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)

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Investigational drug late phase More information Active drug More information Low burden on patient More information

Trial Details

Sponsor: Olema Pharmaceuticals, Inc. (industry)

Phase: 3

Start date: Nov. 16, 2023

Planned enrollment: 510

Trial ID: NCT06016738
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More trial details at ClinicalTrials.gov More info

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chevron Show for: Palazestrant (OP-1250)

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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

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Spokane, Washington, 99218, United States

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Buenos Aires, C14626ABP, Argentina

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