Palazestrant

Shows activity

Also known as:

OP-1250

Cancer types include:

breast cancer

TrialFetch AI Analysis

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Overview

Palazestrant (OP-1250) is an oral endocrine therapy for ER+/HER2- breast cancer being developed by Olema Oncology. It is a complete estrogen receptor antagonist (CERAN) and selective ER degrader (SERD) with brain penetration in preclinical models. A randomized phase 3 monotherapy trial (OPERA-01; NCT06016738) is ongoing after prior endocrine therapy plus a CDK4/6 inhibitor. The drug has FDA Fast Track designation for ER+/HER2- metastatic disease progressing after endocrine therapy including a CDK4/6 inhibitor. (aacrjournals.org)

Mechanism of action

Palazestrant binds ER and completely blocks ER-driven transcription (no agonist activity), while also promoting ER degradation. In vitro and in vivo studies show activity against wild-type and ESR1-mutant ER, favorable oral pharmacokinetics, and intracranial efficacy in ER+ xenograft models, supporting potential activity in CNS disease. (aacrjournals.org)

Clinical development

Monotherapy: First-in-human phase 1/2 (NCT04505826) established a recommended phase 2 dose (RP2D) of 120 mg once daily and reported matured results in 2025. A global randomized phase 3 (OPERA-01) is comparing palazestrant vs standard endocrine therapies after prior ET+CDK4/6 inhibitor. (pmc.ncbi.nlm.nih.gov)
Combinations: Phase 1b/2 studies are evaluating palazestrant with ribociclib, alpelisib, or everolimus (NCT05508906). (cdek.pharmacy.purdue.edu)

Efficacy

Monotherapy (phase 1/2, heavily pretreated ER+/HER2- MBC)
- At the RP2D 120 mg cohort: clinical benefit rate (CBR) 45.7%; median PFS 4.8 months (95% CI, 3.5–7.1) overall and 5.6 months (95% CI, 4.8–NE) in ESR1-mutated tumors. Confirmed partial responses were observed; activity was seen in both ESR1-mutant and wild-type disease. (breast-cancer-research.biomedcentral.com)

Combination with ribociclib (phase 1b/2)
- ESMO Breast 2024 (early cut): CBR 85% among CBR-eligible patients; partial responses observed; pharmacokinetic data indicated no meaningful drug–drug interaction. (ir.olema.com)
- SABCS 2024 (updated cut): among response-evaluable patients, ORR 27% (including confirmed CRs and PRs); CBR 76%; 6‑month PFS rate 73% overall, 68% in those previously treated with CDK4/6 inhibitors; 81% in ESR1‑mutant tumors. Median PFS not reached at ~12 months’ median follow-up. (Conference report.) (1stoncology.com)

Safety

Monotherapy (phase 1/2): Most treatment-emergent adverse events were grade 1–2. Common events included nausea (≈63%), vomiting (≈29%), and fatigue (≈26%). The most common grade ≥3 event was transient neutropenia (≈10%), typically manageable with dose interruption/reduction. (breast-cancer-research.biomedcentral.com)

Combination with ribociclib: Safety consistent with known ribociclib plus endocrine therapy profiles; common AEs included nausea, neutropenia, fatigue, anemia, and diarrhea, predominantly grade 1–2; no clinically meaningful PK interactions were observed between drugs. (oncologypro.esmo.org)

Active trials using Palazestrant

Found 3 active trials using this drug:

A Phase 3 Randomized, Double-Blind, Active-Controlled Study of Palazestrant With Ribociclib Versus Letrozole With Ribociclib for the First-Line Treatment of ER+, HER2- Advanced Breast Cancer (OPERA-02)

Sponsor: Olema Pharmaceuticals, Inc. (industry) Phase: 3 Start date: Nov. 3, 2025

TrialFetch AI summary: Adults (women or men) with ER+, HER2− unresectable locally advanced or metastatic breast cancer who are systemic-therapy naïve for advanced disease (de novo or recurrence >12 months after adjuvant endocrine therapy; ECOG 0–1; measurable or bone-only disease; premenopausal women/men require GnRH suppression) are randomized to palazestrant (OP-1250; oral complete ER antagonist/next-generation SERD that promotes ER degradation, including in ESR1-mutant tumors) plus ribociclib versus standard letrozole plus ribociclib in the first-line setting.

ClinicalTrials.gov ID: NCT07085767

A Phase 3 Randomized, Open-Label Study of OP-1250 Monotherapy vs Standard of Care for the Treatment of ER+, HER2- Advanced or Metastatic Breast Cancer Following Endocrine and CDK 4/6 Inhibitor Therapy (OPERA-01)

Sponsor: Olema Pharmaceuticals, Inc. (industry) Phase: 3 Start date: Nov. 16, 2023

TrialFetch AI summary: This trial enrolls adults with ER+, HER2- advanced or metastatic breast cancer who have progressed on 1–2 lines of endocrine therapy (including a CDK4/6 inhibitor) and randomizes them to receive either palazestrant (OP-1250), an oral complete estrogen receptor antagonist (CERAN) and degradant, or standard endocrine therapy (fulvestrant or aromatase inhibitor). Key exclusions include symptomatic visceral disease, prior chemotherapy for advanced/metastatic disease, and active CNS involvement.

ClinicalTrials.gov ID: NCT06016738

A Phase 1b Open-Label Multicenter Study of OP-1250 (Palazestrant) in Combination With the CDK4/6 Inhibitor Ribociclib, With the PI3K Inhibitor Alpelisib, or With the mTOR Inhibitor Everolimus in Adult Subjects With Advanced and/or Metastatic ER Positive, HER2 Negative Breast Cancer

Sponsor: Olema Pharmaceuticals, Inc. (industry) Phase: 1 Start date: Aug. 31, 2022

TrialFetch AI summary: This study enrolls adults with advanced or metastatic ER-positive, HER2-negative breast cancer (with limited prior systemic therapy) to receive OP-1250 (palazestrant), a complete estrogen receptor antagonist and degrader, in combination with either ribociclib (CDK4/6 inhibitor), alpelisib (PI3K inhibitor), or everolimus (mTOR inhibitor). Eligible patients must have measurable or evaluable disease and ECOG 0-1.

ClinicalTrials.gov ID: NCT05508906