical, Promaxo, Protara, Photocure, Propella, Sanofi, Genzyme, Specialty Networks, Telix, Tolmar, Urogen.

NA: Consultancy to Astellas, Astra Zeneca, Aveo, Bayer, Bristol Myers Squibb, Calithera, Clovis, Eisai, Eli Lilly, EMD Serono, Exelixis, Foundation Medicine, Genentech, Gilead, Janssen, Merck, MEI Pharma, Nektar, Novartis, Pfizer, Pharmacyclics, and Seattle Genetics. Research funding (to his institution): Arnivas, Astellas, Astra Zeneca, Bavarian Nordic, Bayer, Bristol Myers Squibb, Calithera, Celldex, Clovis, Crispr, Eisai, Eli Lilly, EMD Serono, Exelixis, Genentech, Gilead, Glaxo Smith Kline, Immunomedics, Janssen, Lava, Medivation, Merck, Nektar, Neoleukin, New Link Genetics, Novartis, Oric, Pfizer, Prometheus, Rexahn, Roche, Sanofi, Seattle Genetics, Takeda, and Tracon.

PS: Speaker: Bayer, Astellas, Myovant, Dendreon, Pfizer, Merck, Janssen, Accord; compensated consultant: NovoNordisk; research trials: AstraZeneca, Astellas, Bayer, Merck, CG Therapeutics, Pfizer, Janssen, Dendreon, ORIC

MRS: Consulting fees from Ambrx, Astellas, Bayer, Pfizer, Janssen, Lilly; speaking honoraria from Astellas, Bayer, Pfizer, Janssen, Lilly.

TBD: Consulting fees from AstraZeneca, Bayer, Janssen, Sanofi.

PM: Research: Bioxcel, Genentech, Dendreon, Regeneron; consulting: Pfizer, Myovant, Sanofi, Dendreon.

MR: Speaker: Bayer, Janssen; Compensated Consultant: Amgen, Janssen, Bayer, Inmune Bio, Ambryx, Astra-Zeneca, Myovant; Research Support: Merck, Novartis, Lantheus, Janssen.

CJL: Honoraria: Bayer, Amgen, Novartis, Boehringer Ingelheim, Merck, Sharp & Dohme, Exelixis; Clinical Grants: Janssen, ORIC Pharmaceuticals, Novartis.

MJM: Uncompensated advisor to Bayer, and Novartis. Compensated advisor to AstraZeneca, Lantheus, Daiichi, Convergent Therapeutics, Pfizer, ITM Isotope Technologies, Clarity Pharmaceuticals, Blue Earth Diagnostics, POINT Biopharma, Telix, and Z-Alpha. His institution receives research funding from Bayer, Corcept, Roche, Janssen, Celgene, Novartis, and Astellas.

ORIC Authors: Stock and employment at ORIC Pharmaceuticals.

Figures

Figure 1.
Figure 1.. Study Disposition
Figure 2.
Figure 2.. ORIC-101 Pharmacodynamics.
(A) PD modulation after one dose of ORIC-101 in dose expansion patients treated at the RP2D. Results are displayed as the average fold change in the expression of GR target genes FKBP5, GILZ and PER1 from pre-dose to 6 hours post-dose (in red). Diamonds represent change in cortisol pre-dose to 6 hours post-dose. (B) Barplot with GR IHC H-scores in tumor cells in pretreatment biopsies, colored by biopsy site, from dose expansion patients treated at the RP2D. Low GR expression was defined as H-score <100, and high GR expression as H-score ≥200. (C) Barplot with proportional on-treatment change in GR tumor H-score, defined as (on-treatment GR H-score – pretreatment GR H-score) / pretreatment GR H-score, for 9 dose expansion patients with matched tumor biopsies from the same biopsy site. Diamonds represent GR tumor H-score at pretreatment.
Figure 3.
Figure 3.. Genomic Landscape of Dose Expansion Patients.
OncoPrint overview of the most prevalent genomic alterations in plasma samples from dose expansion patients with plasma collected before treatment, at the end of Cycle 2, and/or at the end of treatment. Plasma could not be collected in 2 patients. Displayed are genes from the targeted 152-gene panel that were altered at any timepoint in ≥3 (3/29, 10%) of the study patients. Type of alteration is indicated by color, with “Other” including frame-shift insertions and deletions, in-frame insertions and deletions, and splice site mutations. Screening, on-study and end of treatment samples are shown as columns, grouped per patient. Tumor fraction is shown on top; NA indicates tumor fraction could not be estimated.
Figure 4.
Figure 4.
Biomarker Patient Selection Strategy Consort, with Antitumor Activity at the RP2D Across Patients Defined by AR, AVPC, and GR Status
Figure 5.
Figure 5.
Representative Examples of Tumor Heterogeneity and Resistance Mechanism Redundancy
See this image and copyright information in PMC

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