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

Sep 24, 2026

Endocrine resistance challenges treatment of patients with ER+/HER2− metastatic breast cancer, often requiring escalation from endocrine therapy to more toxic options. Mutations in ESR1 drive endocrine resistance, and new approaches are needed. Palazestrant is a novel oral complete estrogen receptor antagonist (CERAN) and selective estrogen receptor degrader (SERD) designed to fully block estrogen-induced transcription regardless of ESR1 status. A first-in-human phase 1/2 study evaluates RP2D, safety, pharmacokinetics, and antitumor activity in progressing ER+/HER2− MBC.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages15

Reading Time38 min

AccessFree to download

Abstract

Background

Methods

Results

Conclusions

Trial registration

Introduction

Endocrine resistance and treatment context

Hamilton et al. Breast Cancer Research (2025) 27:119 [https://doi.org/10.1186/s13058-025-02049-y](https://doi.org/10.1186/s13058-025-02049-y) Breast Cancer Research RESEARCH Open Access 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 Erika P. Hamilton 1*, Manish R. Patel2, Virginia F. Borges3, Jane L. Meisel4, Meena Okera5, Carlos A. Alemany6, Timothy J. Pluard7, Robert Wesolowski8, Dhanusha Sabanathan9, Kathy D. Miller 10, Alison K. Conlin 11, Nicole McCarthy12, Morena Shaw13, Margaret Tonda13, Mark Shilkrut13 and Nancy U. Lin 14 Abstract 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 progressionfree 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. *Correspondence: Erika P. Hamilton [erika.hamilton@scri.com](erika.hamilton@scri.com) Full list of author information is available at the end of the article © The Author(s) 2025. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit [http://creativecommons.org/licenses/by/4.0/](http://creativecommons.org/licenses/by/4.

FAQs

Why is endocrine resistance a major issue in ER+/HER2− metastatic breast cancer?

Endocrine resistance limits the effectiveness of endocrine therapy, ultimately necessitating a switch to more toxic treatments. Mutations in ESR1 are a key mechanism driving resistance.

What is palazestrant, and how is it designed to address ESR1-related resistance?

Palazestrant is a novel oral complete estrogen receptor antagonist (CERAN) and selective estrogen receptor degrader (SERD). It completely blocks estrogen-induced transcriptional activity regardless of ESR1 mutation status.

What were the main phase 1/2 findings for dosing, safety, and antitumor activity?

Up to 300 mg/day showed no dose-limiting toxicities. Partial responses were observed at 60 and 120 mg/day, and 120 mg/day was selected as the recommended phase 2 dose based on greater clinical benefit. Treatment-emergent adverse events were mostly grade 1–2, with transient neutropenia as the most common grade ≥3 event.

Sep 24, 2026

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