ORIC-101 / ORIC Pharma - LARVOL DELTA

Role of structure-based drug design in the discovery of ORIC-101, a potent and selective steroidal glucocorticoid receptor antagonist advanced into clinical development (ACS-Fall 2025) - "Unlike mifepristone, ORIC-101 could be co-dosed with chemotherapeutic agents readily metabolized by CYP2C8 such as paclitaxel. Furthermore, ORIC-101 demonstrated in vivo antitumor activity by enhancing response to chemotherapy in the GR+ OVCAR5 ovarian cancer xenograft model. ORIC-101 advanced into clinical development (phase 1b)."

Clinical • Metastases • Ovarian Cancer • Solid Tumor • AR • CYP2C9

ORIC-101, a Glucocorticoid Receptor Antagonist, in Combination with Nab-Paclitaxel in Patients with Advanced Solid Tumors. (PubMed, Cancer Res Commun) - P1 | "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."

Combination therapy • Journal • Metastases • Oncology • Solid Tumor

Phase 1 Study of ORIC-101, a Glucocorticoid Receptor Antagonist, in Combination with Enzalutamide in Patients with Metastatic Castration-Resistant Prostate Cancer Progressing on Enzalutamide. (PubMed, Clin Cancer Res) - "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."

Combination therapy • Journal • Metastases • P1 data • Constipation • Fatigue • Gastroenterology • Gastrointestinal Disorder • Genito-urinary Cancer • Metastatic Castration-Resistant Prostate Cancer • Oncology • Prostate Cancer • Solid Tumor • NR3C1

Study of ORIC-101 in Combination With Enzalutamide (clinicaltrials.gov) - P1 | N=41 | Terminated | Sponsor: ORIC Pharmaceuticals | Phase classification: P1b ➔ P1 | N=90 ➔ 41 | Trial completion date: Jun 2023 ➔ Dec 2023 | Active, not recruiting ➔ Terminated; IND Withdrawn

Combination therapy • Enrollment change • Metastases • Phase classification • Trial completion date • Trial termination • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

Study of ORIC-101 in Combination With Anticancer Therapy (clinicaltrials.gov) - P1 | N=83 | Terminated | Sponsor: ORIC Pharmaceuticals | Phase classification: P1b ➔ P1 | N=174 ➔ 83 | Trial completion date: Jun 2023 ➔ Dec 2023 | Active, not recruiting ➔ Terminated; IND Withdrawn

Combination therapy • Enrollment change • Metastases • Phase classification • Trial completion date • Trial termination • Breast Cancer • Colorectal Cancer • Gastrointestinal Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Ovarian Cancer • Solid Tumor • Triple Negative Breast Cancer • ER • HER-2 • NR3C1 • PGR

Dual targeting liver cancer by GPC3 CAR-T cells secreting a bispecific T cell engager antibody for an intracellular tumor antigen AFP (SITC 2023) - "Methods In this study, we engineered GPC3 CAR-T cells (OriC101) to secrete a bispecific T cell engager (BiTE) composed of a TCR mimic antibody targeting AFP-MHC complex (OriA373). Conclusions Hence, by leveraging dual orthogonal cytotoxic modalities with distinct specificities targeting surface and intracellular tumor-associated antigens, we have developed a promising strategy to overcome resistance to CAR-T cell therapy not only in liver cancer but also in other cancer types. Our results, demonstrating the superior activation and memory phenotype of GPC3 CAR-T cells secreting AFP-BiTE (OriC633–05), as well as its significantly enhanced anti-tumor activity against liver cancer cells with low GPC3 expression, and the potential for improved efficacy against liver cancer with high GPC3 expression, highlight the promising potential of this approach (figure 5)."

CAR T-Cell Therapy • IO biomarker • Gastrointestinal Cancer • Liver Cancer • Oncology • Solid Tumor • HLA-A

A Druggable FOXA1-Glucocorticoid Receptor Transcriptional Axis Drives Tumor Growth in a Subset of Non-Small Cell Lung Cancer. (PubMed, Cancer Res Commun) - "To investigate the therapeutic potential for targeting this complex, we examined the effects of highly selective inhibitors of the GR ligand-binding pocket and found that GR antagonism with ORIC-101 suppressed FOXA1/GR target expression, activation of EGF signaling, entry into the S-phase, and attendant proliferation in vitro and in vivo...There is a need to identify novel druggable dependencies. We identify a subset of NSCLCs dependent on FOXA1-GR and sensitive to GR antagonism."

Journal • Genito-urinary Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Prostate Cancer • Solid Tumor • AR • EGF • ER • FOXA1 • NR3C1

An open-label phase Ib study of ORIC-101 in combination with enzalutamide in patients with metastatic prostate cancer progressing on enzalutamide. (ASCO-GU 2020) - P1b; "These findings suggest that combined inhibition of both GR and AR may prolong the duration of response or restore sensitivity to AR antagonists such as enzalutamide or apalutamide. Clinical trial information: NCT04033328. Research Funding: ORIC Pharmaceuticals."

Clinical • Combination therapy • P1 data • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

[VIRTUAL] Biomarker results supporting selection of RP2D from a phase 1b study of ORIC-101, a glucocorticoid receptor antagonist, in combination with nab-paclitaxel in patients with advanced solid tumors. (ASCO 2021) - P1b | "ORIC-101 is a potent, selective, and orally bioavailable small molecule GR antagonist undergoing clinical development in combination with nab-paclitaxel in patients with advanced solid tumors and in combination with enzalutamide in patients with metastatic prostate cancer . Biomarker data from patients enrolled in the phase 1b study provide evidence of on-target tumor cell eradication and PD modulation and support the RP2D and the tumor types selected for the ongoing dose expansion portion of the study."

Biomarker • Clinical • Combination therapy • P1 data • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • FKBP5 • PER1

[VIRTUAL] Biomarker results supporting selection of RP2D from a Phase 1b study of ORIC-101, a glucocorticoid receptor antagonist, in combination with enzalutamide in patients with metastatic prostate cancer progressing on enzalutamide (AACR-NCI-EORTC 2021) - No abstract available

Biomarker • Clinical • Combination therapy • P1 data • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

[VIRTUAL] Initial results from a phase 1b study of ORIC-101, a glucocorticoid receptor antagonist, in combination with enzalutamide in patients with metastatic prostate cancer (AACR-NCI-EORTC 2021) - No abstract available

Clinical • Combination therapy • P1 data • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

[VIRTUAL] ORIC-101 overcomes GR-driven resistance to AR degradation in castration-resistant prostate cancer models (AACR-NCI-EORTC 2020) - P1b | "Currently, a phase 1b study of ORIC-101 in combination with enzalutamide in patients with metastatic prostate cancer is ongoing (NCT04033328). Our data indicate that targeting GR may help overcome resistance to many methods of antiandrogen therapy."

Preclinical • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

[VIRTUAL] ORIC-101 overcomes glucocorticoid receptor-mediated chemoresistance in pancreatic cancer models (AACR-II 2020) - P1b | "These results in PDAC preclinical models support the clinical development of ORIC-101 in overcoming GR-driven chemoresistance. A phase 1b study of ORIC-101 in combination with nab-paclitaxel in patients with advanced or metastatic solid tumors is ongoing (NCT03928314)."

Preclinical • Breast Cancer • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • Triple Negative Breast Cancer

[VIRTUAL] GR antagonist ORIC-101 overcomes GR-mediated resistance to the combination of AR and AKT inhibition in preclinical prostate cancer cell lines (AACR 2021) - P1, P1b, P3 | "We tested three AKT inhibitors: the ATP-competitive inhibitors ipatasertib (GDC-0068) and capivasertib (AZD5363), in addition to the allosteric inhibitor MK2206, in CSS media and 10% FBS, with or without supplementation of the synthetic glucocorticoid, dexamethasone...In the AKTi plus enzalutamide setting, AKT inhibition did not block the enzalutamide-mediated GR upregulation in either PTEN-null or PTEN-wildtype cells.We next evaluated whether increased GR activity mediates resistance to the enzalutamide/AKTi doublet with ipatasertib or capivasertib, and whether this resistance can be reversed with ORIC-101...ORIC-101 was able to reverse these dexamethasone-induced effects, confirmed by reduced secreted PSA levels and cell number measured at end of study. These findings indicate that GR upregulation and activation, an established resistance mechanism for antiandrogens, may drive resistance when combined with an AKT inhibitor, and the GR antagonist ORIC-101..."

Preclinical • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • PTEN

Study of ORIC-101 in Combination With Anticancer Therapy (clinicaltrials.gov) - P1b | N=174 | Active, not recruiting | Sponsor: ORIC Pharmaceuticals | Trial completion date: May 2022 ➔ Jun 2023 | Trial primary completion date: May 2022 ➔ Dec 2022

Combination therapy • Trial completion date • Trial primary completion date • Breast Cancer • Colorectal Cancer • Gastrointestinal Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Ovarian Cancer • Solid Tumor • Triple Negative Breast Cancer • ER • HER-2 • PGR

Study of ORIC-101 in Combination With Enzalutamide (clinicaltrials.gov) - P1b | N=90 | Active, not recruiting | Sponsor: ORIC Pharmaceuticals | Trial completion date: Dec 2022 ➔ Jun 2023

Combination therapy • Trial completion date • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • CTCs • NR3C1

A druggable FOXA1-glucocorticoid receptor transcriptional axis drives tumor growth in NSCLC (AACR 2022) - "Finally, we evaluated the in vivo therapeutic potential of ORIC-101 using NSCLC xenografts and found that single-agent ORIC-101 exhibited potent antitumor effects in these models. Taken together, these data establish a model of FOXA1-GR-dependent tumor growth amongst a subset of NSCLCs and demonstrate that effective blockade of this complex is a rational therapeutic avenue to be explored in the clinic."

Genito-urinary Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Prostate Cancer • Solid Tumor • FOXA1 • TRAF4

Study of ORIC-101 in Combination With Anticancer Therapy (clinicaltrials.gov) - P1b | N=174 | Active, not recruiting | Sponsor: Oric Pharmaceuticals | Recruiting ➔ Active, not recruiting

Combination therapy • Enrollment closed • Breast Cancer • Colorectal Cancer • Gastrointestinal Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Ovarian Cancer • Solid Tumor • Triple Negative Breast Cancer • ER • HER-2 • PGR

Study of ORIC-101 in Combination With Enzalutamide (clinicaltrials.gov) - P1b | N=90 | Active, not recruiting | Sponsor: Oric Pharmaceuticals | Recruiting ➔ Active, not recruiting

Combination therapy • Enrollment closed • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • CTCs

In Vivo Profiling with F-YJH08 Reveals Diverse Tissue Patterns of Antagonist/Glucocorticoid Receptor Interactions. (PubMed, Mol Pharm) - "Profiling target engagement in vivo showed that the GR antagonists RU486 (mifepristone) and CORT125281 engaged GR in fewer normal tissues compared to ORIC-101 or the agonist dexamethasone. Furthermore, F-YJH08 detected GR in human prostate cancer tumor models and measured receptor binding by RU486. In summary, these data show for the first time that antagonist/GR interactions can be measured in vivo with F-YJH08, a finding with clinical relevance as GR antagonists and C-YJH08 are currently in clinical trials."

Journal • Preclinical • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

ORIC Pharmaceuticals Provides Corporate Update and Highlights Key Upcoming Milestones (GlobeNewswire) - "ORIC anticipates the following upcoming milestones:...ORIC-101: Updates from two Phase 1b combination trials in 1H 2022; ORIC-533: Initial Phase 1b data in 1H 2023; ORIC-114: Initial Phase 1b data in 1H 2023; ORIC-944: Initial Phase 1b data in 1H 2023; New program and/or indication to be announced in 2022"

Clinical • New indication • P1 data • Genito-urinary Cancer • Gynecologic Cancers • Hematological Malignancies • Lung Cancer • Multiple Myeloma • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Prostate Cancer • Solid Tumor

ORIC Pharmaceuticals Presents Initial Clinical Data from Phase 1b Trial of ORIC-101 in Combination with Enzalutamide and Preclinical Data on ORIC-114 at AACR-NCI-EORTC (GlobeNewswire) - P1b, N=90; NCT04033328; Sponsor: Oric Pharmaceuticals; "25 patients were enrolled across Parts I/II of the study, which included 7 patients treated at non-RP2D doses and 18 patients treated at the RP2D of 240 mg of ORIC-101 and 160 mg of enzalutamide once daily; treatment-related adverse events were primarily Grade 1 or 2, with only four Grade 3 events, which all resolved with dose interruption....ORIC-101 is also being evaluated in a Phase 1b trial in combination with nab-paclitaxel in up to 132 patients across four cohorts, including pancreatic ductal adenocarcinoma, ovarian cancer, triple negative breast cancer, and other advanced solid tumors. Enrollment continues in this study at 12 clinical sites across the United States and an additional update is expected in 2022."

Enrollment status • P1 data • Breast Cancer • Gastrointestinal Cancer • Gynecologic Cancers • Oncology • Ovarian Cancer • Pancreatic Cancer • Solid Tumor • Triple Negative Breast Cancer

ORIC Pharmaceuticals Announces Multiple Data Presentations at AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics (GlobeNewswire) - "ORIC Pharmaceuticals...announced three poster presentations at the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics to be held October 7-10, 2021....Full abstracts and poster presentations will be available for on-demand viewing via the online platform for AACR-NCI-EORTC on October 7, 2021, at 9 a.m. ET."

P1 data • Preclinical • Breast Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer

[VIRTUAL] ORIC-101 comprehensively inhibits glucocorticoid pathways to overcome therapeutic resistance in pan-cancer models (AACR-II 2020) - P1b | "A novel GR antagonist, ORIC-101, is in early clinical development in combination with nab-paclitaxel in advanced solid tumors (NCT03928314).We set out to understand the transcriptional consequences of activating GR in a panel of 9 triple negative breast cancer (TNBC), 12 non-small cell lung cancer (NSCLC) and 12 pancreatic ductal adenocarcinoma (PDAC) cell lines, covering three indications likely to be encountered in clinical trials. Importantly, ORIC-101 completely reversed these Dex-induced changes at both the gene and the pathway level. Our results not only elucidate the direct mechanism of GR-mediated chemotherapy resistance but also showcase the ability of ORIC-101 to revert all transcriptional changes caused by GR activation."

Pan Tumor • Preclinical • Breast Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • Thoracic Cancer • Triple Negative Breast Cancer

[VIRTUAL] Initial results from a phase 1b study of ORIC-101, a glucocorticoid receptor antagonist, in combination with nab-paclitaxel in patients with advanced solid tumors. (ASCO 2021) - P1b | "The combination of ORIC-101 and nab-paclitaxel demonstrated an acceptable tolerability profile and does not require prophylactic G-CSF . PK and PD showed no evidence of drug-drug-interaction and demonstrated GR target inhibition . Preliminary antitumor activity was observed in patients with solid tumors that previously progressed on a taxane-containing regimen ."

Clinical • Combination therapy • P1 data • Alopecia • Anemia • Breast Cancer • Fatigue • Gastrointestinal Cancer • Hematological Disorders • Hepatology • Hormone Receptor Breast Cancer • Leukopenia • Neutropenia • Oncology • Pancreatic Cancer • Solid Tumor • Thrombocytopenia • Triple Negative Breast Cancer