Breast cancer continues to pose a significant threat to women's health worldwide. Although patients today have a broad spectrum of treatment options—including surgery, radiotherapy, chemotherapy, endocrine therapy, and targeted therapies— clinical management still faces obstacles such as drug resistance, side effects, and the lack of effective therapies for certain subtypes like triple-negative breast cancer (TNBC). As a result, researchers are intensifying their efforts to develop more effective therapeutic strategies.
Hundreds of investigational therapies, ranging from small molecules and antibodies to antibody-drug conjugates (ADCs), nucleic acid-based drugs and peptides are currently under clinical development to address these challenges.
FDA Approvals in 2025: Breakthroughs in ADC Therapy
Datroway: A New Trop-2 ADC for HR+/HER2- Breast Cancer
In January 2025, the U.S. FDA approved Datroway (datopotamab deruxtecan), a Trop-2 directed ADC developed by AstraZeneca and Daiichi Sankyo, for adult patients with unresectable or metastatic hormone receptor-positive (HR+), HER2-negative breast cancer. This decision was based on a Phase III trial showing that Datroway significantly reduced the risk of disease progression or death by 37% compared to the investigator's choice of chemotherapy. Median progression-free survival (PFS) was 6.9 months in patients treated with Datroway versus 4.9 months with chemotherapy. [1]
Enhertu: Expanding Treatment for HER2-Low and Ultra-Low Breast Cancer
Also approved in January, Enhertu (trastuzumab deruxtecan) was approved by the FDA for the treatment of unresectable or metastatic HR+, HER2-low (IHC 1+ or IHC 2+/ISH-) or HER2 ultra-low (IHC 0) breast cancer. The approval was based on results from the DESTINY-Breast06 Phase III trial, in which Enhertu showed a 36% reduction in the risk of disease progression or death versus chemotherapy. A median PFS was 13.2 months with Enhertu versus 8.1 months with chemotherapy, and the confirmed objective response rate (ORR) was 62.6% versus 34.4%, respectively. [2]
Clinical Progress: ADC Therapies for TNBC
ASCENT-04: Trodelvy Plus Keytruda Shows Promise as First-Line Treatment for PD-L1–Positive TNBC
At the 2025 ASCO Annual Congress, Gilead presented the data from the pivotal Phase 3 ASCENT-04 study. Trodelvy® (sacituzumab govitecan-hziy) plus Keytruda® (pembrolizumab) reduced the risk of disease progression or death by 35% (HR: 0.65) versus standard of care Keytruda plus chemotherapy in first-line treatment for patients with PD-L1+ metastatic triple-negative breast cancer (TNBC). The combination showed a median PFS of 11.2 months versus 7.8 months in the control group. [3]
Figure 1. ASCENT-04 results [3]
OptiTROP-Breast05: Sacituzumab tirumotecan (sac-TMT) as first-line treatment for a/mTNBC
At the 2025 ASCO Annual Congress, results from the Phase II OptiTROP-Breast05 study were presented. This study enrolled 41 patients with previously untreated a/mTNBC, regardless of PD-L1 or TROP2 expression status. In the overall population, the ORR was 70.7% (29/41, 3 unconfirmed PR) and the disease control rate (DCR) was 92.7%. Median duration of response (mDoR) was 12.2 mo, while the mPFS was 13.4 mo, and the 12-mo PFS rate was 64.6%. Among patients with PD-L1 CPS <10, ORR reached 71.9%, DCR 93.8%, and median PFS was 13.1 mo with a 12-mo PFS rate of 59.1%. [4]
Figure 2. OptiTROP-Breast05 results [4]
PROTAC-Based Protein Degradation Therapies
Vepdegestrant: A First-in-Class PROTAC on the Horizon
In June, Arvinas and Pfizer submitted a New Drug Application (NDA) for vepdegestrant, a PROTAC estrogen receptor degrader, for ER+/HER2- advanced or metastatic breast cancer patients with ESR1 mutations. The drug has received Breakthrough Therapy Designation and, if approved, will become the first FDA-approved PROTAC degrader in breast cancer.
Camizestrant (AstraZeneca)
AstraZeneca's SERENA-6 Phase III trial found that camizestrant, an oral SERD, combined with CDK4/6 inhibitors significantly extended PFS (16.0 vs 9.2 months) in HR+/HER2- breast cancer patients with emerging ESR1 mutations detected via ctDNA. [5]
Giredestrant (Roche)
Early-phase trial results of giredestrant in combination with immunotherapy and CDK4/6 inhibitors showed promising efficacy in ER+/HER2- advanced breast cancer, especially in patients with ESR1 mutations.
BMS-986449 (Bristol Myers Squibb)
A CELMoD-based molecular glue degrader targeting transcription factors Helios and Eos in regulatory T cells, BMS-986449 has completed patient enrollment in a Phase 1/2 trial for TNBC. It aims to enhance anti-tumor immunity by reprogramming Tregs.
Bispecific Antibody Therapies
In May 2025, The Lancet Oncology published clinical data on zanidatamab (developed by BeOne Medicines and Zymeworks), a HER2-targeted bispecific antibody. When combined with palbociclib and fulvestrant, it achieved a disease control rate of 91.3% in previously treated HR+/HER2+ metastatic breast cancer, showing favorable safety and efficacy.
Cancer Vaccines
Bria-IMT Demonstrates Promise BriaCell Therapeutics’ Bria-IMT cancer vaccine, an allogeneic whole-cell immunotherapy, showed improved overall survival compared to ADCs in HR+ metastatic breast cancer and approximately 70% higher survival versus chemotherapy in TNBC. These results suggest Bria-IMT may be a powerful complement to checkpoint inhibitors.
Conclusion
The first half of 2025 has been a landmark period in the fight against breast cancer, with major therapeutic advances in ADCs, PROTACs, bispecific antibodies, and cancer vaccines. These developments are reshaping the treatment landscape and offering new hope for patients across multiple breast cancer subtypes.
References:
[1] https://www.astrazeneca.com/media-centre/press-releases/2025/dato-dxd-approved-in-us-for-hr-p-breast-cancer.html Datroway (datopotamab deruxtecan) approved in the US for patients with previously treated metastatic HR-positive, HER2-negative breast cancer
[2] https://www.astrazeneca.com/media-centre/press-releases/2025/enhertu-approved-in-us-for-breast-cancer-post-et.html Enhertu approved in the US as first HER2-directed therapy for patients with HER2-low or HER2-ultralow metastatic breast cancer following disease progression after one or more endocrine therapies
[3] https://www.gilead.com/news/news-details/2025/trodelvy-plus-keytruda-reduces-risk-of-disease-progression-or-death-by-35-versus-keytruda-and-chemotherapy-in-first-line-pd-l1-metastatic-triple-negative-breast-cancer Trodelvy® Plus Keytruda® Reduces Risk of Disease Progression or Death by 35% Versus Keytruda and Chemotherapy in First-Line PD-L1+ Metastatic Triple-Negative Breast Cancer
[4] https://ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.1019 Sacituzumab tirumotecan (sac-TMT) as first-line treatment for unresectable locally advanced/metastatic triple-negative breast cancer (a/mTNBC): Initial results from the phase II OptiTROP-Breast05 study.
[5] https://www.nejm.org/doi/abs/10.1056/NEJMoa2502929 First-Line Camizestrant for Emerging ESR1-Mutated Advanced Breast Cancer