FDA Grants Breakthrough Designation to Zovegalisib for Breast Cancer

The U.S. Food and Drug Administration (FDA) has granted breakthrough therapy designation to zovegalisib in combination with Faslodex (fulvestrant) for some patients with advanced breast cancer.

Relay Therapeutics, Inc. announced the designation in a news release for the treatment of adult patients with PIK3CA mutant, hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) locally advanced or metastatic breast cancer. This designation applies to patients whose cancer has returned or progressed following treatment with a CDK4/6 inhibitor.

The FDA provides this status to accelerate the development and review of medicines intended for serious conditions when early clinical evidence suggests a potential for substantial improvement over available therapies.

Main data that support the findings

Approximately 40% of patients with HR+/HER2- advanced breast cancer harbor PIK3CA mutations. These activating mutations drive tumor growth and are associated with poorer outcomes compared to patients who do not have them. While CDK4/6 inhibitors are part of the standard of care, most patients eventually experience disease progression, leaving them with limited therapeutic options.

The breakthrough therapy designation was supported by clinical data from the phase 1/2 ReDiscover trial. The application included data across all types of PIK3CA mutations, including kinase and non-kinase varieties. Specifically, the FDA reviewed data from two dosing groups with comparable exposures: 600 milligrams (mg) twice daily taken while fasting (52 patients) and 400 mg twice daily taken with food (57 patients). The 400 mg dose is currently being used in an ongoing phase 3 trial.

Clinical evidence from the 600 mg fasting group was presented at the American Society of Clinical Oncology 2025 Annual Meeting and the 2025 San Antonio Breast Cancer Symposium. Data for the 400 mg fed dose is scheduled to be presented for the first time at the ESMO Targeted Anticancer Congress 2026 on March 16.

Trial details

The phase 1/2 ReDiscover trial was designed to evaluate the safety, tolerability and preliminary antitumor activity of zovegalisib when used with Faslodex or in combination with both Faslodex and CDK inhibitors. Zovegalisib is an investigational allosteric, pan-mutant and isoform-selective PI3Kα inhibitor. It was discovered using the Dynamo platform, which integrated computational and experimental approaches to target proteins that were previously difficult to address.

To design the medicine, researchers solved the full-length cryo-EM structure of PI3Kα and used molecular dynamic simulations to identify differences between healthy and mutant versions of the protein. The goal was to create a medicine that overcomes the limitations of older inhibitors, which often affected healthy cells and led to dose reductions. Zovegalisib is now being evaluated in the phase 3 ReDiscover-2 trial for patients with metastatic breast cancer and in a first-in-human study for patients with vascular anomalies driven by the same mutation.

Safety

The development of zovegalisib focused on improving the therapeutic index by creating a mutant-selective inhibitor. Traditional inhibitors often lacked selectivity between mutant and healthy (wild-type) PI3Kα. This lack of precision resulted in toxicity that frequently led to sub-optimal inhibition of the target or caused patients to stop treatment entirely.

The ReDiscover trial evaluated the safety and tolerability of zovegalisib to address these historical challenges. By selecting for the mutant version of the protein, the medicine is designed to reduce off-target effects. The breakthrough therapy designation allows for increased engagement with senior FDA leadership and enhanced guidance on development to ensure the safety and efficacy of the program are monitored closely as it advances through the phase 3 ReDiscover-2 trial.

References

1. “Relay Therapeutics Announces Zovegalisib Granted Breakthrough Therapy Designation by U.S. FDA for PIK3CA-mutant, HR+/HER2- Advanced Breast Cancer,” News release; Feb 3, 2026.

Editor's note: This article is for informational purposes only and is not a substitute for professional medical advice, as your own experience will be unique. Use this article to guide discussions with your oncologist. Content was generated with AI and reviewed by a human editor.

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