Journal Article

Palazestrant, a novel oral Complete Estrogen Receptor Antagonist (CERAN) and Selective Estrogen Receptor Degrader (SERD), in patients with ER+/HER2− advanced or metastatic breast cancer: phase 1/2 study results

Hamilton, Erika P., Shilkrut, Mark, Lin, Nancy U., Patel, Manish R., Pluard, Timothy J., Tonda, Margaret, Meisel, Jane L., Alemany, Carlos A., Sabanathan, Dhanusha, Miller, Kathy D., Shaw, Morena, Borges, Virginia F., Okera, Meena, Wesolowski, Robert, Conlin, Alison K., McCarthy, Nicole

2025

Overview

Background Endocrine resistance is a major challenge in treating patients with ER+ /HER2− metastatic breast cancer (MBC) necessitating a switch from endocrine therapy to more toxic therapies. Mutations in ESR1 constitute a key mechanism of resistance to endocrine therapy in ER+ /HER2− BC. Therapies that overcome endocrine resistance are needed. Palazestrant is a novel oral complete estrogen receptor (ER) antagonist (CERAN) and selective ER degrader (SERD) belonging to a new class of ER-targeting agents that completely blocks estrogen-induced transcriptional activity, regardless of ESR1 mutation status. This first-in-human, open-label, multicenter, phase 1/2 dose-escalation/expansion study was designed to determine the recommended phase 2 dose (RP2D) and to evaluate safety, pharmacokinetics, and antitumor activity of palazestrant in patients with ER+ /HER2− MBC with disease progression on prior treatment. Methods Adults with ER+ /HER2‒ MBC who received ≥ 1 prior line of endocrine therapy for advanced disease and ≤ 2 prior chemotherapy regimens for metastatic disease were eligible. Patients received once-daily oral palazestrant (30–300 mg) in 28-day cycles until progression or intolerable toxicity. Results This study enrolled 146 patients. No dose-limiting toxicities were observed at doses up to 300 mg/day palazestrant. Confirmed partial responses were observed with 60 and 120 mg/day palazestrant. Both doses showed similar and tolerable safety profiles, favorable pharmacokinetics, and steady-state plasma concentrations above the predicted threshold for complete ER inhibition. Greater clinical benefit at palazestrant 120 mg/day (46%) versus 60 mg/day (19%) led to selection of 120 mg/day as RP2D and study expansion dose. At 120 mg/day, the median progression-free survival was 4.8 months (95% CI, 3.5–7.1) overall and 5.6 months (95% CI, 4.8–NE) among patients with cancers with ESR1 mutations. Most treatment-emergent adverse events (TEAEs) were grade 1–2. The most common TEAEs were nausea (62.8%), vomiting (29.1%), and fatigue (25.6%). The most common grade ≥ 3 TEAE was transient neutropenia (10.5%) managed by dose interruption and reduction. Conclusions Palazestrant demonstrated a manageable safety profile, with antitumor activity observed in patients with heavily pretreated cancers with wild-type and ESR1 -mutated BC. These data support the ongoing phase 3 study evaluating palazestrant in patients with ER+ /HER2 − MBC. Trial registration ClinicalTrials.gov, NCT04505826 . Registered August 6, 2020.

• Publisher: BioMed Central,Springer Nature B.V,BMC
• Subject: Administration, Oral / Adult / Aged / Antitumor activity / Biomarkers / Biomedical and Life Sciences / Biomedicine / Breast cancer / Breast Neoplasms - drug therapy / Breast Neoplasms - genetics / Breast Neoplasms - metabolism / Breast Neoplasms - mortality / Breast Neoplasms - pathology / Cancer / Cancer Research / Cancer therapies / Chemotherapy / Complete estrogen receptor antagonist / Cyclin-dependent kinases / Endocrine therapy / ErbB-2 protein / Estrogen Receptor alpha - antagonists & inhibitors / Estrogen Receptor alpha - genetics / Estrogen Receptor Antagonists - administration & dosage / Estrogen Receptor Antagonists - adverse effects / Estrogen Receptor Antagonists - pharmacokinetics / Estrogen Receptor Antagonists - therapeutic use / Estrogen receptor mutation / Estrogen receptor-positive human epidermal growth factor receptor 2-negative metastatic breast cancer / Estrogen receptors / Estrogens / Female / Humans / Kinases / Laboratories / Metastases / Metastasis / Middle Aged / Mutation / Neoplasm Metastasis / Neutropenia / Oncology / Palazestrant / Patients / Pharmacokinetics / Plasma / Pyridines - administration & dosage / Pyridines - adverse effects / Pyridines - pharmacokinetics / Pyridines - therapeutic use / Receptor, ErbB-2 - genetics / Receptor, ErbB-2 - metabolism / Receptors, Estrogen - antagonists & inhibitors / Receptors, Estrogen - metabolism / Selective estrogen receptor degrader / Surgical Oncology / Toxicity / Tumors / Womens health