Context Therapeutics (NASDAQ:CNTX) has announced that its clinical trial collaborator, Stemline Therapeutics Inc, a wholly-owned subsidiary of The Menarini Group, has received approval from the US Food and Drug Administration (FDA) for ORSERDU (elacestrant) for the treatment of postmenopausal women or adult men with estrogen receptor–positive (ER+), HER2-negative (HER2-), Estrogen Receptor 1 gene (ESR1)-mutated advanced or metastatic breast cancer with disease progression following at least one line of endocrine therapy.
The Philadelphia-based women’s oncology company noted that ORSERDU has shown improved efficacy over the current standard-of-care (SOC) treatment, fulvestrant, in patients with ER+, HER2-, ESR1-mutated advanced or metastatic breast cancer.
"This is a watershed moment for the industry, which has spent the last 20 years trying to develop a next-generation endocrine therapy that is pharmacologically superior to endocrine monotherapies, including fulvestrant,” Context CEO Martin Lehr said in a statement.
“ORSERDU has the potential to fundamentally change the treatment paradigm for patients with ESR1-mutated breast cancer, which is found in approximately 40% of the estimated 43,500 patients with metastatic hormone-driven breast cancer in the United States.”
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Citing the American Cancer Society, Context said breast cancer is the second most common cancer among women, occurring in one in eight women (13%) over the course of a woman’s lifetime, with around 280,000 new cases of invasive breast cancer and 51,400 cases of non-invasive breast cancer expected in 2023. It said approximately 40% of patients with ER+, HER2- breast cancer will have ESR1 mutations, which is associated with poor prognosis. Endocrine monotherapy has displayed limited efficacy in ESR1 mutations.
Context noted that ORSERDU is approved under the FDA’s Priority Review and Fast Track designation based on the results of the registrational Phase III trial EMERALD, which demonstrated statistically significant progression-free survival (PFS) with elacestrant vs SOC endocrine monotherapy (fulvestrant, letrozole, anastrozole, exemestane), meeting both primary endpoints in all patients and in those patients whose tumors harbor ESR1 mutations.
In a group of patients whose tumors had ESR1 mutations, elacestrant reduced the risk of progression or death by 45% (PFS HR=0.55, 95% CI: 0.39, 0.77) vs SOC. A post-hoc analysis of the PFS results based on the duration of prior CDK4/6i inhibitors (CDK4/6i) usage was presented at San Antonio Breast Cancer Symposium in December 2022. The median PFS was 8.6 months on elacestrant vs 1.9 months for SOC, in those patients whose tumors harbored ESR1 mutations and had been treated with a CDK4/6i for at least 12 months.
ONA-XR
The company noted that ONA-XR (onapristone extended-release) is an oral, twice-a-day, selective progesterone receptor (PR) antagonist designed to block both ligand-dependent and ligand-independent activity of PR. Currently, there are no approved therapies that selectively target PR+ cancers.
Preliminary preclinical and clinical data suggest that ONA-XR has anticancer activity by inhibiting progesterone receptor binding to chromatin, downregulating cancer stem cell mobilization, and blocking immune evasion. In addition to the Phase 1b/2 ELONA clinical trial evaluating the combination of ONA-XR and ORSERDU to treat ESR1-mutated metastatic breast cancer, ONA-XR is being studied in Phase 2 clinical trials, including in endometrial cancer (OATH) and breast cancer (SMILE). ONA-XR is an investigational drug that has not been approved for marketing by any regulatory authority.
In January 2023, Context enrolled the first patient in the ELONA trial, an open-label, Phase 1b/2 breast cancer clinical trial being conducted in partnership with Menarini. It said the ELONA study is designed to explore the efficacy of ONA-XR in combination with ORSERDU, Menarini’s oral selective estrogen receptor degrader approved by the FDA, in patients with locally advanced or metastatic ER+, HER2-, ESR1-mutated breast cancer who have received prior treatment with a CDK4/6 inhibitor. Data from the Phase 1b portion of the trial is expected in the fourth quarter of 2023.
"Our collaboration with Menarini in the ongoing Phase 1b/2 ELONA trial is evaluating the potential of Context’s oral progesterone receptor antagonist onapristone extended-release (ONA-XR), to enhance ORSERDU’s activity in both ESR1-mutated and wild type metastatic breast cancer,” Lehr said. “Such a combination could potentially improve outcomes in patients without adding significant toxicity.”
Context Therapeutics is a clinical-stage biopharmaceutical company committed to advancing medicines for female cancers. The company’s pipeline includes small molecule and bispecific antibody drug candidates that target cancer signaling pathways.
Onapristone extended-release (ONA-XR), a novel, first-in-class potent and selective progesterone receptor antagonist, is currently in three Phase 2 clinical trials and one Phase 1b/2 clinical trial in hormone-driven breast, ovarian, and endometrial cancers.
Context is also developing CTIM-76, a selective Claudin 6 (CLDN6) x CD3 bispecific antibody for CLDN6 positive tumors, currently in preclinical development.
Contact the author at stephen.gunnion@proactiveinvestors.com