Two major Phase III clinical trials are advancing treatment options for patients with advanced hormone receptor-positive, HER2-negative breast cancer, targeting specific genetic mutations that drive treatment resistance.
PIK3CA-Targeted Combination Therapy Trial
A Phase III, double-blind, placebo-controlled study is evaluating combination therapy in postmenopausal women with locally advanced or metastatic estrogen receptor-positive breast cancer. The trial specifically targets patients with PIK3CA mutations, requiring central testing confirmation using the cobas PIK3CA mutation assay.
Eligible participants must have experienced radiologic evidence of disease progression while receiving aromatase inhibitor therapy, either during adjuvant treatment within 12 months or during treatment for advanced disease within one month. The study excludes patients with HER2-positive disease and those previously treated with PI3K inhibitors, mTOR inhibitors, or AKT inhibitors.
Key inclusion criteria include an Eastern Cooperative Oncology Group performance status of 0 or 1, measurable disease per RECIST v1.1 criteria, and adequate hematologic and end-organ function. Participants must provide tumor tissue samples for PIK3CA mutation testing and cannot have received prior fulvestrant therapy.
SERENA-6: Targeting ESR1 Mutations
The SERENA-6 trial represents a Phase III, double-blind, randomized study assessing AZD9833, an investigational selective estrogen receptor degrader (SERD), in patients with advanced breast cancer harboring ESR1 mutations. This study focuses on patients currently receiving CDK4/6 inhibitor and aromatase inhibitor combination therapy.
Participants must have adenocarcinoma of the breast with locoregionally recurrent or metastatic disease not amenable to surgical resection or curative radiation therapy. The trial requires documentation of estrogen receptor-positive, HER2-negative breast cancer and detection of ESR1 mutations through central testing of circulating tumor DNA using the Guardant360® CDx assay.
Eligible patients must be currently receiving aromatase inhibitor therapy (letrozole or anastrozole) combined with a CDK4/6 inhibitor (palbociclib, abemaciclib, or ribociclib) for at least six months as initial endocrine-based treatment for advanced disease, without evidence of disease progression.
Addressing Treatment Resistance
Both trials address critical resistance mechanisms in advanced breast cancer. The PIK3CA-targeted study focuses on patients who have developed resistance to aromatase inhibitor therapy, while SERENA-6 targets ESR1 mutations that commonly emerge during prolonged endocrine therapy.
The SERENA-6 trial excludes patients with advanced, symptomatic visceral disease at risk of life-threatening complications, active CNS metastases, and those with previous exposure to investigational SERDs or fulvestrant. Similarly, the PIK3CA study excludes patients with untreated CNS metastases and those requiring anti-hyperglycemic medications for diabetes.
Clinical Significance
These trials represent important advances in precision medicine approaches for advanced breast cancer. By targeting specific genetic alterations - PIK3CA mutations in one study and ESR1 mutations in SERENA-6 - both trials aim to overcome common resistance mechanisms that limit the effectiveness of standard endocrine therapies.
The focus on circulating tumor DNA testing in SERENA-6 demonstrates the growing importance of liquid biopsy technologies in guiding treatment decisions, while the requirement for tissue-based PIK3CA testing in the first trial highlights the continued relevance of traditional biomarker assessment methods.
