Abstract OT2-01-04: ELONA: An open-label, phase 1b-2 study of elacestrant, in combination with onapristone in patients with estrogen receptor-positive, progesterone receptor-positive, HER2-negative advanced or metastatic breast cancer

Abstract Objectives: The addition of a CDK 4/6 inhibitors to endocrine therapy, in the first or second line setting, provides a significant improvement in progression free survival (PFS), and in some cases in overall survival (OS), with a tolerable toxicity profile. Regardless, most patients experience disease progression on these agents and ultimately develop endocrine resistance, thus, emphasizing the critical need for novel treatments. Elacestrant showed a statistically significant improvement in PFS when compared to standard of care endocrine therapy after progression on CDK4/6 inhibitors in combination with endocrine therapy (Bidard et al, 2022). Onapristone is a type I antiprogestin which prevents the progesterone receptor (PgR) from dimerizing and blocks ligand-induced protein kinase-mediated phosphorylation of the PgR. The clinical anticancer activity of onapristone, in immediate release formulation, has been previously documented in patients with hormone therapy-naïve (Robertson et al, 1999) or tamoxifen-resistant (Jonat et al, 2002) breast cancer (BC). More recently, onapristone, in extended release formulation, was evaluated in doses up to 50 mg BID in a phase 1 trial that enrolled 52 heavily pretreated patients with metastatic solid tumors, with no dose limiting toxicity observed. Among the 20 breast cancer patients enrolled, 7 (35%) had stable disease (Cottou et al, 2018). Methods: ELONA is a phase 1b/2, open-label, multicenter study. The phase 1b portion of the study will assess the safety, pharmacokinetics (PK), pharmacodynamics, and preliminary efficacy of elacestrant plus onapristone to determine the combinations’ recommended phase 2 dose. The primary endpoint of the phase 2 part of the trial is objective response rate and secondary endpoints will include safety, duration of response, clinical benefit rate, PFS, and OS, in addition to pharmacodynamics markers using ctDNA. Eligible patients are pre-, peri- and post-menopausal women and men aged ≥18 years with ER+/PgR+,HER2- tumors and an Eastern Cooperative Oncology Group performance status ≤2 with at least one measurable lesion at baseline, as per RECIST version 1.1. Prior therapy in the metastatic setting includes at least one anti-hormonal therapy in combination with a CDK4/6i. No prior chemotherapy regimen in the metastatic setting is allowed. The phase 1b dose-escalation portion of the study will evaluate dose-limiting toxicities (DLTs) of the combination in up to 4 cohorts of 6 patients each. Citation Format: Erika Hamilton, Lajos Pusztai, Hatem H. Soliman, Sara Hurvitz, Krzysztof Grzegorzewski, Nassir Habboubi, Priya Marreddy, Tarek Sahmoud, Nuhad Ibrahim. ELONA: An open-label, phase 1b-2 study of elacestrant, in combination with onapristone in patients with estrogen receptor-positive, progesterone receptor-positive, HER2-negative advanced or metastatic breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT2-01-04.