ER Antagonist OP-1250 Demonstrates Continued Anti-Tumor Activity in Advanced ER+ HER2– Breast Cancer

Among patients with advanced and/or metastatic hormone receptor–positive HER-2 negative breast cancer, complete estrogen receptor antagonist OP-1250 continued to yield clinical benefits such as reductions in target tumor lesions.

OP-1250, an estrogen receptor antagonist (CERAN) and selective estrogen receptor degrader (SERD), has continued to produce strong anti-tumor activity among patients with advanced and/or metastatic ER-positive, HER2-negative breast cancer, according to a press release from Olema Oncology on preliminary results from a dose-escalation and expansion study (NCT04505826).

Data from the study were presented during the 34th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics in Barcelona, Spain. Across 2 dose cohorts, the study reported 6 partial responses (PRs) per RECIST criteria among 57 evaluable patients with measurable lesions and at least 1 on-treatment tumor assessment. Of these responses, 4 have been confirmed and 2 require confirmation with a follow-up scan. A total of 41% of patients experienced reductions in target lesions, and demonstrated evidence of anti-tumor activity in both wild-type and mutant ERs across both doses.

“The results we presented today from our monotherapy dose expansion study provide further validation of our belief in OP-1250’s potential to become the endocrine therapy of choice for [ER-positive] breast cancer. OP-1250 has a compelling profile for a CERAN/SERD as it is well-tolerated, achieves high drug exposure, and has demonstrated encouraging efficacy across both wild-type and ESR1 mutant tumors,” Sean P. Bohen, MD, PhD, president and chief executive officer at Olema Oncology, said in the press release. “Our mission is to transform the breast cancer treatment landscape and to develop therapies that offer the potential to improve outcomes for women living with cancer. We believe in the potential of OP-1250, and we look forward to initiating our first pivotal Phase 3 trial mid-next year.”

The open-label, multi-center phase 1/2 study enrolled a total of 68 patients who had been diagnosed with recurrent, locally advanced or metastatic ER-positive HER2-negative breast cancer. Investigators assigned patients to receive either 60 mg or 120 mg of oral OP-1250 once per day.

A total of 69% of patients received 2 or more previous lines of therapy, 32% received prior chemotherapy, 96% were previously treated with CDK4/6 inhibitors, and 65% had received previous treatment with fulvestrant (Faslodex). Circulating tumor DNA was assessed among 46 patients, 59% of whom had activating ESR1 mutations at baseline.

The primary end point of the study was determining the maximum tolerated dose and recommend phase 2 dose (RP2D) of OP-1250 monotherapy.

Patients were eligible to enroll on the study if they had an ECOG performance status of 0 or 1. Additional inclusion criteria included not receiving prior endocrine therapy more than 2 weeks prior to the first dose, as well as prior fulvestrant, chemotherapy, antibody therapy, or investigational therapy in 4 or less weeks prior to the first dose of OP-1250 as well as adequate hepatic and renal function.

Based on high oral bioavailability and dose proportional exposure, OP-1250 demonstrated favorable pharmacokinetics in the study. Additionally, the overall pharmacokinetics, tolerability, and efficacy of OP-1250 supported the selection of a RP2D of 120 mg daily, which surpassed the targeted efficacy thresholds of pre-clinical models.

No dose-limiting toxicities were observed in patient treatment with OP-1250 regardless of dose level. The most frequent treatment-related adverse effects (TRAEs) that occurred in 15% or more of patients included nausea (42%), fatigue (25%), and vomiting (15%). One patient experienced grade 3 neutropenia concurrent with progressive disease. Additionally, 3 patients experienced grade 4 neutropenia in the 120 mg cohort, although these events were infrequent in addition to being manageable and reversible. Of these patients, 1 had a confirmed response with no further incidence of neutropenia after a 1-week dose interruption before restating therapy at 60 mg. Moreover, 2 other patients discontinued treatment with recovery of their neutrophil accounts.


Olema Oncology announces complete ER antagonist OP-1250 continues to demonstrate robust activity in phase 1/2 clinical trial. News release. Olema Oncology. October 26, 2022. Accessed October 28, 2022.