Alliance Foundation Trials and Natera Launch Phase III NAVIGATE Trial to Evaluate MRD-Guided Breast Cancer Treatment
Alliance Foundation Trials, LLC (AFT), a national organization focused on advancing innovative and practice-changing cancer clinical trials, and Natera, Inc. (NASDAQ: NTRA), a company specializing in cell-free DNA testing and precision medicine, have announced the launch of AFT-70 NAVIGATE, a randomized Phase III clinical trial designed to evaluate a molecular residual disease (MRD)-guided treatment strategy for patients with intermediate- and high-risk estrogen receptor-positive (ER-positive), human epidermal growth factor receptor 2-negative (HER2-negative) early breast cancer.
The study is being sponsored and led by AFT, with collaboration and co-funding from Natera and Genentech, a member of the Roche Group. The trial is intended to investigate whether highly sensitive blood-based MRD monitoring can help physicians determine which patients may require treatment intensification and which patients could potentially avoid prolonged exposure to additional therapy.
AFT-70 NAVIGATE will focus on the use of giredestrant as an endocrine therapy backbone together with longitudinal monitoring using Natera’s Signatera molecular residual disease test. Under the investigational treatment strategy, a CDK4/6 inhibitor would be introduced only if a patient develops detectable MRD during follow-up. The approach is designed to move beyond treatment decisions based solely on clinical and pathological characteristics assessed at diagnosis and instead incorporate real-time molecular information about residual disease.
The trial is expected to enroll more than 2,000 patients with Stage II-III ER-positive/HER2-negative breast cancer who are eligible to receive endocrine therapy. Approximately 200 clinical sites across the United States and internationally are expected to participate in the study.
Evaluating a More Personalized Approach to Adjuvant Treatment
ER-positive/HER2-negative breast cancer represents a substantial proportion of early breast cancer cases. Although many patients have favorable long-term outcomes with appropriate treatment, a subset remains at risk of disease recurrence despite completing surgery and other standard treatments.
Adjuvant treatment can include endocrine therapy and, for eligible patients with higher-risk disease, CDK4/6 inhibitors. While CDK4/6 inhibitors can reduce the risk of recurrence in appropriate patient populations, their use may also involve additional adverse effects, monitoring requirements, treatment complexity and financial or logistical burdens.
AFT-70 NAVIGATE is designed around the premise that treatment intensity could potentially be individualized according to a patient’s molecular response following standard-of-care therapy. Rather than automatically providing a CDK4/6 inhibitor to every eligible patient from the beginning of adjuvant treatment, the investigational strategy will use serial Signatera testing to monitor for molecular evidence of residual disease.
Patients who have no detectable MRD after completing standard-of-care treatment will be randomized between the control and investigational approaches. Standard treatment may include surgery, radiotherapy and chemotherapy when clinically indicated.
In the control arm, patients will receive standard-of-care endocrine therapy together with upfront CDK4/6 inhibition. In the investigational arm, patients will receive giredestrant as monotherapy initially. A CDK4/6 inhibitor will be added if Signatera testing subsequently becomes positive.
The primary endpoint of the study is non-inferiority in four-year distant recurrence-free survival. This means the trial is designed to determine whether the MRD-guided approach can maintain cancer control comparable to the conventional strategy while potentially reducing unnecessary exposure to CDK4/6 inhibition among patients who remain molecularly negative.
Giredestrant Selected as the Endocrine Therapy Backbone
Giredestrant, an investigational next-generation oral selective estrogen receptor degrader (SERD), has been selected as the endocrine therapy backbone for the investigational arm of NAVIGATE.
The selection follows findings from the Phase III lidERA trial, which evaluated giredestrant in patients with ER-positive/HER2-negative early breast cancer. According to the companies, lidERA demonstrated a statistically significant and clinically meaningful improvement in invasive disease-free survival compared with standard endocrine monotherapy.
These findings provide the clinical rationale for evaluating giredestrant as the endocrine component of an MRD-directed treatment strategy. The NAVIGATE study will build on this evidence by examining whether molecular monitoring can help determine when additional treatment with a CDK4/6 inhibitor is needed.
The strategy reflects an evolving approach to precision oncology in which treatment decisions may be adjusted according to measurable biological indicators rather than relying exclusively on characteristics established at the time of initial diagnosis.
Signatera to Provide Longitudinal MRD Monitoring
Signatera has been selected as the MRD testing platform for AFT-70 NAVIGATE. The assay is designed to detect circulating tumor DNA (ctDNA) in blood and provide a molecular indication of residual cancer following treatment.
The selection of Signatera is supported by clinical evidence generated in ER-positive/HER2-negative early breast cancer, including experience from the AFT-05 PALLAS and MonarchE clinical trials.
For NAVIGATE, Natera will use its newer ultrasensitive Genome-based technology. According to the companies, the technology incorporates reporting of phased and structural variants and has analytical sensitivity below one part per million (ppm). The increased sensitivity is intended to support detection of very low levels of molecular disease that may not be identifiable through conventional clinical assessments.
The longitudinal nature of the testing is particularly important to the NAVIGATE strategy. A single assessment provides information at one point in time, while serial MRD testing can potentially show whether molecular evidence of disease remains absent or emerges during follow-up.
Under the investigational strategy, a patient who remains Signatera-negative would continue without CDK4/6 inhibition. If the test becomes positive, treatment would be escalated through the addition of a CDK4/6 inhibitor.
This approach could potentially allow physicians to respond to changes in a patient’s molecular disease status before a recurrence becomes clinically detectable.
Large International Phase III Study
AFT expects NAVIGATE to enroll more than 2,000 patients at approximately 200 sites in the United States and internationally. The study population will consist of patients with Stage II-III ER-positive/HER2-negative early breast cancer who are eligible for endocrine therapy.
Patients will first complete appropriate standard-of-care treatment. Following treatment, those without detectable MRD using Signatera will enter the randomized portion of the trial.
The study’s design is intended to answer an important clinical question: Can patients who remain molecularly negative safely avoid upfront CDK4/6 inhibitor treatment while maintaining comparable long-term disease control?
If the MRD-guided strategy demonstrates non-inferior distant recurrence-free survival, the findings could provide evidence for a more selective approach to adjuvant therapy. Such a strategy could potentially reduce exposure to treatment for patients whose molecular monitoring suggests a lower immediate risk of distant recurrence.
At the same time, patients who develop detectable MRD could receive treatment intensification, creating a treatment model in which therapy is adjusted according to changes in molecular risk.
Researchers Highlight Potential to Reduce Treatment Burden
Evanthia Galanis, M.D., D.Sc., president of Alliance Foundation Trials, said the collaboration combines expertise in breast cancer research, clinical care and molecular testing to address the question of how treatment can become more precise while avoiding unnecessary toxicity.
According to Galanis, using MRD technology to guide treatment decisions could have the potential to change care for eligible breast cancer patients by allowing treatment intensity to be individualized.
Komal Jhaveri, M.D., FACP, FASCO, study chair, breast medical oncologist and early drug development specialist at Memorial Sloan Kettering Cancer Center, emphasized that patients with ER-positive/HER2-negative breast cancer do not all have the same recurrence risk.
Jhaveri noted that current adjuvant treatment decisions remain substantially influenced by clinical and pathological characteristics determined at diagnosis. The NAVIGATE trial combines giredestrant with longitudinal Signatera testing to provide a dynamic assessment of recurrence risk.
The study will investigate whether MRD monitoring can identify patients who are most likely to benefit from adding a CDK4/6 inhibitor and distinguish them from patients in whom the additional therapy could potentially be omitted.
Gaorav Gupta, M.D., Ph.D., study co-chair, breast radiation oncologist and co-leader of the Breast Cancer Research Program at UNC Lineberger Comprehensive Cancer Center, also highlighted the importance of balancing treatment benefits with treatment burden.
CDK4/6 inhibitors can play an important role in the treatment of certain patients, but they can also introduce side effects, monitoring requirements and additional treatment burden. According to Gupta, highly sensitive blood-based MRD testing could potentially help identify patients who may be able to defer additional therapy without compromising cancer control.
Collaboration Across Clinical Research and Precision Medicine
The NAVIGATE study represents a collaboration between AFT, Natera and Genentech, bringing together clinical trial infrastructure, precision oncology technology and pharmaceutical development.
Minetta Liu, M.D., chief medical officer of oncology and early cancer detection at Natera, said the company has a longstanding partnership with AFT and shares its commitment to developing innovative clinical trials across cancer types.
Liu said AFT-70 NAVIGATE has the potential to enhance treatment strategies for patients with intermediate- and high-risk hormone receptor-positive breast cancer by using molecular information to inform treatment decisions.
The trial also reflects a broader movement toward incorporating measurable biomarkers into cancer treatment. Traditional risk assessment often depends on tumor characteristics, disease stage and other clinical factors available at diagnosis. MRD testing offers a complementary approach by evaluating whether molecular evidence of cancer remains after treatment.
Potential Implications for Precision Breast Cancer Care
The central concept behind NAVIGATE is not simply to provide more treatment, but to determine which patients may need additional treatment based on evidence of residual disease.
If the study successfully demonstrates that an MRD-guided strategy can achieve non-inferior four-year distant recurrence-free survival, the results could support a treatment model in which CDK4/6 inhibition is reserved for patients who demonstrate molecular evidence suggesting an increased risk of recurrence.
Such an approach could have implications for both patients and healthcare systems. Patients who remain molecularly negative could potentially avoid or delay exposure to additional therapy, while those who develop detectable MRD could receive treatment escalation at a point when molecular disease is identified.
The Phase III design and large international enrollment are intended to provide evidence capable of informing future treatment strategies for ER-positive/HER2-negative early breast cancer.
Ultimately, AFT-70 NAVIGATE will test whether combining an active endocrine therapy backbone with highly sensitive longitudinal MRD monitoring can provide a more individualized approach to adjuvant treatment. By using molecular disease status to guide the timing and intensity of CDK4/6 inhibitor therapy, the study seeks to determine whether patients can maintain strong protection against distant recurrence while reducing unnecessary treatment exposure.
For patients with intermediate- and high-risk ER-positive/HER2-negative early breast cancer, the findings could help advance a more dynamic model of care in which treatment decisions evolve alongside a patient’s molecular disease status rather than being determined solely by risk characteristics measured at diagnosis.
About Alliance Foundation Trials, LLC (AFT)
Alliance Foundation Trials, LCC, is a research organization that develops and conducts cancer clinical trials, working closely with the Alliance for Clinical Trials in Oncology scientific investigators, institutional member network, research partners, and non-NCI funding organizations.
AFT seeks to fulfill the vision of the Alliance for Clinical Trials in Oncology to reduce the impact of cancer on people by uniting a broad community of scientists and clinicians from many disciplines committed to discovering, validating, and disseminating effective strategies for the prevention and treatment of cancer. AFT’s current studies are supported by industry collaborators and the Patient Outcomes Research Institute (PCORI). To learn more, visit AllianceFoundationTrials.org.
About Natera
Natera is a global leader in cell-free DNA and precision medicine, dedicated to oncology, women’s health, and organ health. We aim to make personalized genetic testing and diagnostics part of the standard-of-care to protect health and inform earlier, more targeted interventions that help lead to longer, healthier lives. Natera’s tests are supported by more than 400 peer-reviewed publications that demonstrate excellent performance.
Natera operates ISO 13485-certified and CAP-accredited laboratories certified under the Clinical Laboratory Improvement Amendments (CLIA) in Austin, Texas, and San Carlos, California, and through Foresight Diagnostics, its subsidiary, operates an ISO 27001-certified and CAP-accredited laboratory certified under CLIA in Boulder, Colorado.