Sponsor: Olema Pharmaceuticals, Inc. (industry)
Phase: 3
Start date: Nov. 16, 2023
Planned enrollment: 510
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)
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)
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)
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)
Notes: As of October 7, 2025, no randomized phase 3 efficacy readout has been publicly reported. Data above reflect the most recent peer‑reviewed publications and conference abstracts. (breast-cancer-research.biomedcentral.com)
Last updated: Oct 2025
Goal: Compare the efficacy and safety of palazestrant (OP-1250) monotherapy versus standard-of-care endocrine therapy in ER+, HER2- advanced or metastatic breast cancer after progression on prior endocrine therapy combined with a CDK4/6 inhibitor, with the aim of improving progression-free and overall survival, including in ESR1-mutant and ESR1–wild-type subgroups.
Patients: Adult women and men with ER+, HER2- locally advanced or metastatic breast cancer not amenable to curative therapy, with evaluable disease (measurable or bone-only), ECOG 0–1, adequate organ function, and prior exposure to a CDK4/6 inhibitor with endocrine therapy in the advanced setting (with or without one additional line of endocrine monotherapy; most recent endocrine therapy duration ≥6 months). Pre-, peri-, and postmenopausal women are eligible; men and pre/perimenopausal women must receive GnRH/LHRH agonists. Key exclusions include symptomatic visceral crisis, prior chemotherapy for metastatic disease, prior elacestrant or investigational ER-directed therapy, symptomatic/untreated CNS disease, and significant comorbidities or contraindications to SOC endocrine therapy.
Design: International, multicenter, randomized, open-label, active-controlled phase 3 study. Two-part design: an initial dose-selection cohort (~120 participants) randomizing two palazestrant doses versus standard-of-care, followed by an expansion cohort (~390 participants) randomizing the selected palazestrant dose versus standard-of-care. Stratification includes ESR1 mutation status with blinded independent review for PFS.
Treatments: Experimental: Palazestrant (OP-1250), an oral complete estrogen receptor antagonist (CERAN) and selective estrogen receptor degrader (SERD). It fully antagonizes ER without agonist activity and promotes receptor degradation, aiming to overcome endocrine resistance including ESR1 mutations. Phase 2 monotherapy data in heavily pretreated ER+/HER2- disease showed median PFS of 4.6 months overall and 5.6 months in ESR1-mutant tumors, with clinical benefit rates of approximately 40% overall and 52% in ESR1-mutant patients; safety was favorable with predominantly grade 1–2 adverse events. Comparator: Investigator’s choice of standard endocrine therapy—fulvestrant or an aromatase inhibitor (anastrozole, letrozole, or exemestane)—consistent with guideline-based post-CDK4/6 endocrine options.
Outcomes: Primary endpoints: In the dose-selection part, incidence of adverse events, dose reductions, and drug discontinuations through 16 weeks; in the randomized trial, blinded independent review committee–assessed progression-free survival, analyzed separately for ESR1 mutation–detected and –not detected populations. Key secondary endpoint: overall survival, also assessed separately by ESR1 mutation status. Additional safety and tolerability assessments are included.
Burden on patient: Moderate to low. Both arms receive oral or intramuscular endocrine therapies typical of standard practice; monitoring includes periodic clinic visits, labs, and imaging at intervals similar to routine metastatic breast cancer care. As a phase 3 study without intensive pharmacokinetic sampling or mandatory serial biopsies described, incremental burden beyond standard-of-care is limited to study-specific assessments and visit schedules; patients requiring GnRH/LHRH agonists will have additional injections per standard practice. Travel and time commitments align with typical follow-up for metastatic ER+ disease.
Last updated: Oct 2025
Key inclusion criteria:
* Adult female or male participants.
* ER+, HER2- locally advanced or metastatic breast cancer that is not amenable to curative therapy.
* Evaluable disease (measurable disease or bone-only disease).
* Previously received a CDK4/6 inhibitor in combination with an endocrine therapy in the advanced setting. One additional line of ET as a monotherapy is allowed. Duration of the most recent prior ET must be at least 6 months.
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
* Adequate hematologic, hepatic, and renal functions.
* Female participants can be pre-, peri- or postmenopausal.
* Male and pre- or peri-menopausal female participants must be willing to take a GnRH (or LHRH) agonist.
Key exclusion criteria:
* Symptomatic visceral disease, imminent organ failure, or any other reason that makes the participant ineligible for endocrine monotherapy.
* Previously received chemotherapy in the advanced/metastatic setting.
* Previously received treatment with elacestrant or an investigational estrogen receptor-directed therapy.
* History of allergic reactions to study treatment.
* Any contraindications to the selected standard-of-care endocrine therapy in the local prescribing information.
* Symptomatic central nervous system metastases, carcinomatous meningitis, leptomeningeal disease, or a spinal cord compression that require immediate treatment.
* Clinically significant comorbidities such as significant cardiac or cerebrovascular disease, gastrointestinal disorders that could affect absorption of study treatment.
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