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Clinical Trial
. 2024 Sep 1;4(9):2415-2426.
doi: 10.1158/2767-9764.CRC-24-0115.

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

Christopher T Chen  1 , Vishesh Khanna  1 , Shivaani Kummar  1   2 , Raghad M Abdul-Karim  3 , David Sommerhalder  3 , Anthony W Tolcher  3 , Naoto T Ueno  4 , Sarah Lindsey Davis  5 , Douglas W Orr  6 , Erika Hamilton  7 , Manish R Patel  8 , Alexander I Spira  9 , Shekeab Jauhari  10 , Vaia Florou  11 , Maureen Duff  12 , Rongda Xu  12 , Jian Wang  12 , Shravani R Barkund  12 , Haiying Zhou  12 , Aleksandr Pankov  12 , Wayne Kong  12 , Nadine S Jahchan  12 , Erica L Jackson  12 , Jessica D Sun  12 , Melissa R Junttila  12 , Pratik S Multani  12 , Anneleen Daemen  12 , Edna Chow Maneval  12 , Pamela N Munster  13
Affiliations
Clinical Trial

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

Christopher T Chen et al. Cancer Res Commun. .

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.

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Conflict of interest statement

C.T. Chen reports grants from Oric Pharmaceuticals during the conduct of the study; personal fees from Boxer Capital and Guidepoint Global, grants from ADC Therapeutiucs, Gilead Sciences, Kinnate Biopharma, Mersana Therapeutics, Palleon Pharmaceuticals, Rain Oncology, Riboscience, D3 Bio, Takeda, Revolution Medicines, and Tango Therapeutics outside the submitted work. S. Kummar reports other from Bayer, Springworks Therapeutics, Mirati, Mundibiopharma, XYOne Therapeutics, GI Innovations, HarbourBiomed, BPGbio Therapeutics, Genome and Company, Oxford Biotherapeutics, Gilead, Genome Insight, and Fortress Biotech, Inc. outside the submitted work; and PathomIQ (co-founder), Arxeon (co-founder spouse). A.W. Tolcher reports personal fees and other from ABBVIE, Inc., Aclaris Therapeutics, Affinia Therapeutics, Inc., AGENUS, Inc., ASANA BIOSCIENCES, ASCENTAGE, Astex Pharmaceuticals, Axlmmune, Bayer, Blu Print Oncology, Coretag Therapeutics, Daiichi Sankyo, Inc., Exelixis, Inc., FibroGen, GILDE HEALTHCARE PARTNERS, HBM PARTNERS, IDEA Pharma, Ikena Oncology, Immuneering, Immunomet Therapeutics, Inc., Impact Therapeutics US, Inc., Karma Oncology B.V., Kirilys Therapeutics, Inc., Lengo Therapeutics, Inc., Link Immunotherapeutics, Medicxi, Merck KGA, Mekanistic Therapeutics, Menarini Ricerche, Mersana, NANOBIOTIX, Nerviano Medical Sciences S.r.I. (NMS), Novo Nordisk Inc., Novo Ventures, Nurix Therapeutics, Ocellaris Pharma, Inc. & Eli Lilly, Partner Therapeutics, Pfizer Inc., PIERRE FABRE, Praxia Precision Medicines, PYRAMID BIOSCIENCES, Qualigen Therapeutics, Roche, RYVU THERAPEUTICS, Seattle Genetics, Singzyme Pte Ltd., SK Life Science, SOTIO Biotechnology Co., Senti Biosciences, Sun Pharma Advanced Research Company (SPARC), TheraTechnologies, Transcenta Therapeutics Inc., Transgene, Trillium Therapeutics Inc., TUBULIS, Venus Oncology, Verastem Oncology, and VIDA VENTURES ADVISORS, LLC during the conduct of the study; ABBVIE, Inc., Aclaris Therapeutics, Affinia Therapeutics, Inc., AGENUS, Inc., ASANA BIOSCIENCES, ASCENTAGE, Astex Pharmaceuticals, Axlmmune, Bayer, Blu Print Oncology, Coretag Therapeutics, Daiichi Sankyo, Inc., Exelixis, Inc., FibroGen, GILDE HEALTHCARE PARTNERS, HBM PARTNERS, IDEA Pharma, Ikena Oncology, Immuneering, Immunomet Therapeutics, Inc., Impact Therapeutics US, Inc., Karma Oncology B.V., Kirilys Therapeutics, Inc., Lengo Therapeutics, Inc., Link Immunotherapeutics, Medicxi, Merck KGA, Mekanistic Therapeutics, Menarini Ricerche, Mersana, NANOBIOTIX, Nerviano Medical Sciences S.r.I. (NMS), Novo Nordisk Inc., Novo Ventures, Nurix Therapeutics, Ocellaris Pharma, Inc. & Eli Lilly, Partner Therapeutics, Pfizer Inc., PIERRE FABRE, Praxia Precision Medicines, PYRAMID BIOSCIENCES, Qualigen Therapeutics, Roche, RYVU THERAPEUTICS, Seattle Genetics, Singzyme Pte Ltd., SK Life Science, SOTIO Biotechnology Co., Senti Biosciences, Sun Pharma Advanced Research Company (SPARC), TheraTechnologies, Transcenta Therapeutics Inc., Transgene, Trillium Therapeutics Inc., TUBULIS, Venus Oncology, Verastem Oncology, VIDA VENTURES ADVISORS, LLC, ADAGENE, Inc., BIOINVENT, Boeringer Ingelheim International GmbH, Bright Peak Therapeutics, Cullinan Oncology, Elucida Oncology, EMD SERONO/MERCK KGaA, HEXAGON BIO, INC., IMMUNOME, JAZZ, Leerink, MIRATI, NBE THERAPEUTICS, Nested Therapeutics, Inc., Pheon Therapeutics, PYXIS Oncology, Roche, SPARC, Spirea Limited Inc., Tagworks Pharmaceuticals, Vincerx, VRISE Therapeutics, Inc., Zentalis Pharmaceuticals, and ZielBio, Inc. outside the submitted work; in addition, A.W. Tolcher has a patent to Ascentage issued and a patent to Zentalis issued. N.T. Ueno reports Consulting roles are held with the following companies: AstraZeneca plc ($13300), Bayer AG (Pfizer Inc., Gilead Sciences, Inc., Chugai Pharmaceutical Co., CytoDyn Inc., Daiichi Sankyo, Inc., DynaMed, LLC, Eisai Co., Ltd., KeChow Pharma, Inc., Lavender Health Ltd., OBI Pharma Inc., OncoCyte Co., Ourotech, Inc., DBA Pear Bio, Kirilys Therapeutics, Inc., Peptilogics, Inc., Phoenix Molecular Designs, Preferred Medicine, Inc., Puma Biotechnology, Inc., Sumitomo Dainippon Pharma, Inc., Sysmex Co. Ltd., Takeda Pharmaceuticals, Ltd., Unitech Medical, Inc., CARNA Biosciences, Inc., ChemDiv, Inc., DualityBio, LARVOL, Oncolys BioPharma Inc., Rakuten Medical, Inc., Merck Co., AnHeart Therapeutics Inc., Carisma Therapeutics, Inc., Lilly, Inc., and Therimunex. Speaker or preceptorship roles are held with the following companies: Bristol-Myers Squibb, CareNet Inc, Chugai Pharmaceutical Co., Genomic Health, Kyowa Hakko Kirin Co., Ltd., Sumitomo Dainippon Pharma, Inc., and Medscape. Research agreements are in place with the following companies: AnHeart Therapeutics Inc., Eisai Co., Ltd., Gilead Sciences, Inc., Phoenix Molecular Designs, Daiichi Sankyo, Inc., Puma Biotechnology, Inc., Merck Co., Oncolys BioPharma Inc., OBI Pharma Inc., ChemDiv, Inc., Tolero Pharmaceuticals, Inc., and VITRAC Therapeutics, LLC. S.L. Davis reports other from Oric during the conduct of the study; other from BMS, Symphogen, I-Mab, TriSalus Life Sciences, Tvardi Therapeutics, EMD Serono, and Merck outside the submitted work. E. Hamilton reports grants from ORIC Pharmaceuticals during the conduct of the study; grants from Abbvie and Acerta, grants and other from Accutar Biotechnology, Arvinas, and AstraZeneca, grants from ADC Therapeutics, AKESOBIO Australia, Amgen, Aravive, ArQule, Artios, AtlasMedx, BeiGene, Black Diamond, Bliss BioPharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, Cascadian Therapeutics, Clovis, Compugen, Context Therapeutics, Cullinan, Curis, and CytomX, grants and other from Daiichi Sankyo, grants from Dana Farber Cancer Inst, Dantari, Deciphera, Duality Biologics, eFFECTOR Therapeutics, and Eisai, grants and other from Ellipses Pharma, Elucida Oncology, EMD Serono, Fochon Pharmaceuticals, FujiFilm, and G1 Therapeutics, grants and other from Gilead Sciences, grants from H3 Biomedicine, Harpoon, Hutchinson MediPharma, Immunogen, Immunomedics, Incyte, Infinity Pharmaceuticals, Inspirna, Investis Bio, Jacobio, Karyopharm, K-Group Beta, Kind Pharmaceuticals, and Leap Therapeutics, grants and other from Lilly, grants from Loxo Oncology, Lycera, Mabspace Biosciences, Macrogenics, and MedImmune, grants and other from Mersana, Merus, Millennium, Molecular Templates, Myriad Genetic Laboratories, grants and other from Novartis, and Nucana, grants and other from Olema, grants from OncoMed, Oncothyreon, ORIC Pharmaceuticals, Orinove, and Orum Therapeutics, grants and other from Pfizer, grants from PharmaMar, grants from Pieris Pharmaceuticals, Pionyr Immunotherapeutics, Plexxikon, Prelude Therapeutics, Profound Bio, Radius Health, Regeneron, Relay Therapeutics, Repertoire Immune Medicine, and Rgenix, grants and other from Roche/Genentech, grants from SeaGen, Sermonix Pharmaceuticals, Shattuck Labs, Silverback Therapeutics, and StemCentRx, grants and other from Stemline Therapeutics, grants from Sutro, Syndax, Syros, Taiho, TapImmune, Tesaro, Tolmar, Torque Therapeutics, Treadwell Therapeutics, Verastem, Zenith Epigenetics, and Zymeworks, other from Circle Pharma, Entos, Fosun Pharma, Janssen, Jazz Pharmaceuticals, Jefferies, Johnson and Johnson, Medical Pharma Services, Tempus Labs, Theratechnologies, Tubulis, Verascity Science, and Zentalis Pharmaceuticals outside the submitted work. M.R. Patel reports other from ORIC during the conduct of the study; other from see https://coi.asco.org/share/BLY-NDGV/Manish%20Patel outside the submitted work; and see https://coi.asco.org/share/BLY-NDGV/Manish%20Patel, includes research funding to institution. A.I. Spira reports personal fees from CytomX Therapeutics, AstraZeneca/MedImmune, Merck, Takeda, Amgen, Janssen Oncology, Novartis, Bristol-Myers Squibb, Bayer, Prelude Therapeutics, Abbvie, Astellas Pharma, Incyte, Amgen, Novartis, Mirati Therapeutics, Gritstone Oncology, Jazz Pharmaceuticals, Takeda, Janssen Research & Development, Mersana, Gritstone Bio, Daiichi Sankyo/AstraZeneca, Regeneron, Lilly, Black Diamond Therapeutics, Sanofi, ArriVent Biopharma, AstraZeneca/MedImmune, Merck, Bristol-Myers Squibb, and Blueprint Medicines, grants from LAM Therapeutics, Roche, AstraZeneca, Boehringer Ingelheim, Astellas Pharma, MedImmune, Novartis, Incyte, Abbvie, Ignyta, Takeda, Macrogenics, CytomX Therapeutics, Astex Pharmaceuticals, Bristol-Myers Squibb, Loxo, Gritstone, Plexxikon, Amgen, Loxo, Daiichi Sankyo, ADCT, Janssen Oncology, Rubius, Synthekine, Mersana, Blueprint Medicines, Regeneron, Alkermes, Revolution Medicines, Medikine, Black Diamond Therapeutics, BluPrint Oncology, Nalo Therapeutics, Scorpion Therapeutics, ArriVent Biopharma, Revolution Medicines, and Prelude Therapeutics outside the submitted work. S. Jauhari reports Employement—Merus NV. V. Florou reports personal fees from Incyte, Deciphera, Springwork Therapeutics, and Aadi Bioscience outside the submitted work. M. Duff reports I am an employee of ORIC Pharmaceuticals, so was paid by ORIC for my work as an employee. R. Xu reports other from ORIC Pharmaceuticals, Inc. during the conduct of the study. S.R. Barkund reports other from ORIC Pharmaceuticals, Inc. during the conduct of the study; in addition, S.R. Barkund has a patent to ORIC-101 pending. A. Pankov reports other from ORIC Pharmaceuticals during the conduct of the study; in addition, A. Pankov has a patent to ORIC-101 Patents pending. E.L. Jackson reports personal fees from Scorpion Therapeutics outside the submitted work. M.R. Junttila reports personal fees from ORIC Pharmaceuticals. Inc. during the conduct of the study; personal fees from ORIC Pharmaceuticals. Inc. outside the submitted work. P.S. Multani reports other from ORIC Pharmaceuticals during the conduct of the study; other from ORIC Pharmaceuticals outside the submitted work. A. Daemen reports other from ORIC Pharmaceuticals, Inc. during the conduct of the study; in addition, A. Daemen has a patent to ORIC-101 pending. E. Chow Maneval reports other from ORIC Pharnaceuticals during the conduct of the study. P.N. Munster reports grants from UCSF during the conduct of the study; grants from InventisBIo, revolution medicine, BlissBio, Arvinias, seagen, Merck, AZ, GSK, AMG, Dragonfly, Blueprint, Nurix, Scorpion, and IGM outside the submitted work. No disclosures were reported by the other authors.

Figures

Figure 1
Figure 1
GR antagonism by ORIC-101 overcomes taxane resistance in preclinical models. A and B, Effect of ORIC-101 on dexamethasone-induced chemoprotection in vitro as measured by (A) caspase 3/7 apoptosis assays and (B) colony formation assays, in three TNBC lines (HCC1806, MDA-MB-231, Hs578T), three PDAC lines (BxPC3, SW1990, PSN1), and ovarian cancer line COV362. Veh: vehicle; Dex: 30 nmol/L dexamethasone; 101: 0.5 μmol/L ORIC-101; Chemo = 100 nmol/L paclitaxel + 100 nmol/L gemcitabine; PTX = 100 nmol/L paclitaxel; DTX = 100 nmol/L docetaxel; Gem = 100 nmol/L gemcitabine. A, The caspase activities of Veh were assigned as 1, and the values for other conditions were relative to Veh. One representative experiment with three biological repeats is shown (mean ± SEM). *, P < 0.05; **, P < 0.01; ***, P < 0.001 by one-way ANOVA using Tukey’s test to correct for multiple comparisons. B, One representative experiment with three biological repeats is shown. Numbers in white indicate the percentage of confluency quantitated by Celigo S. C, Effect of ORIC-101 on paclitaxel response in taxane-naïve HCC1806 TNBC xenografts in cortisol-treated mice. Mice were treated with paclitaxel 20 mg/kg by intraperitoneal injection every 3 days for a total of eight cycles (20 mg/kg, IP, Q3D × 8), cortisol (100 mg/L in drinking water, ad libitum) or ORIC-101 75 mg/kg by oral administration twice daily (75 mg/kg, PO, BID) starting on day 0 for the duration of the study. Arrowheads indicate PTX dosing days. Data are displayed as mean ± SEM. D and E, Effect of ORIC-101 in paclitaxel-relapsed HCC1806 TNBC xenografts in cortisol-treated mice. D, Animals were dosed with paclitaxel (15 mg/kg, IP, Q3Dx5) as indicated by the black arrowheads or ORIC-101 (150 mg/kg, PO, QD) as indicated by gray line. n = 15 in each group. Data is displayed as mean ± SEM. E, PFS, defined as the time elapsed between treatment initiation of the second cycle of paclitaxel and tumor progression or death from any cause, as a percentage of all animals in each cohort. A Kaplan–Meier plot was constructed to show the percentage of animals remaining in the study following treatment (P < 0.0001 by log-rank test). F, Overall survival, defined as the time elapsed between treatment initiation of the second cycle of paclitaxel and death from any cause as a percentage of all animals in each cohort, was not significantly different between the cohorts (by log-rank test).
Figure 2
Figure 2
Study disposition flow diagram of patient disposition. Note: int, intermittent regimen of ORIC-101 administered 5 days on, 2 days off for 21 days out of 28-day cycles; cont, continuous regimen of ORIC-101 administered for 21 days out of 28-day cycles; AE, adverse event; clin, clinical; OST, other solid tumors; PD, progressive disease; radiog, radiographic.
Figure 3
Figure 3
ORIC-101 pharmacodynamics in PBMCs and tumor specimens. A, Pharmacodynamic (PD) modulation (average expression of GR target genes FKBP5, GILZ, and PER1) on day 1 of cycle 1 as observed in 40 dose expansion patients with PBMC sample collection and cortisol assessment at C1D1 (pre-dose and 6 hours post-dose), and with pre-dose cortisol levels >200 nmol/L. Samples are colored by cohort. B, PD suppression from cycle 1 day 1 (pre-dose) to day 15 (pre-dose) as observed in 26 patients with PBMC sample collection and cortisol assessment at C1D1 pre-dose and C1D15 pre-dose, and with C1D1 pre-dose cortisol levels >200 nmol/L. C, PD suppression from cycle 1 day 1 (pre-dose) to cycle 2 day 1 (pre-dose) as observed in 28 patients with PBMC sample collection and cortisol assessment at C1D1 pre-dose and C2D1 pre-dose, and with C1D1 pre-dose cortisol levels >200 nmol/L. D, PD modulation on day 1 of cycle 2 as observed in 30 dose expansion patients with PBMC sample collection and cortisol assessment at C2D1 (pre-dose and 6 hours post-dose) and with pre-dose cortisol levels >200 nmol/L. E, On-treatment change in GR activation signaling in 10 patients (four dose escalation, six dose expansion) with paired tumor biopsies. The horizontal arrows indicate directionality of observed changes in GR activation as indicated by GR Signature Score (average expression of FKBP5, GILZ, PER1, and KLF9) from screening to end of cycle 2 or end of treatment, in the 10 patients. The solid line shows the expected distribution of GR activation from a reference cohort of archival and fresh tumor biopsies collected during this ORIC-101 trial. Patients with decreased GR signaling are highlighted in the boxed area. F, Association of on-treatment decrease in GR activation signaling with longer time on treatment.
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References

    1. Azher S, Azami O, Amato C, McCullough M, Celentano A, Cirillo N. The non-conventional effects of glucocorticoids in cancer. J Cell Physiol 2016;231:2368–73. - PubMed
    1. Block TS, Murphy TI, Munster PN, Nguyen DP, Lynch FJ. Glucocorticoid receptor expression in 20 solid tumor types using immunohistochemistry assay. Cancer Manag Res 2017;9:65–72. - PMC - PubMed
    1. Volden PA, Conzen SD. The influence of glucocorticoid signaling on tumor progression. Brain Behav Immun 2013;30:S26–31. - PMC - PubMed
    1. Hou WJ, Guan JH, Dong Q, Han YH, Zhang R. Dexamethasone inhibits the effect of paclitaxel on human ovarian carcinoma xenografts in nude mice. Eur Rev Med Pharmacol Sci 2013;17:2902–8. - PubMed
    1. Kroon J, Puhr M, Buijs JT, van der Horst G, Hemmer DM, Marijt KA, et al. . Glucocorticoid receptor antagonism reverts docetaxel resistance in human prostate cancer. Endocr Relat Cancer 2016;23:35–45. - PMC - PubMed

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