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Palazestrant plus ribociclib as first-line treatment for ER+/HER2- advanced breast cancer

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)

Phase 3 Interventional Olema Pharmaceuticals, Inc. · NCT07085767

This trial will test whether using palazestrant instead of letrozole, both given with ribociclib, helps adults with ER+/HER2- advanced breast cancer who have not had prior systemic treatment for their advanced disease.

Quick facts

PhasePhase 3
Study typeInterventional
Enrollment1000 (estimated)
Ages18 Years and up
SexAll
SponsorOlema Pharmaceuticals, Inc. Industry-sponsored
Locations85 sites (Hot Springs, Arkansas and 84 other locations)
Trial IDNCT07085767 on ClinicalTrials.gov

What this trial studies

This is a randomized, double-blind, active-controlled phase 3 trial that will enroll about 1,000 adults with ER+/HER2- locally advanced or metastatic breast cancer and randomize them 1:1. Participants receive either palazestrant plus ribociclib with a letrozole-matching placebo or letrozole plus ribociclib with a palazestrant-matching placebo. The study compares efficacy and safety between the two arms while maintaining blinding with matching placebos. Eligible participants include men and women with measurable or bone-only disease and ECOG performance status 0–1.

Who should consider this trial

Good fit: Adults (men and women, including pre-, peri- or postmenopausal) with ER+/HER2- locally advanced or metastatic breast cancer who have not received systemic anti-cancer therapy for their advanced disease, have measurable or bone-only disease, and have ECOG 0–1 are ideal candidates.

Not a fit: Patients who have already received systemic therapy for advanced ER+/HER2- disease, who had recurrence during adjuvant endocrine therapy, or who previously received fulvestrant, elacestrant, or other investigational endocrine therapies are unlikely to be eligible or benefit from this specific comparison.

Why it matters

Potential benefit: If successful, this regimen could provide a more effective endocrine option that delays disease progression and prolongs time on therapy for people with ER+/HER2- advanced breast cancer.

How similar studies have performed: Combining estrogen receptor degraders (such as fulvestrant or newer oral SERDs) with CDK4/6 inhibitors has shown benefit in prior studies, but palazestrant itself remains a newer agent being tested in late-phase trials.

Eligibility criteria

Show full inclusion / exclusion criteria 
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 per RECIST 1.1 or bone-only disease).
* De novo advanced breast cancer or with disease recurrence occurring after 12 months of completing adjuvant endocrine therapy (with or without CDK4/6 inhibitors)
* 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.

Exclusion Criteria:

* Disease recurrence during adjuvant endocrine therapy
* Currently receiving or previously received systemic anti-cancer therapy for ER+, HER2- advanced breast cancer.
* Previously received treatment with fulvestrant, elacestrant or an investigational endocrine therapy in any setting.
* History of allergic reactions to study treatment.
* Any contraindications to letrozole and ribociclib.
* Symptomatic central nervous system metastases, carcinomatous meningitis, leptomeningeal disease, or a spinal cord compression that require immediate treatment.

Where this trial is running

Hot Springs, Arkansas and 84 other locations

+35 more sites — see ClinicalTrials.gov for the full list.

Study contacts

How to participate

  1. Review the eligibility criteria above with your treating physician.
  2. Visit the official trial page on ClinicalTrials.gov for the most current contact information and recruitment status.
  3. Contact the listed study coordinator or principal investigator to request pre-screening. Pre-screening is free and never obligates you to enroll.
View on ClinicalTrials.gov → Find more trials like this →
Conditions Breast CancerLocally Advanced Breast CancerMetastatic Breast CancerER Positive Breast CancerHER2 Negative Breast CarcinomaRandomizedMulticenterDouble-Blind
Last reviewed 2026-06-13 by the Find a Trial editorial team. Information on this page is for educational purposes and is not medical advice. Always consult qualified healthcare professionals about clinical trial participation.