Phase III trial tests MRD-guided treatment for patients with ER-positive/HER2-negative breast cancer

Alliance Foundation Trials, LLC (AFT), a national leader in conducting innovative, practice-changing cancer clinical trials, and Natera, Inc., a global leader in cell-free DNA and precision medicine, today announced the launch of AFT-70 NAVIGATE, a randomized phase III trial evaluating a novel molecular residual disease (MRD)-guided treatment strategy for patients with intermediate and high-risk ER-positive/HER2-negative early breast cancer. The trial is sponsored and led by AFT, with collaboration and co-funding from Natera and Genentech, a member of the Roche Group.

AFT-70 NAVIGATE is designed to test whether patients can maintain excellent outcomes while more selectively using CDK4/6 inhibitors, rather than exposing all patients to prolonged combination therapy. The strategy pairs giredestrant, an investigational highly active next-generation oral selective estrogen receptor degrader (SERD), with longitudinal Signatera Genome MRD monitoring, to identify patients who may benefit from treatment escalation with a CDK4/6 inhibitor.

Giredestrant was selected as the endocrine therapy backbone for the investigational arm based on results from the phase III lidERA trial, which showed giredestrant achieved a statistically significant and clinically meaningful improvement in invasive disease-free survival compared with standard endocrine monotherapy in patients with ER-positive/HER2-negative early breast cancer. These findings support the potential for giredestrant to provide an endocrine therapy backbone on which an MRD-guided treatment strategy can be built.

Signatera was selected as the MRD test for this trial based on its extensive clinical evidence in HR+/HER2- early breast cancer, including from the AFT-05 PALLAS and MonarchE trials, and because of its new ultrasensitive Genome-based technology with Phased and Structural Variants reporting analytical sensitivity below 1 ppm (parts per million).

AFT expects to enroll more than 2,000 patients with stage II-III ER-positive/HER2-negative breast cancer who are eligible for endocrine therapy at approximately 200 sites across the U.S. and internationally. Patients with no detectable MRD by Signatera after completing standard-of-care treatment, including surgery, radiotherapy, and chemotherapy when indicated, will be randomly assigned to one of two approaches: (1) a control arm receiving standard-of-care endocrine therapy plus upfront CDK4/6 inhibition; or (2) an investigational arm receiving giredestrant monotherapy, with CDK4/6 inhibition added only if Signatera becomes positive. The primary endpoint is non-inferiority in 4-year distant recurrence-free survival.

This collaboration brings together leading expertise in breast cancer research, clinical care, and molecular testing to address an important question for patients: How can we make treatment more precise while avoiding unnecessary toxicity?. By using MRD technology to guide treatment decisions, this trial has the potential to transform care for eligible breast cancer patients and individualize treatment intensity."

Evanthia Galanis, MD, DSc, President, Alliance Foundation Trials, LLC

"We know that patients with ER-positive, HER2-negative breast cancer do not all face the same risk of recurrence, yet adjuvant treatment decisions are still largely based on clinical and pathological features measured at diagnosis," said Komal Jhaveri, MD, FACP, FASCO, study chair, breast medical oncologist, and early drug development specialist at Memorial Sloan Kettering Cancer Center. "The AFT-70 NAVIGATE trial combines two important advances: an endocrine therapy backbone with giredestrant and longitudinal MRD testing with Signatera that can provide a dynamic measure of recurrence risk. The trial will determine whether MRD-guided monitoring can distinguish patients most likely to benefit from adding a CDK4/6 inhibitor from those in whom it can be safely omitted. It's an important step forward using biology-not just baseline risk-to guide adjuvant therapy."

"More treatment is not always better treatment," said Gaorav Gupta, MD, PhD, study co-chair, breast radiation oncologist, and co-leader of the Breast Cancer Research Program at UNC Lineberger Comprehensive Cancer Center. "CDK4/6 inhibitors can be an important part of care for some patients, but they can also add side effects, monitoring, and treatment burden. If highly sensitive blood-based MRD testing can identify patients who can safely defer additional therapy, we may be able to spare many patients from the burdens of more treatment while maintaining excellent cancer control. That is the promise we hope to explore through this study."

"Natera and AFT have a longstanding partnership and shared commitment to cutting-edge trials across many cancer types," said Minetta Liu, MD, chief medical officer, oncology and early cancer detection, Natera. "AFT-70 NAVIGATE creates enormous potential to enhance treatment options for patients with intermediate and high-risk, hormone receptor positive breast cancer."