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Clinical Trial
. 2025 Jul 1;27(1):119.
doi: 10.1186/s13058-025-02049-y.

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 Patel  2 , Virginia F Borges  3 , Jane L Meisel  4 , Meena Okera  5 , Carlos A Alemany  6 , Timothy J Pluard  7 , Robert Wesolowski  8 , Dhanusha Sabanathan  9 , Kathy D Miller  10 , Alison K Conlin  11 , Nicole McCarthy  12 , Morena Shaw  13 , Margaret Tonda  13 , Mark Shilkrut  13 , Nancy U Lin  14
Affiliations
Clinical Trial

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 et al. Breast Cancer Res. .

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 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.

Keywords: Complete estrogen receptor antagonist; Endocrine therapy; Estrogen receptor mutation; Estrogen receptor-positive human epidermal growth factor receptor 2-negative metastatic breast cancer; Palazestrant; Selective estrogen receptor degrader.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: The study was conducted in accordance with the ethical principles of the Declaration of Helsinki, the International Council on Harmonization of Technical Requirements for Pharmaceuticals for Human Use – Good Clinical Practice (ICH-GCP) guidelines, and all applicable local and national (US Food and Drug Administration [FDA]) regulatory requirements. All patients provided written informed consent prior to participation in the study. Competing interests: Erika P. Hamilton has received research support paid to her institution from AbbVie, Acerta Pharma, Accutar Biotech, ADC Therapeutics, Akesobio Australia, Amgen, Aravive, ArQule, Artios, Arvinas, AstraZeneca, Atlas Medx, BeiGene, Black Diamond, Bliss Biopharmaceutical, Boehringer Ingelheim, Bristol-Myers Squibb, Cascadian Therapeutics, Clovis, Compugen, Context Therapeutics, Cullinan, Curis, CytomX, Daiichi Sankyo, Dana Farber Cancer Institute, Dantari, Deciphera, Duality Biologics, eFFECTOR Therapeutics, Eisai, Ellipses Pharma, Elucida Oncology, EMD Serono, Fochon Pharmaceuticals, FujiFilm, G1 Therapeutics, Gilead Sciences, H3 Biomedicine, Harpoon, Hutchinson MediPharma, Immunogen, Immunomedics, Incyte, Infinity Pharmaceuticals, Inspirna, InventisBio, Jacobio, Karyopharm, K-Group Beta, Kind Pharmaceuticals, Leap Therapeutics, Lilly, Loxo Oncology, Lycera, MabSpace Biosciences, MacroGenics, MedImmune, Mersana, Merus, Millennium, Molecular Templates, Myriad Genetic Laboratories, Novartis, NuCana, Olema, Oncomed, Oncothyreon, ORIC Pharmaceuticals, Orinove, Orum Therapeutics, Pfizer, PharmaMar, Pieris Pharmaceuticals, Pionyr Immunotherapeutics, Plexxikon, Prelude Therapeutics, Profound Bio, Radius Health, Regeneron, Relay Therapeutics, Repertoire Immune Medicine, Rgenix, Roche/Genentech, Seagen, Sermonix Pharmaceuticals, Shattuck Labs, Silverback Therapeutics, Stemcentrx, Stemline Therapeutics, Sutro, Syndax, Syros, Taiho, TapImmune, Tesaro, Tolmar, Torque Therapeutics, Treadwell Therapeutics, Verastem Oncology, Zenith Epigenetics, and Zymeworks. She has also acted as a consultant/advisor and received payments to her institution from Accutar Biotechnology, AstraZeneca, Daiichi Sankyo, Ellipses Pharma, Entos Pharmaceuticals, Fosun Pharma, Gilead Sciences, Jazz Pharmaceuticals, Jefferies LLC, Lilly, Medical Pharma Services, Mersana, Novartis, Olema Pharmaceuticals, Pfizer, Roche/Genentech, Stemline Therapeutics, Tempus Labs, Theratechnologies, Tubulis, Verascity Science, and Zentalis Pharmaceuticals. Manish R. Patel has acted in a leadership role for ION Pharma, has received honoraria from Janssen Oncology, has acted in a consulting or advisory role for Accutar Biotech, Daiichi Sankyo/UCB Japan, Kura Oncology, Nurix, and Olema Oncology, and has received research support paid to his institution from Acerta Pharma, ADC Therapeutics, Agenus, Allorio Therapeutics, Artios, AstraZeneca, BioNTech AG, BioTheryX, Boehringer Ingelheim, Bristol-Myers Squibb/Celgene, Compugen, Conjupro Biotherapeutics, Cullinan Oncology, Cyteir Therapeutics, Daiichi Sankyo, Erasca, Inc., Genentech/Roche, Gergiamune, Gilead Sciences, GlaxoSmithKline, H3 Biomedicine, Hengrui Therapeutics, Hotspot Therapeutics, Hutchison MediPharma, Immune-Onc Therapeutics, Immunitas, Incyte, Janssen, Kineta, Klus Pharma, Kura Oncology, Kymab, Lilly, Loxo, LSK Biopartners, Mabspace, Macrogenics, Merck, Millenium, Moderna Therapeutics, Novartis, Nurix, ORIC Pharmaceuticals, Pfizer, Pionyr, Prelude Therapeutics, Puretech, Ribon Therapeutics, Seven and Eight Biopharmaceuticals, Step Pharma, Syndax, Taiho Pharmaceutical, Tesaro, and Vividon Therapeutics. Virginia F. Borges has acted in a consulting or advisory role for AstraZeneca, Gilead, Pfizer, and Seagen, has received research support paid to her institution from AstraZeneca, Gilead, Olema, Pfizer, and Seagen, and owns stocks in Pearl Scientific. Jane L. Meisel has acted in a consulting or advisory role for AstraZeneca, Clovis, Genentech, GSK, Novartis, Olema, Pfizer, Puma, and Seagen, and has received research support paid to her institution from AstraZeneca, Olema, Pfizer, Seagen, and Sermonix. Meena Okera has no conflicts of interest to disclose relating to the work. Carlos A. Alemany has received research support paid to his institution from Bayer, Bristol-Myers Squibb, Exelixis, Janssen, Johnson & Johnson, Merck, Novartis, Olema Oncology, Pfizer, and Seagen. Timothy J. Pluard has received research support paid to his institution from Pfizer, Novartis, Gilead, Stemline, AstraZeneca, Arvinas, Scorpion Therapeutics, H3Biomedicine, Olema Pharmaceuticals, Dantari, Daiichi, Sanofii, Jazz Pharmaceuticals, Carrick Therapeutics, Daiichi, Merck, Sermoix, and has acted in a consulting or advisory role for Pfizer, AstraZeneca, Arvinas, Gilead, Jazz. Speaking: Gilead, Stemline, AstraZeneca. Robert Wesolowski has acted as an Advisory Board member and Scientific Steering Committee member for Celcuity, and has served on an Advisory Board for Pfizer. Dhanusha Sabanathan has no conflicts of interest to disclose relating to the work, aside from acknowledging the sponsor of the study (Olema Oncology). Kathy D. Miller has no conflicts of interest to disclose relating to the work, aside from acknowledging the sponsor of the study (Olema Oncology). Alison K. Conlin has acted in a consulting or advisory role for AstraZeneca, Gilead Sciences, and Seattle Genetics/Astellas, and has received payment for travel/accommodation/expenses from Seattle Genetics/Astellas. Nicole McCarthy has acted in a consulting or advisory role for AstraZeneca, Gilead Sciences, Merck, and Novartis, and has received a travel grant from Novartis. Margaret Tonda and Mark Shilkrut are employees of and own stocks in Olema Oncology. Nancy U. Lin has received research support paid to her institution from Genentech, Pfizer, Merck, Seattle Genetics, Zion Pharmaceuticals, Olema Oncology, and AstraZeneca. She has received honoraria for consulting work from Puma, Seattle Genetics, Daiichi-Sankyo, AstraZeneca, Denali Therapeutics, Prelude Therapeutics, Olema Oncology, Aleta BioPharma, Affinia Therapeutics, Voyager Therapeutics, Janssen, Blueprint Medicines, Stemline/Menarini, Artera Inc., and Reverie Labs. Manish R. Patel has acted in a leadership role for ION Pharma, has received honoraria from Janssen Oncology, has acted in a consulting or advisory role for Accutar Biotech, Daiichi Sankyo/UCB Japan, Kura Oncology, Nurix, and Olema Oncology, and has received research support paid to his institution from Acerta Pharma, ADC Therapeutics, Agenus, Allorio Therapeutics, Artios, AstraZeneca, BioNTech AG, BioTheryX, Boehringer Ingelheim, Bristol-Myers Squibb/Celgene, Compugen, Conjupro Biotherapeutics, Cullinan Oncology, Cyteir Therapeutics, Daiichi Sankyo, Erasca, Inc., Genentech/Roche, Gergiamune, Gilead Sciences, GlaxoSmithKline, H3 Biomedicine, Hengrui Therapeutics, Hotspot Therapeutics, Hutchison MediPharma, Immune-Onc Therapeutics, Immunitas, Incyte, Janssen, Kineta, Klus Pharma, Kura Oncology, Kymab, Lilly, Loxo, LSK Biopartners, Mabspace, Macrogenics, Merck, Millenium, Moderna Therapeutics, Novartis, Nurix, ORIC Pharmaceuticals, Pfizer, Pionyr, Prelude Therapeutics, Puretech, Ribon Therapeutics, Seven and Eight Biopharmaceuticals, Step Pharma, Syndax, Taiho Pharmaceutical, Tesaro, and Vividon Therapeutics. Virginia F. Borges has acted in a consulting or advisory role for AstraZeneca, Gilead, Pfizer, and Seagen, has received research support paid to her institution from AstraZeneca, Gilead, Olema, Pfizer, and Seagen, and owns stocks in Pearl Scientific. Jane L. Meisel has acted in a consulting or advisory role for AstraZeneca, Clovis, Genentech, GSK, Novartis, Olema, Pfizer, Puma, and Seagen, and has received research support paid to her institution from AstraZeneca, Olema, Pfizer, Seagen, and Sermonix. Meena Okera has no conflicts of interest to disclose relating to the work. Carlos A. Alemany has received research support paid to his institution from Bayer, Bristol-Myers Squibb, Exelixis, Janssen, Johnson & Johnson, Merck, Novartis, Olema Oncology, Pfizer, and Seagen. Timothy J. Pluard has received research support paid to his institution from Pfizer, Novartis, Gilead, Stemline, AstraZeneca, Arvinas, Scorpion Therapeutics, H3Biomedicine, Olema Pharmaceuticals, Dantari, Daiichi, Sanofii, Jazz Pharmaceuticals, Carrick Therapeutics, Daiichi, Merck, Sermoix, and has acted in a consulting or advisory role for Pfizer, AstraZeneca, Arvinas, Gilead, Jazz. Speaking: Gilead, Stemline, AstraZeneca. Robert Wesolowski has acted as an Advisory Board member and Scientific Steering Committee member for Celcuity, and has served on an Advisory Board for Pfizer. Dhanusha Sabanathan has no conflicts of interest to disclose relating to the work, aside from acknowledging the sponsor of the study (Olema Oncology). Kathy D. Miller has no conflicts of interest to disclose relating to the work, aside from acknowledging the sponsor of the study (Olema Oncology). Alison K. Conlin has acted in a consulting or advisory role for AstraZeneca, Gilead Sciences, and Seattle Genetics/Astellas, and has received payment for travel/accommodation/expenses from Seattle Genetics/Astellas. Nicole McCarthy has acted in a consulting or advisory role for AstraZeneca, Gilead Sciences, Merck, and Novartis, and has received a travel grant from Novartis. Margaret Tonda and Mark Shilkrut are employees of and own stocks in Olema Oncology. Nancy U. Lin has received research support paid to her institution from Genentech, Pfizer, Merck, Seattle Genetics, Zion Pharmaceuticals, Olema Oncology, and AstraZeneca. She has received honoraria for consulting work from Puma, Seattle Genetics, Daiichi-Sankyo, AstraZeneca, Denali Therapeutics, Prelude Therapeutics, Olema Oncology, Aleta BioPharma, Affinia Therapeutics, Voyager Therapeutics, Janssen, Blueprint Medicines, Stemline/Menarini, Artera Inc., and Reverie Labs.

Figures

Fig. 1
Fig. 1
Palazestrant Mechanism of Action. Oncogenic signals activate the ER to drive cancer cell growth. Selective estrogen receptor modulators (SERMs) block only the AF2 domain, leaving the AF1 domain active and capable of gene transcription. Palazestrant is a complete ER antagonist (CERAN) and selective ER degrader (SERD) that acts by blocking both AF1 and AF2 domains to completely block ER-driven transcriptional activity. AF, activation function; DBD, DNA-binding domain; EGFR, epidermal growth factor receptor; ER, estrogen receptor; mTOR, mammalian target of rapamycin; N-CoR, nuclear receptor corepressor, SERM, selective estrogen receptor modulator
Fig. 2
Fig. 2
Study design. Phase 1 of the study comprised a dose escalation phase (1a; rolling 6 dose escalation design) to identify the MTD and a dose expansion phase (1b) using selected doses of palazestrant to further characterize the safety, pharmacokinetics, and antitumor activity of treatment and to establish the RP2D. Phase 2 further explored the safety and antitumor activity of palazestrant at the RP2D in patients with measurable disease (primary cohort), nonmeasurable evaluable disease (exploratory cohort), and CNS metastases (exploratory cohort, not included in this report). The data presented in this report include patients from phase 1a/1b as well as cohorts of patients with measurable disease and nonmeasurable evaluable disease from phase 2. CBR, clinical benefit rate; CNS, central nervous system; CR, complete response; MTD, maximum tolerated dose; ORR, overall response rate; PR, partial response; RP2D, recommended phase 2 dose; SD, stable disease
Fig. 3
Fig. 3
Steady-State Plasma Concentration–Time Profiles for Palazestrant (30 to 300 mg QD; Phase 1a/1b/2 data). Palazestrant was administered once daily at the indicated dose. Plasma samples were collected on cycle 2, day 1, at the indicated timepoints following administration to determine plasma drug concentration. Data presented are arithmetic mean and standard deviation; the heavy dashed black line represents the target (efficacious) exposure based on estradiol-supplemented preclinical models (Cmin: 226 ng/mL). Cmin, minimum plasma concentration; QD, once daily
Fig. 4
Fig. 4
Antitumor Activity in Patients Receiving 120 mg/day Palazestrant. A Best overall response and change from baseline in target lesion size among the 64 patients with evaluable baseline and postbaseline target lesions (66 response-evaluable patients treated with 120 mg/day palazestrant; 2 patients did not have evaluable postbaseline target lesions). B Duration of treatment and best overall responses among patients receiving 120 mg/day palazestrant (n = 86). Arrows represent patients still receiving treatment; the absence of a box represents missing data. All prior treatments are in the advanced disease setting. In (B), each lane represents 1 patient. Reasons for treatment discontinuation included disease progression, adverse events, withdrawal of consent, and other reasons (treatment was discontinued in 1 patient after a post-treatment biopsy showed HER2-positive disease; 1 patient discontinued treatment for financial reasons). aUnconfirmed PRs. bOne patient continued treatment beyond progression due to clinical benefit per principal investigator assessment. CDK4/6i, cyclin-dependent kinase 4/6 inhibitor; chemo, chemotherapy; ESR1, estrogen receptor 1 gene; ESR1-mut, ESR1-mutation detected; ESR1-mut-nd, ESR1 mutation not detected; fulv, fulvestrant; HER2, human epidermal growth factor receptor 2; MD, measurable disease; PD, progressive disease; PR, partial response; SD, stable disease; VD, visceral disease
Fig. 5
Fig. 5
Progression-free survival. Kaplan–Meier survival curves for progression-free survival. A All patients receiving 120 mg/day palazestrant (n = 86). B Patients receiving 120 mg/day palazestrant who had an ESR1 mutation at baseline (n = 36). ESR1, estrogen receptor 1 gene; NE, not estimable; PFS, progression-free survival
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