Benzinga | Oct 7, 2021 08:56AM EDT

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

ORIC Pharmaceuticals, Inc. (NASDAQ:ORIC), a clinical stage oncology company focused on developing treatments that address mechanisms of therapeutic resistance, today announced multiple presentations, including initial clinical data from an ongoing Phase 1b study evaluating ORIC-101, a glucocorticoid receptor antagonist, in combination with enzalutamide, in patients with metastatic prostate cancer progressing on enzalutamide. The abstracts and presentations are available for on-demand viewing via the online platform for AACR-NCI-EORTC as of October 7, 2021, at 9 a.m. ET.

Presentations:

* Initial results from a Phase 1b study of ORIC-101, a glucocorticoid receptor antagonist, in combination with enzalutamide in patients with metastatic prostate cancer

* 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

* ORIC-114, an orally bioavailable, irreversible kinase inhibitor, has superior brain penetrant properties and enhanced potency in preclinical studies of HER2-positive breast cancer

"We are pleased to share initial data from our ORIC-101 clinical program in patients with metastatic prostate cancer. The combination was well tolerated without evidence of drug-drug interaction affecting enzalutamide dosing and has demonstrated preliminary evidence of antitumor activity in the relevant patient population," said Pratik S. Multani, MD, chief medical officer. "Given the tumor heterogeneity in metastatic prostate cancer, we've made significant progress in identifying a key patient population that may benefit from ORIC-101 and, within these patients, seen preliminary evidence of more pronounced clinical benefit in patients whose tumors express higher GR levels. Patients are continuing to enroll in the expansion cohort and we look forward to reporting an update from the Phase 1b trial in 2022."

ORIC-101: Glucocorticoid Receptor (GR) Antagonist

The Phase 1b clinical trial of ORIC-101 in combination with enzalutamide is a single arm, multicenter, open-label study conducted in two parts, intended to establish the recommendedPhase 2 dose (RP2D), safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity when administered in patients with metastatic prostate cancer progressing on enzalutamide.

In the Part I dose escalation portion of the trial, three cohorts of patients were enrolled to evaluate daily dosing of ORIC-101 with doses ranging from 80 to 240 mg, in combination with 160 mg of enzalutamide once daily dosing. Following the completion of the dose escalation portion of the study, the RP2D was determined to be 240 mg of ORIC-101 and 160 mg of enzalutamide once daily.

In the Part II dose expansion portion of the trial, up to 48 patients with metastatic prostate cancer progressing on enzalutamide are expected to be enrolled and treated with the combination at the RP2D. Patients are enrolled independent of GR status, with retrospective analysis of GR expression and other potentially predictive biomarkers. Enrollment continues in the Part II dose expansion cohorts at nine clinical sites across the United States.

As of the August 20, 2021, data cut-off date:

Preliminary Safety Analyses:

* 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.

* RP2D was well tolerated; treatment-related adverse events were primarily Grade 1 or 2, with only four Grade 3 events, which all resolved with dose interruption.

* Tolerability profile for the combination was generally consistent with that of single agent enzalutamide.

Preliminary PK Analysis:

* Plasma concentrations exceeded the threshold for GR inhibition at all dose levels.

* ORIC-101 exposure increased with dose.

* No evidence observed of drug-drug interaction impacting enzalutamide levels.

Preliminary Biomarker Analyses:

* GR pathway suppression, evaluated using GR target gene expression, was observed after one dose of ORIC-101 in peripheral blood mononuclear cells from 22 of 23 patients.

* Moderate to high GR expression (IHC H-score ? 100) in prostate tumor cells was observed in 76% of pretreatment biopsies.

* Translational efforts identified a key patient population, in line with published literature, consisting of the ~60% of patients with tumors lacking biomarkers of AR resistance (e.g., ARv7 splice variant, AR L702H point mutation) and AR independence (e.g., lineage switching).

Preliminary Antitumor Activity:

* Within the key patient population (n=8), 75% (6 of 8) of patients' tumors expressed moderate to high GR and 25% (2 of 8) of patients' tumors expressed low GR.

* The two patients with low GR came off treatment at less than two months. In contrast, the six patients with moderate to high GR demonstrated prolonged time on treatment (with two patients on treatment for over seven months, and another four patients still ongoing at varying durations at the time of the data cut).

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.

ORIC-114: EGFR/HER2 Inhibitor

ORIC-114 is a brain penetrant, orally bioavailable, irreversible inhibitor designed to selectively target EGFR and HER2 with high potency against exon 20 insertion mutations. These are the first publicly disclosed preclinical data with ORIC-114 demonstrating compelling activity in HER2-positive breast cancer models.

Key Findings of the Presentation:

* ORIC-114 demonstrated greater cell potency on HER2-positive breast cancer cell lines relative to non-amplified cell lines and was more potent than lapatinib and tucatinib, two approved tyrosine kinase inhibitors for the treatment of HER2-positive breast cancer.

* ORIC-114 demonstrated robust tumor regressions in a HER2-positive breast cancer in vivo model without significant body weight loss.

* ORIC-114 demonstrated superior brain exposure compared to other EGFR exon 20 and HER2 targeted agents.

Separately, today the company disclosed head to head in vivo preclinical data in an EGFR exon 20 NSCLC xenograft model demonstrating good tolerability and improved efficacy, including a 90% complete response rate, versus multiple clinical stage exon 20 inhibitors.