Advances in breast cancer: What’s new from ESMO 2025
ESMO 2025 showcased the breadth and urgency of breast cancer research, which remains one of the most diagnosed malignancies worldwide, and its major subtypes: HR+, HER2+ and TNBC respond differently to treatment and develop resistance through distinct mechanisms.
Although systemic therapy has improved outcomes, long-term survival remains suboptimal, and treatment-related toxicities are still problematic. Sequencing also remains uncertain. This year at ESMO 2025, several late-breaking abstracts and presidential symposia focused on closing these gaps through targeted combinations, improved tolerability, and better biomarker driven strategies.
CDK4/6 dominates in the early setting
Adjuvant use of CDK4/6 inhibitors is redefining the management of high-risk HR+ early-stage disease. In the monarchE study, adding abemaciclib to endocrine therapy significantly improved invasive disease-free and distant relapse-free survival, and dose reductions did not compromise benefit, while the NATALEE trial suggests that ribociclib may reduce recurrence risk in a broader population. Beyond approved agents, new molecules aim to address resistance: Pfizer’s atirmociclib offers CDK4 selective inhibition and its KAT6 inhibitor, PF07248144, produced a 37% response rate and a median PFS of 10.7 months; Olema’s OP3136 demonstrated preclinical synergy with CDK4/6 blockade. A wave of next-generation oral SERDs and protein degraders -camizestrant, giredestrant, imlunestrant (recently approved), palazestrant, and ARV471 - aims to achieve deeper oestrogen receptor blockade and restore endocrine sensitivity.
Hyper-fragmentation in the 2L+ HR+ market
The second line HR+ setting has splintered into targeted niches. Resistance to first-line CDK4/6 inhibition can arise from RB1 loss, CDK4 amplification, and kinase mutations, prompting exploration of alternative pathways. Several regimens are already approved for the 2L+ setting (CAPITELLO-291, OlympiaD, EMERALD, BOLERO-2, and SOLAR-1), with many more in development. For example, in the Phase 3 evERA trial, giredestrant + everolimus significantly improved PFS versus fulvestrant + everolimus. Dual PI3K/ESR1m inhibition is also promising, as shown in VIKTORIA-1 , where gedatolisib + fulvestrant ± palbociclib reduced the risk of progression by ~70% and extended median PFS to 7.4–9.3 months. In ReDiscover-2, RLY2608, a mutant-selective PI3Kα inhibitor, delivered a median PFS of 10.3 months and a 38.7% response rate with fulvestrant. Epigenetic modulators (KAT6 inhibitors) and protein degraders remain additional avenues in 2L development. Another oral SERD, giredestrant reduced the risk of disease progression or death by 44% and 62% in the intention-to-treat (ITT) and ESR1-mutated populations, respectively, as shown in evERA.
Another emerging strategy is the use of TROP2 ADCs, such as sacituzumab tirumotecan (sac-TMT), which showed a statistically significant improvement in mPFS (HR 0.35) in the China-only Phase 3 OptiTROPBreast02 trial comparing sac-TMT to chemotherapy in previously treated HR+/HER2- mBC.
New standard of care in triple negative breast cancer
Triple negative breast cancer (TNBC) has long been an area of unmet need, but immunotherapy and antibody-drug conjugates (ADCs) are changing the paradigm. Gilead’s sacituzumab govitecan remains the standard in the 2L disease, and at ESMO 2025, data from early ASCENT-03 (PD-L1-negative) and PRO data from‑ ASCENT-04 (PD-L1-positive) positioned sacituzumab govitecan as a potential 1L standard as well. Furthermore, daopotamab deruxtecan (Dato‑DXd), another TROP2-directed ADC achieved a 5-month overall survival improvement in 1L TNBC (TROPION-Breast02). Finally, bispecific antibodies like BNT327 and novel ADCs aim to deliver targeted cytotoxic payloads while engaging immune activation.
HER2-positive disease sees ADCs push forward
The HER2+ landscape continues to be reshaped by ADCs. The DESTINY-Breast09 trial showed that trastuzumab deruxtecan (T‑DXd) significantly improved progression-free survival compared with the historic THP regimen in the 1L setting with ~70% of patients remaining progression-free at two years. This leadership extends to earlier disease stages with data presented at ESMO 2025: DESTINY-Breast11demonstrated a pCR rate of 67.3% in the neoadjuvant setting and the DESTINY-Breast05 showed a 53% reduction in the risk of invasive disease recurrence or death in the adjuvant setting. Finally, for HR+/HER2+ metastatic disease, maintenance palbociclib + anti-HER2 therapy + endocrine therapy in the PATINA trial extended median PFS to 44.3 months vs 29.1 months, while patient-reported outcomes (PRO) data at ESMO 2025 reaffirm a favourable risk-benefit ratio.
What else is in store?
As the therapeutic toolbox expands, oncologists face increasing complexity in determining how and when to deploy each modality. Serial biomarker testing via tissue biopsy, liquid biopsy, or circulating tumour DNA will likely become integral to detecting resistance mutations and guiding treatment transitions.
Key questions persist: what is the optimal sequencing of CDK4/6 inhibitors, SERDs, PI3K/AKT/mTOR inhibitors, and ADCs? Can early use of CDK4-selective agents or KAT6 inhibitors delay resistance? And how can efficacy be balanced with cost and quality of life?
Investigators are exploring whether next-generation SERDs and complete oestrogen receptor antagonists could eventually replace aromatase inhibitors or tamoxifen in the adjuvant setting, though this will be challenging, given the long-term safety, efficacy, and affordability of existing endocrine therapies.
New agents, such as mutant-selective PI3K inhibitors, are designed to reduce adverse events like hyperglycaemia; however, high drug costs may limit real-world adoption unless substantial survival benefits are demonstrated. Ensuring equitable access to these complex regimens across healthcare systems remains essential.
ESMO 2025 highlighted both extraordinary progress and the continued need for innovation to further improve outcomes across all breast cancer subtypes.
About the authors
Hymlaire Lamisere, PhD, is a senior business analyst at Lifescience Dynamics with a Doctorate in Immunology and over three years of consulting experience in the biopharmaceutical industry. He has supported clients across oncology, cardiometabolic, and rare diseases, with expertise in competitive intelligence, market research, and strategic advisory. His work spans pipeline strategy, conference intelligence, and cross-functional insight generation to inform commercialisation and medical strategy
Will Torres is a consultant at Lifescience Dynamics. He has over six years of life sciences consulting experience, working across a broad range of therapy areas, including oncology, rare disease, and infectious disease. Torres has managed projects across a broad range of practice areas such as competitive intelligence, market research, and strategic advisory.
Kasia Koczula is an engagement manager at Lifescience Dynamics, bringing over eight years of consulting experience in the life sciences sector. She holds a PhD in Haematological Oncology and has worked across a broad range of therapy areas, including oncology, cardiovascular diseases, and rare diseases. Koczula specialises in competitive intelligence, market research, and strategic advisory services, supporting clients with evidence-based insights to drive informed decision-making.
