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
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. T...
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BMC
2025-07-01
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| Series: | Breast Cancer Research |
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| Online Access: | https://doi.org/10.1186/s13058-025-02049-y |
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| author | Erika P. Hamilton Manish R. Patel Virginia F. Borges Jane L. Meisel Meena Okera Carlos A. Alemany Timothy J. Pluard Robert Wesolowski Dhanusha Sabanathan Kathy D. Miller Alison K. Conlin Nicole McCarthy Morena Shaw Margaret Tonda Mark Shilkrut Nancy U. Lin |
| author_facet | Erika P. Hamilton Manish R. Patel Virginia F. Borges Jane L. Meisel Meena Okera Carlos A. Alemany Timothy J. Pluard Robert Wesolowski Dhanusha Sabanathan Kathy D. Miller Alison K. Conlin Nicole McCarthy Morena Shaw Margaret Tonda Mark Shilkrut Nancy U. Lin |
| author_sort | Erika P. Hamilton |
| collection | DOAJ |
| description | 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. |
| format | Article |
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| institution | Kabale University |
| issn | 1465-542X |
| language | English |
| publishDate | 2025-07-01 |
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| series | Breast Cancer Research |
| spelling | doaj-art-eae843ce2875403c92f4e3a8082f50b52025-08-20T03:45:43ZengBMCBreast Cancer Research1465-542X2025-07-0127111510.1186/s13058-025-02049-yPalazestrant, 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 resultsErika P. Hamilton0Manish R. Patel1Virginia F. Borges2Jane L. Meisel3Meena Okera4Carlos A. Alemany5Timothy J. Pluard6Robert Wesolowski7Dhanusha Sabanathan8Kathy D. Miller9Alison K. Conlin10Nicole McCarthy11Morena Shaw12Margaret Tonda13Mark Shilkrut14Nancy U. Lin15Sarah Cannon Research InstituteFlorida Cancer Specialists/Sarah Cannon Research InstituteAnschutz Medical Campus, University of Colorado Cancer CenterWinship Cancer Institute, Emory UniversityCancer Research SAAdventHealth Cancer InstituteSaint Luke’s Cancer Institute - Koontz Center for Advanced Breast CancerDivision of Medical Oncology, The Ohio State University Comprehensive Cancer CenterFaculty of Medicine, Health and Human Sciences, Macquarie UniversityIndiana University Melvin and Bren Simon Comprehensive Cancer CenterProvidence Cancer InstituteICON Cancer CentreOlema OncologyOlema OncologyOlema OncologyDepartment of Medical Oncology, Dana-Farber Cancer InstituteAbstract 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.https://doi.org/10.1186/s13058-025-02049-yComplete estrogen receptor antagonistSelective estrogen receptor degraderEstrogen receptor-positive human epidermal growth factor receptor 2-negative metastatic breast cancerEndocrine therapyPalazestrantEstrogen receptor mutation |
| spellingShingle | Erika P. Hamilton Manish R. Patel Virginia F. Borges Jane L. Meisel Meena Okera Carlos A. Alemany Timothy J. Pluard Robert Wesolowski Dhanusha Sabanathan Kathy D. Miller Alison K. Conlin Nicole McCarthy Morena Shaw Margaret Tonda Mark Shilkrut Nancy U. Lin 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 Breast Cancer Research Complete estrogen receptor antagonist Selective estrogen receptor degrader Estrogen receptor-positive human epidermal growth factor receptor 2-negative metastatic breast cancer Endocrine therapy Palazestrant Estrogen receptor mutation |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | Complete estrogen receptor antagonist Selective estrogen receptor degrader Estrogen receptor-positive human epidermal growth factor receptor 2-negative metastatic breast cancer Endocrine therapy Palazestrant Estrogen receptor mutation |
| url | https://doi.org/10.1186/s13058-025-02049-y |
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