2025 FDA Approvals Highlight the Growing Role of Biomarkers in Breast Cancer

Breast cancer remains the most commonly diagnosed cancer among women worldwide, but it is not a single disease. Distinct molecular subtypes—defined by hormone receptor (HR) status, HER2 expression, and emerging genomic alterations such as ESR1 mutations—drive differences in prognosis, treatment selection, and resistance patterns. As precision oncology continues to refine how these subgroups are defined, targeted therapies are increasingly reshaping the treatment landscape across both early and metastatic disease.

At the 2025 San Antonio Breast Cancer Symposium, experts highlighted three recent FDA approvals that reflect this shift toward more biologically tailored care: datopotamab deruxtecan-dlnk (Dato-DXd, Datroway; AstraZeneca, Daiichi Sankyo), trastuzumab deruxtecan (Enhertu; AstraZeneca, Daiichi Sankyo), and imlunestrant (Inluriyo; Eli Lilly & Co). Together, these agents expand options for patients with HR-positive (HR+)/HER2–negative (HER2–) disease, HER2-low and HER2-ultralow tumors, and ESR1-mutated metastatic breast cancer.

Dato-DXd Improves Survival, Response in HR+/HER2– Breast Cancer

Dato-DXd is a TROP2-directed antibody–drug conjugate (ADC) composed of a humanized IgG1 monoclonal antibody linked to a topoisomerase I inhibitor payload via a cleavable tetrapeptide linker. It was approved by the FDA in January 2025 for adult patients with unresectable or metastatic HR+/HER2– (IHC 0, IHC1+ or IHC2+/ISH-) breast cancer who have received prior endocrine-based therapy and chemotherapy.^1,2

TROPION-Breast01 (NCT05104866; TB-01) was an open-label, randomized phase 3 study that enrolled 732 patients with inoperable or metastatic HR+/HER2– breast cancer who had received 1 or 2 prior lines of systemic therapy. Patients were randomized to receive Dato-DXd (n = 365) or investigator’s choice of single-agent chemotherapy (n = 367), including eribulin, capecitabine, vinorelbine, or gemcitabine. Randomization was stratified by prior chemotherapy exposure, prior CDK4/6 inhibitor use, and geographic region.^1-3

The primary end points were PFS and overall survival (OS), with secondary end points including objective response rate (ORR), duration of response (DOR), and disease control rate.^1,2

Dato-DXd significantly improved median PFS compared with chemotherapy (6.9 months [95% CI, 5.7–7.4] vs 4.9 months [95% CI, 4.2–5.5]; HR, 0.63 [95% CI, 0.52–0.76]; P < .0001). Although OS numerically favored Dato-DXd (18.6 months vs 18.3 months), the difference was not statistically significant at the time of analysis (HR, 1.01 [95% CI, 0.83–1.22]).^1,2

"TB‑01 met its PFS primary end point, demonstrating a statistically significant improvement… with a hazard ratio of 0.63, or a 37% reduction in risk of disease progression or death,” said Melanie Royce, MD, PhD, medical oncologist and a clinical reviewer for the FDA.¹

Confirmed ORRs were 36% (95% CI, 31–42) in the Dato-DXd arm and 23% (95% CI, 19–28) in the chemotherapy arm. Median DOR was 6.7 months (95% CI, 5.6–9.8) with Dato-DXd compared with 5.7 months (95% CI, 4.9–6.8) with chemotherapy.^1,2

The safety profile of Dato-DXd was consistent with prior analyses. The most common adverse events included stomatitis, nausea, fatigue, alopecia, constipation, dry eye, vomiting, keratitis, and laboratory abnormalities such as decreased leukocytes, lymphocytes, hemoglobin, neutrophils, and elevated liver enzymes. Grade 3 or higher treatment-related adverse events occurred in approximately 21% of patients treated with Dato-DXd versus 45% of those receiving chemotherapy. The most frequently reported grade 3 or greater events included stomatitis, fatigue, anemia, and neutropenia.^1,2

T-DXd is Safe, Efficacious for HER2-Low, Ultralow Breast Cancer

The FDA approved T-DXd for the treatment of adults with unresectable or metastatic HR+, HER2-low or HER2-ultralow breast cancer following progression on 1 or more endocrine therapies. It is composed of a HER2-targeted monoclonal antibody linked to a topoisomerase I inhibitor payload, enabling potent antitumor activity even in tumors with low or ultralow HER2 expression.^1,4

“T‑DXD represents the first approval of a HER2‑targeted therapy for patients with HER2 ultra‑low breast cancer,” said Royce.¹

The decision was supported by results from the phase 3 DESTINY-Breast06 trial (NCT04494425), which evaluated trastuzumab deruxtecan versus investigator’s choice of chemotherapy in chemotherapy-naïve patients with HR+/HER2-low or HER2-ultralow metastatic breast cancer. Trastuzumab deruxtecan reduced the risk of disease progression or death by 36% compared with chemotherapy (HR, 0.64; 95% CI, 0.54–0.76; P < .0001).^1,4,5

At the primary analysis, patients treated with trastuzumab deruxtecan achieved a median PFS of 13.2 months, compared with 8.1 months for those receiving chemotherapy. The confirmed ORR was 62.6% in the trastuzumab deruxtecan arm versus 34.4% in the chemotherapy arm. Exploratory analyses showed consistent efficacy across patients with HER2-low and HER2-ultralow expression.^1,4

“Endocrine therapy is typically used in the initial treatment of HR-positive metastatic breast cancer, and following progression, subsequent chemotherapy is associated with poor outcomes,” said Aditya Bardia, MD, MPH, an investigator in the DESTINY-Breast06 trial. “With a median PFS exceeding one year and a response rate of more than 60%, trastuzumab deruxtecan offers a potential new standard of care following endocrine therapy.”¹

Regarding safety, grade 3 or higher adverse events occurred in 52.8% of patients treated with trastuzumab deruxtecan and 44.4% of those receiving chemotherapy. Serious adverse events of adjudicated interstitial lung disease or pneumonitis were reported in 49 patients. Investigators noted that the safety profile was consistent with prior studies, with no new safety signals identified.^1,4

Imlunestrant Targets ESR1 In ER+/HER2– Metastatic Breast Cancer

The FDA approved imlunestrant (Inluriyo; Eli Lilly & Co) for the treatment of adults with estrogen receptor–positive (ER+), HER2–, ESR1-mutated advanced or metastatic breast cancer whose disease has progressed following at least 1 line of endocrine therapy.^1,6

Imlunestrant is an oral estrogen receptor antagonist designed to provide continuous ER inhibition, including in tumors harboring ESR1 mutations, a common mechanism of endocrine resistance. The agent is administered once daily and is also being evaluated in combination with abemaciclib (Verzenio; Eli Lilly & Co) for advanced disease and as adjuvant therapy in early-stage breast cancer.^1,6

EMBER-3 (NCT04975308) was a randomized, open-label phase 3 trial that enrolled 874 patients with ER+/HER2– locally advanced or metastatic breast cancer whose disease had recurred or progressed following aromatase inhibitor therapy, with or without prior CDK4/6 inhibition. Patients were randomized to imlunestrant monotherapy (n = 331), imlunestrant plus abemaciclib (n = 213), or standard endocrine therapy (n = 330). Among the study population, 256 patients had tumors with ESR1 mutations.^1,6,7

The primary end point was investigator-assessed PFS, with secondary end points including response outcomes, overall survival, and safety.^1,6

Among patients with ESR1-mutated disease, median PFS was 5.5 months with imlunestrant compared with 3.8 months with standard endocrine therapy. The restricted mean survival time at 19.4 months was significantly longer with imlunestrant (7.9 months vs 5.4 months; difference, 2.6 months; P < .001).^1,6 In the overall population, median PFS was similar between imlunestrant and endocrine therapy (5.6 vs 5.5 months; HR, 0.87; P = .12). However, in a separate comparison, imlunestrant plus abemaciclib significantly improved median PFS versus imlunestrant alone (9.4 vs 5.5 months; HR, 0.57; P < .001).^1,6

The safety profile of imlunestrant was generally favorable. Grade 3 or higher adverse events occurred in 17.1% of patients receiving imlunestrant, 20.7% of those receiving endocrine therapy, and 48.6% of patients treated with imlunestrant plus abemaciclib. Most adverse events with imlunestrant were low grade, and treatment discontinuation due to adverse events was infrequent.^1,6

This approval introduces a new oral treatment option for patients with ESR1-mutated metastatic breast cancer, a population with limited therapeutic choices and high rates of endocrine resistance and further expands the evolving endocrine-based treatment landscape.^1,6

"Ultimately, the benefit‑risk assessment of our review of immunestrant was favorable… there is now an additional therapeutic option for patients with ESR1 mutations in this disease space that may aid in more patient‑centered treatment selections."¹

By extending targeted approaches to patients with HER2-low and HER2-ultralow disease and addressing endocrine resistance driven by ESR1 mutations, these therapies move the field closer to more personalized and durable disease control. As pharmacists integrate these agents into practice, ongoing research will help clarify optimal sequencing, combination strategies, and long-term outcomes across nuanced patient populations.

REFERENCES

1. Amiri-Kordestani L, DeMichele A, Royce M, et al. FDA session: HR+ Metastatic Breast Cancer in 2025: Progress, Regulatory Approvals, and the Trials Ahead. Presented at: SABCS 2025. December 9-12, 2025. San Antonio, TX

2. McGovern G. FDA approves Dato-DXd for adults with unresectable or metastatic HR+, HER2- breast cancer. Pharmacy Times. January 17, 2025. Accessed December 13, 2025. https://www.pharmacytimes.com/view/fda-approves-dato-dxd-for-adults-with-unresectable-or-metastatic-hr-her2--breast-cancer

3. A phase-3, open-label, randomized study of Dato-DXd versus investigator's choice of chemotherapy (ICC) in participants with inoperable or metastatic HR-positive, HER2-negative breast cancer who have been treated with one or two prior lines of systemic chemotherapy (TROPION-Breast01). Clinicaltrials.gov. Updated April 14, 2025. Accessed December 13, 2025. https://clinicaltrials.gov/study/NCT05104866

4. Halpern L. FDA grants trastuzumab deruxtecan approval for endocrine-treated patients with metastatic HR+, HER2-low breast cancer. Pharmacy Times. January 28, 2025. Accessed December 13, 2025. https://www.pharmacytimes.com/view/fda-grants-trastuzumab-deruxtecan-approval-for-endocrine-treated-patients-with-metastatic-hr-her2-low-breast-cancer

5. Study of trastuzumab deruxtecan (T-DXd) vs investigator's choice chemotherapy in HER2-low, hormone receptor positive, metastatic breast cancer (DB-06). Clinicaltrials.gov. June 18, 2025. Accessed December 13, 2025. https://clinicaltrials.gov/study/NCT04494425

6. McGovern G. FDA approves imlunestrant tablets for ER+, HER2–, ESR1-mutated advanced or metastatic breast cancer. Pharmacy Times. September 25, 2025. Accessed December 13, 2025. https://www.pharmacytimes.com/view/fda-approves-imlunestrant-tablets-for-er-her2-esr1-mutated-advanced-or-metastatic-breast-cancer

7. A study of imlunestrant, investigator's choice of endocrine therapy, and imlunestrant plus abemaciclib in participants with ER+, HER2- advanced breast cancer (EMBER-3). Clinicaltrials.gov. Updated July 11, 2025. Accessed December 13, 2025. https://clinicaltrials.gov/study/NCT04975308