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OPERA-01: a phase III study of palazestrant for ER+, HER2- advanced breast cancer after CDK4/6 inhibitor therapy
Barbara Pistilli1, Meritxell Bellet Ezquerra2, Lucia Del Mastro3
1Department of Medical Oncology, Gustave Roussy, Villejuif, France.
Abstract:
Endocrine therapy (ET) resistance is a major concern when treating estrogen receptor-positive (ER+) human epidermal growth factor receptor 2-negative (HER2-) breast cancer. A combination of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) and ET is the current first-line standard of care (SOC) for patients with ER+, HER2- advanced breast cancer. Despite the benefits of ET plus a CDK4/6i, disease progression due to endocrine resistance remains a significant challenge. More effective ETs that can overcome resistance are needed to improve clinical outcomes and maintain quality of life by delaying chemotherapy. Palazestrant is a novel oral, complete estrogen receptor antagonist (CERAN) and selective estrogen receptor degrader (SERD) that blocks both transcriptional activation function domains, AF1 and AF2, resulting in complete inhibition of ER-driven transcription, regardless of estrogen receptor 1 (ESR1) mutation status. As monotherapy, palazestrant showed tolerable safety, favorable pharmacokinetics, and antitumor efficacy in heavily pretreated patients during phase I/II studies. OPERA-01 (NCT06016738) is a phase III study designed to evaluate the safety and efficacy of palazestrant monotherapy compared to SOC ET in patients with ER+, HER2- locally advanced or metastatic breast cancer, regardless of ESR1 mutation status, whose disease advanced following treatment with at least one ET in combination with a CDK4/6i.Clinical Trial Registration: Clinicaltrials.gov NCT06016738. Registered 17 August 2023.
Insights
Palazestrant, a novel endocrine therapy, is being studied in OPERA-01 to treat advanced ER+, HER2- breast cancer resistant to current treatments. This trial compares palazestrant to standard care for improved outcomes.
Area of Science:
- Oncology
- Endocrinology
- Pharmacology
Background:
- Endocrine therapy (ET) resistance is a significant challenge in treating estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer.
- While cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) combined with ET are standard first-line care, disease progression due to resistance remains a problem.
- Novel ETs are needed to overcome resistance, improve patient outcomes, and delay chemotherapy initiation.
Purpose of the Study:
- To evaluate the safety and efficacy of palazestrant monotherapy compared to standard of care (SOC) endocrine therapy (ET).
- To assess palazestrant in patients with ER+, HER2- locally advanced or metastatic breast cancer who experienced disease progression after at least one ET plus CDK4/6i combination therapy.
- To investigate palazestrant's effectiveness regardless of estrogen receptor 1 (ESR1) mutation status.
Main Methods:
- The OPERA-01 study (NCT06016738) is a phase III clinical trial.
- Participants are patients with ER+, HER2- locally advanced or metastatic breast cancer with disease progression following prior ET plus CDK4/6i treatment.
- The study compares palazestrant monotherapy against SOC ET.
Main Results:
- Palazestrant is a novel oral complete estrogen receptor antagonist (CERAN) and selective estrogen receptor degrader (SERD).
- It blocks both AF1 and AF2 domains, leading to complete inhibition of ER-driven transcription, irrespective of ESR1 mutation status.
- Phase I/II studies indicated tolerable safety, favorable pharmacokinetics, and antitumor efficacy in heavily pretreated patients.
Conclusions:
- Palazestrant represents a promising therapeutic option for ER+, HER2- advanced breast cancer.
- Its novel mechanism of action may overcome endocrine resistance.
- The OPERA-01 study will provide crucial data on palazestrant's role in this patient population.
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