During a special session on Thursday, December 11, the 2025 San Antonio Breast Cancer Symposium® gave attendees a behind-the-scenes look at regulatory considerations for three drugs approved by the U.S. Food and Drug Administration (FDA) in the hormone receptor (HR)-positive metastatic disease setting in 2025 — imlunestrant, datopotamab deruxtecan (Dato-DXd), and trastuzumab deruxtecan (T-DXd). The session also highlighted challenges around designing relevant clinical trials in the context of a rapidly evolving treatment landscape.

FDA session: HR-positive Metastatic Breast Cancer in 2025: Progress, Regulatory Approvals, and the Trials Ahead will be available to registered SABCS® 2025 participants through March 31, 2026, as an on-demand recording on the symposium’s virtual platform.

Laleh Amiri-Kordestani, MD, Director of Division of Oncology 1 in the Center for Drug Evaluation and Research (CDER) Office of Oncologic Diseases at the FDA, and Angela DeMichele, MD, MSCE, Professor of Medicine at the University of Pennsylvania, served as co-moderators for the session.

Session panelists included: Christy Osgood, MD, a pediatric oncologist and the Supervisory Associate Director for the Division of Oncology 1 at the FDA; Mirat Shah, MD, MHS, a medical oncologist in the Office of Oncologic Diseases at the FDA; and Stephanie Walker, RN, BSN, a registered nurse and patient advocate.

Dato-DXd and T-DXd approvals

Melanie Royce, MD, PhD, a medical oncologist and medical reviewer for the Division of Oncology 1 at the FDA, reviewed data for two antibody-drug conjugates (ADCs) approved for HR-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancers.

“HR-positive, HER2-negative breast cancer is common and a predominant subtype of breast cancer,” Dr. Royce said, “In the current landscape, it includes tumors classified as HR-positive, with [either] HER2-low, HER2-ultralow, or HER2 IHC 0 [status].”

Dato-DXd, a TROP2-directed ADC, was approved for treating patients with HR-positive, HER2-negative (including HER2-low/-ultralow), unresectable or metastatic breast cancer after prior systemic therapy. This approval was based on results from the TROPION-Breast-01 trial, in which patients treated with Dato-DXd had a 37% lower risk of disease progression or death than those treated with chemotherapy. At final analysis, overall survival (OS) was not statistically significant between groups. “However, there was no clear signal for OS detriment,” said Dr. Royce.

T-DXd, a HER2-directed ADC, was approved for treating patients with HR-positive, HER2-low/-ultralow, unresectable or metastatic breast cancer that has progressed on one or more endocrine therapies in the metastatic setting. This approval was based on results from the DESTINY-Breast06 trial. In this trial, patients receiving T-DXd were 36% less likely to experience disease progression or death during follow-up. Progression-free survival (PFS) benefits were observed for both HER2-low and HER2-ultralow subgroups in exploratory analyses.

In reviewing the regulatory decisions, Dr. Royce pointed out several factors that informed these ADC approvals:

• A modest PFS benefit without OS benefit can support approval, particularly if consistent PFS results are observed in key subgroups.
• A lack of clear OS benefit in the final analysis does not preclude approval as long as there is no clear signal for potential OS detriment.
• It is essential that the experimental arm does not introduce unacceptable toxicity.

Imlunestrant approval

Maria Garcia-Jimenez, MD, MHS, a medical oncologist and clinical reviewer for the Division of Oncology 1 at the FDA, discussed the approval of imlunestrant monotherapy in patients with estrogen receptor (ER)-positive, HER2-negative, advanced or metastatic breast cancer harboring ESR1 gene mutations, with disease progression after at least one prior line of endocrine therapy. The approval was based on results from the EMBER-3 clinical trial.

Although ESR1 mutation status was not a stratification factor for the trial, the PFS benefit of imlunestrant specific to the subpopulation with ESR1-mutated breast cancer informed the approval. In this population, patients treated with imlunestrant were 38% less likely to have experienced disease progression or death during follow-up than those in the control arm. OS results were not mature at the time of FDA approval.

Key regulatory considerations included the robust prespecified sensitivity analyses and efficacy findings for the key secondary endpoints, supportive biologic rationale, consistent findings from other trials of imlunestrant, and the lack of a signal for potential OS detriment.

Fulvestrant was considered an appropriate control arm at the time of trial design. “However, there is emerging evidence that fulvestrant may underperform in patients who received prior CDK4/6 inhibitor therapy,” Dr. Garcia-Jimenez said, alluding to data from a poster (PS1-10-13) presented during SABCS 2025.

Designing clinical trials in HR-positive metastatic cancer

Dr. DeMichele reviewed challenges in trial design in the context of the rapidly changing therapeutic landscape for HR-positive metastatic cancer.

A challenge of the evolving landscape is that newly approved therapies may render eligibility criteria and control/comparator arms in some trials irrelevant, she explained.

Increasingly, data showing OS benefit is not a prerequisite for regulatory approval, and Dr. DeMichele argued that outcomes should reflect practical benefits – this might mean approval of a new treatment that offers less toxicity and longer PFS but no OS benefit. However, the question remains of whether OS data are required to assess safety of the treatment.

Another challenge is that clinical trials often bring up additional questions that might influence how the treatment is applied in the clinic. To resolve practice-related questions raised in pivotal phase III/registrational trials, additional studies, such as investigator-initiated trials and real-world analyses, are needed. In her discussion of practice-related issues raised by new approvals, Dr. DeMichele highlighted the challenge of reliably assessing HER2-ultralow status. She asked, “Is HER2-ultralow really a solid biomarker in clinical practice for T-DXd?”

In this context, she mentioned the ongoing QuantifyHER trial, which integrates a quantitative immunofluorescence-based assay for measuring ultralow levels of HER2 in metastatic breast cancers.

Dr. DeMichele also pointed out that data regarding the efficacy of Dato-DXd in patients previously exposed to sacituzumab govitecan, and vice versa, are needed to help optimize ADC sequencing.

Patient perspectives and discussion themes

Walker shared her personal breast cancer journey and noted, “I am a big proponent, like many here who are living with metastatic breast cancer, of treatments that are very effective, with less toxicities, to improve our quality of life.”

The robust discussion and Q&A following the presentations underscored some recurring themes, such as the potential for using surrogate endpoints, mainly PFS2 (which measures time to second progression), the significance of patient-centered outcomes, and weighing safety profiles of new drugs against modest/limited efficacy improvements.

Dr. Shah prefaced her discussion on challenges with PFS2 use as a regulatory endpoint, stating, “It is of great interest to all of us, including the FDA, to understand whether the benefit of a therapy could extend beyond that line of treatment and into the next line and beyond.” She noted, however, that this endpoint poses challenges from the regulatory perspective, including its inability to provide data that is specific to the experimental drug.

Dr. Osgood clarified regulatory perspectives on safety outcomes, stating, “It’s very difficult to design a trial where we actually do a comparative safety [analysis] … so I think that it’s hard to talk about a statistically significant or a substantially different safety profile.” That being said, she emphasized that regulatory decisions do consider differences in safety profiles even if the efficacy differences are modest. Further, as noted by Dr. Amiri-Kordestani, “Patient-reported outcomes can help inform approvals and are included in drug labels.”