ESMO 2025: Updates in the HR+ Metastatic Breast Cancer Landscape
X Marks the Target Therapy
As the hormone-positive metastatic breast cancer landscape evolves, healthcare professionals continue to ask, “what agents should we use after CDK 4/6 inhibitors?” Answering this requires consideration of the various resistance mechanisms that drive disease progression. While PIK3CA mutations are truncal mutations that most often present at tumorigenesis, ESR1 mutations are acquired over time during treatment. Other resistance mechanisms include loss of ER expression, RB1 or FAT1, CCNE1/2 amplification, and additional alterations in PI3K/AKT/mTOR, RAS, FGFR, and TP53, among others.
The European Society for Medical Oncology (ESMO) Congress 2025 included many presentations about targeted therapy within the metastatic HR-positive, HER2-negative breast cancer space.
Phase 3 evERA Trial
In this phase 3 trial, giredestrant, a next-generation oral selective estrogen receptor degrader (SERD), was tested in combination with everolimus, a mammalian target of rapamycin (mTOR) inhibitor. Patients with ER-positive, HER2-negative advanced breast cancer who had received up to two prior lines of endocrine therapy (ET) in the advanced setting and had progression on prior CDK 4/6i were randomized 1:1 to giredestrant plus everolimus versus standard of care (ET; including exemestane, fulvestrant or tamoxifen) plus everolimus. The study had two co-primary endpoints: progression-free survival (PFS) in both the intention to treat (ITT) population and in the ESR1 mutant (ESR1m) population.
Within the ESR1m population, the combination of giredestrant and everolimus yielded a median PFS (mPFS) of 9.99 months compared to 5.45 months in the control arm (hazard ratio [HR], 0.38, 95% confidence interval [CI], 0.27-0.54; P < 0.0001). In the ITT population, the combination of giredestrant and everolimus demonstrated an mPFS of 8.77 months compared to 5.49 months in the control arm (HR, 0.56; 95% CI, 0.44-0.71; P < 0.0001). However, this benefit largely appeared to be driven by the ESR1m population.
While overall survival (OS) data are immature, they are trending favorably. Additionally, the overall response rate (ORR) doubled and a prolonged median duration of response was observed. The combination treatment did not raise new safety signals. This treatment regimen potentially represents a promising new combination SERD regimen in patients harboring ESR1 alterations.
VIKTORIA-1: Part 1 of the 2-Part Trial Presented at ESMO 2025
In this trial, patients with HR-positive, HER2-negative, PIK3CA-wild type (WT) advanced breast cancer were evaluated for the use of gedatolisib (a multitarget panPI3K mTORC1 &mTORC2 [PAM] inhibitor administered intravenously on a weekly regimen) plus fulvestrant with or without palbociclib after progression on a CDK 4/6 inhibitor in combination with an aromatase inhibitor. This study comprised two parts; the first evaluated the PIK3CA-WT population, and the second evaluated the mutant population. The presentation held at ESMO 2025 covered the first study. Patients were randomized 1:1:1 to gedatolisib plus fulvestrant plus palbociclib, gedatolisib plus fulvestrant, or fulvestrant monotherapy. An optional crossover of the first two arms at progression was allowed. The primary endpoint of the study was PFS.
In comparison to fulvestrant alone, the gedatolisib triplet (gedatolisib + fulvestrant + palbociclib) resulted in a 7.3-month improvement in PFS (9.3 months vs 2.0 months, respectively; HR, 0.24; 95% CI, 0.17-0.35; P < 0.001). The gedatolisib doublet (gedatolisib + fulvestrant) resulted in a 5.4-month improvement in PFS compared to fulvestrant monotherapy (7.4 months vs 2.0 months, respectively; HR, 0.33, 95% CI, 0.24-0.48; P < 0.001).
Benefit from gedatolisib was present in all subgroups, including in patients who had received palbociclib. While the data are immature, there appears to be a promising trend in OS. The safety signals were similar to other drugs in this class, with few patients discontinuing gedatolisib due to treatment-related adverse events (2.7%). There were higher rates of grade 3 stomatitis (19.2%). Additionally, low rates of grade 3 hyperglycemia were observed (2.3%), and patients with well-controlled type 2 diabetes were included in the trial. This was the first phase 3 study that showed improvement in PFS with a PAM inhibitor in patients with PIK3CA-WT.
Patient-Reported Outcomes from SERENA-6
In the SERENA-6 trial, patients with HR-positive advanced breast cancer found to have molecular progression with the emergence of an ESR1 mutation on circulating tumor (ct) DNA were either switched to camizestrant (oral SERD) or continued standard of care therapy. Initially presented at ASCO 2025, results showed improvement in median time to deterioration (mTTD), but many questions arose surrounding patient-reported outcomes (PROs) from this trial.
Mayer et al. presented follow up data at ESMO 2025. Improvements in TTD were observed in the physical, role, emotional, and pain domains. There was a 7.3-month improvement in mTTD (HR, 0.74; 95% CI 0.44-1.24) in the physician domain and a 7.4-month improvement in mTTD in the role domain (HR, 0.73; 95% CI 0.48-1.10). mTTD was not reached for the emotional domain in the camizestrant arm. This gain in mTTD in the pain domain may be due to a delay in the development of bone metastasis.
Putting It Together
The theme here is that combination therapies may be highly active, but must be selected for the correct patient (pending regulatory approval). The use of various factors, including disease sites, tumor biology, and patient values and preferences, may help clinicians identify which therapy optimizes the balance between disease control and patient quality of life.