HR+ Metastatic Breast Cancer Updates from SABCS 2025
February 6, 2026
Key Points
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Data updates from the AMBRE and MONALEESA trials further cement CDK4/6 inhibitors as the preferred frontline therapy for hormone receptor (HR)–positive metastatic breast cancer
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The VIKTORIA-1, SERENA-6, evERA, and EMBER-3 trials showed that various second-line therapies improved outcomes versus standard of care regimens for patients with HR–positive, HER2–negative advanced breast cancer.
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Sacituzumab govitecan did not show significant progression-free survival (PFS) improvement compared with chemotherapy, although data are still maturing.
SABCS 2025 Data for HR+ Metastatic Breast Cancer
Cohosts of the Oncology Brothers podcast, Rahul Gosain, MD, MBA, of Wilmot Cancer Institute, and Rohit Gosain, MD, of Roswell Park Comprehensive Cancer Center, joined with breast medical oncologist Hope Rugo, MD, FASCO, of City of Hope Comprehensive Cancer Center, to highlight key presentations in HR–positive metastatic breast cancer from the 2025 San Antonio Breast Cancer Symposium (SABCS 2025).
The discussion reviewed seven studies related to three broad categories: frontline CDK4/6 inhibitors from the AMBRE and MONALEESA-3 trials; second-line treatment options from the VIKTORIA-1, SERENA-6, evERA, and EMBER-3 trials; and the feasibility of antibody-drug conjugates from the ASCENT-07 trial.
CDK4/6 Inhibitors Versus Chemotherapy in AMBRE
Abemaciclib plus endocrine therapy improved median PFS compared with chemotherapy alone (13.9 months vs 7 months; hazard ratio [HR], 0.67; 95% CI, 0.46-0.98; P = .035) in frontline treatment for HR–positive, HER2–negative advanced breast cancer with high visceral tumor burden and high circulating tumor cell count. In addition, there was no significant difference in objective response rate, quality of life, PFS2, or overall survival (OS) with abemaciclib versus chemotherapy. These data support CDK4/6 inhibitor plus endocrine therapy as the strongest frontline treatment, even for patients with high tumor burden, said Dr. Rugo.
MONALEESA-3 Subgroup Analysis at SABCS 2025
In a subanalysis of the MONALEESA-3 trial, the addition of ribociclib to fulvestrant improved median PFS (20.5 months vs 9.5 months; HR, 0.56; 95% CI, 0.37-0.86) and median OS (51.2 months vs 30.8 months; HR, 0.62; 95% CI, 0.39-0.98) for patients with invasive lobular carcinoma subtype of HR–positive, HER2–negative advanced breast cancer. Median PFS and OS were even longer in patients receiving ribociclib plus fulvestrant as frontline therapy.
The doctors briefly discussed selection among CDK4/6 inhibitors. Dr. Rugo said that most patients would start with ribociclib, while palbociclib may be appropriate for patients who are older or have cardiac comorbidities. The diarrhea associated with abemaciclib remains a potentially limiting toxicity, although abemaciclib may be effective for patients who experience unmanageable liver toxicity or cytopenias with ribociclib, Dr. Rugo said.
Gedatolisib for HR+, HER-, PIK3CA–Unmutated Advanced Breast Cancer
The VIKTORIA-1 trial evaluated gedatolisib with palbociclib and fulvestrant, gedatolisib with fulvestrant, and fulvestrant alone in second-line treatment of HR–positive, HER2–negative, PIK3CA–wild type advanced breast cancer. Compared with fulvestrant alone, both the gedatolisib triplet (9.3 months vs 2 months; HR, 0.24; 95% CI, 0.17-0.35; P < .0001) and doublet (7.4 months vs 2 months; HR, 0.33; 95% CI, 0.24-0.48; P < .0001) improved median PFS.
SERENA-6: Switching Endocrine Therapy to Camizestrant
In an earlier interim analysis, the SERENA-6 trial found switching from aromatase inhibitor to camizestrant while continuing CDK4/6 inhibitor significantly improved PFS for patients who had emergent ESR1 mutations during frontline therapy for HR–positive, HER2–negative advanced breast cancer. The SABCS 2025 presentation included updated PFS data and an exploratory analysis of ESR1 mutation allele frequency in circulating tumor DNA.
After 18.7 months of follow-up, the median PFS was 16.6 months (95% CI, 14.7-19.4) with camizestrant versus 9.2 months (95% CI, 7.2-9.7) with control (HR, 0.46; 95% CI, 0.34-0.62; P < .00001). At cycle 3 day 1, camizestrant “profoundly reduced” median ESR1 variant allele frequency (median change from baseline, -100% [interquartile range (IQR), -100 to -100]), while the control did not (median change from baseline, +66.7% [IQR, -67.9 to 465.0]). ESR1 mutation allele frequency increased by 500% or more from baseline in 0.8% of camizetrant arm patients versus 24.4% of control arm patients, according to the SERENA-6 presentation.
Oral SERDs Outperform Standard Endocrine Therapy in evERA
In the phase 3 evERA trial, the oral selective estrogen receptor degrader (SERD) giredestrant with everolimus improved PFS versus standard endocrine therapy plus everolimus in estrogen receptor (ER)–positive, HER2–negative advanced breast cancer previously treated with a CDK4/6 inhibitor. The SABCS 2025 presentation covered prespecific exploratory subgroup analysis, and reported giredestrant improved PFS regardless of PIK3CA mutation, PIK3CA/AKT1/PTEN alteration, or ESR1 mutation. In evERA, giredestrant consistently offered a benefit regardless of duration of prior CDK4/6 inhibitor therapy.
Imlunestrant Treatment Outcomes in EMBER-3
The primary analysis of the phase 3 EMBER-3 trial on ER–positive, HER2–negative advanced breast cancer previously reported that imlunestrant significantly improved PFS versus standard of care for ESR1–mutated patients, and imlunestrant plus abemaciclib significantly improved PFS versus imlunestrant for all patients. An interim OS analysis was presented at SABCS 2025. After a median follow-up of 28.5 months, imlunestrant showed a clinically meaningful although not significant improvement in OS versus standard therapy in ESR1–mutated patients, and imlunestrant plus abemaciclib showed a favorable OS trend versus imlunestrant for all patients, regardless of ESR1 status, according to the presentation.
In the event that multiple second-line therapies are approved based on the VIKTORIA-1, SERENA-6, evERA, and EMBER-3 trials, treatment choice will likely be individualized for each patient’s preferences and tolerability, Dr. Rugo said.
ASCENT-07 Does Not Show Benefit With Sacituzumab Govitecan
The phase 3 ASCENT-07 trial evaluated sacituzumab govitecan versus chemotherapy in patients with HR–positive, HER2–negative locally advanced unresectable or metastatic breast cancer previously treated with endocrine therapy. The study randomized 456 patients to sacituzumab govitecan and 234 to chemotherapy. In total, 93% of the sacituzumab govitecan group and 92% of the chemotherapy group had previously received a CDK4/6 inhibitor.
After a median follow-up of 15.4 months, sacituzumab govitecan did not significantly improve PFS compared with physician’s choice of chemotherapy (HR, 0.85; 95% CI, 0.69-1.05; P = .13) per blinded independent central review, according to the SABCS 2025 presentation. The authors stated sacituzumab govitecan showed an early trend for improved OS, and the study would continue to assess OS.