8 Practice-Changing Breast Cancer Presentations From ESMO 2025
Key Points
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Updates from the monarchE, VIKTORIA-1, and evERA trials showed improved outcomes with abemaciclib, gedatolisib, and giredestrant, respectively, for patients with hormone receptor (HR)-positive, HER2-negative breast cancer.
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Trastuzumab deruxtecan (T-DXd) showed benefit across high-risk, HER2-positive breast cancer populations in the DESTINY-Breast11, DESTINY-Breast05, and DESTINY-Breast09 trials.
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In the ASCENT-03 and TROPION-Breast02 trials, first-line therapy with antibody-drug conjugates (ADCs) increased response rate and efficacy versus standard of care.
ESMO 2025 Breast Cancer Presentations
On the Oncology Brothers podcast, Virginia Kaklamani, MD, DSc, of UT Health San Antonio, and cohosts Rahul Gosain, MD, MBA, of Wilmot Cancer Institute, and Rohit Gosain, MD, of Roswell Park Comprehensive Cancer Center, highlighted presentations from major breast cancer trials at the 2025 European Society of Medical Oncology (ESMO) Congress. The doctors reviewed data from the monarchE, VIKTORIA-1, evERA, DESTINY-Breast05, DESTINY-Breast11, DESTINY-Breast09, ASCENT-03, and TROPION-Breast02 trials.
Updated Data From monarchE Shows OS Benefit
The phase 3 monarchE trial enrolled patients with HR-positive, HER2-negative, high-risk, early breast cancer. Participants were randomized to receive at least 5 years of endocrine therapy (ET) with or without adjuvant abemaciclib for 2 years. High-risk disease was defined as either 4 or more positive auxiliary lymph nodes or 1 to 3 positive nodes plus grade 3 disease or tumor size of 5 cm or greater.
After a median follow-up of 6.3 years, adjuvant abemaciclib significantly improved overall survival (OS) with a 15.8% reduced risk of death compared with ET alone (hazard ratio [HR], 0.84; 95% CI, 0.72-0.98; P = .027). Abemaciclib also maintained previously reported benefits in invasive disease-free survival (IDFS; HR, 0.73; 95% CI, 0.66-0.82) and distant relapse-free survival (DRFS; HR, 0.75; 95% CI, 0.66-0.84). The 7-year IDFS and DRFS rates for abemaciclib versus ET alone were 77.4% versus 70.9% and 80.0% versus 74.9%, respectively.
“We haven’t had [OS benefit] before in the adjuvant setting… so this is really big and it solidifies the fact that, for high-risk patients, we should be using a CDK4/6 inhibitor in the adjuvant setting,” said Dr. Kaklamani.
First Results From VIKTORIA-1
First results from the VIKTORIA-1 trial, presented at ESMO, showed that treatment with gedatolisib plus fulvestrant with or without palbociclib improved outcomes versus fulvestrant alone in patients with HR-positive, HER2-negative, PIK3CA-unmutated, advanced breast cancer that progressed during or after initial therapy with CDK4/6 plus aromatase inhibitors. The trial randomized 392 patients to receive either gedatolisib, fulvestrant, and palbociclib; gedatolisib and fulvestrant; or fulvestrant only.
At a median follow-up of 10.1 months, the study met its primary median progression-free survival (PFS) endpoint with both the triplet (median PFS, 9.3 vs 2 months; HR, 0.24; 95% CI, 0.17-0.35; P < .0001) and doublet (median PFS, 7.3 vs 2 months; HR, 0.33; 95% CI, 0.24-0.48; P < .0001) combinations compared with fulvestrant alone. Interim OS analysis also favored both the triplet (HR, 0.69; 95% CI, 0.43-1.12) and doublet (HR, 0.74; 95% CI, 0.46-1.19) regimens versus fulvestrant only. The objective response rate (ORR) was 32% with the triplet, 28.3% with the doublet, and 1% with fulvestrant monotherapy.
Gedatolisib was associated with high rates of stomatitis, although the trial protocol did not mandate the use of steroidal mouth washes. “This is a drug that, based on the PFS, we will be using for 9 months plus, so it’s important for us to consider the fact that we would have to use a steroidal mouth wash,” Dr. Kaklamani said.
Oral SERD Combination Superior to ET in evERA
In the evERA trial, giredestrant, an oral selective estrogen receptor degrader (SERD), plus everolimus was compared with standard ET plus everolimus in patients with estrogen receptor-positive, HER2-negative, advanced breast cancer who previously received CDK4/6 inhibitor therapy. Approximately 55% of the 373 randomized patients had detectable ESR1 mutation.
After a median follow-up of 18.6 months, in the ESR1-mutated population, the giredestrant group had an investigator-assessed PFS of 9.99 months (95% CI, 8.08-12.94) compared with 5.45 months (95% CI, 3.75-5.62) in the ET group (HR, 0.38; 95% CI, 0.27-0.54; P < .0001). In the intention-to-treat population, the giredestrant group had a median PFS of 8.77 months (95% CI, 6.60-9.59) versus 5.49 months (95% CI, 4.01-5.59) in the ET group (HR, 0.56; 95% CI, 0.44-0.71; P < .0001).
“The bottom line for this trial is giredestrant is an oral SERD that is active in tumors that have ESR1 mutations; in combination with everolimus, I expect it to be used in the second-line setting in the non-PIK3CA-mutated patient population,” said Dr. Kaklamani. Giredestrant is competing with gedatolisib in this setting, and more data will be needed to inform treatment selection, she added.
T-DXd in HER2+ Disease
The presentation for the DESTINY-Breast11 trial reported data on neoadjuvant T-DXd followed by paclitaxel, trastuzumab, and pertuzumab (T-DXd-THP) compared with dose-dense doxorubicin plus cyclophosphamide (ddAC) followed by THP (ddAC-THP) in patients with untreated, high-risk, HER2-positive, early breast cancer.
The pathological complete response (pCR) rate was 67.3% with T-DXd-THP versus 56.3% (95% CI, 4.0-18.3; P = .003) with ddAC-THP. The pCR benefit for T-DXd-THP versus ddAC-THP was observed in both HER2-positive (61.4% vs 52.3%) and HER2-negative (83.1% vs 67.1%) subgroups. The T-DXd-THP arm also showed an early trend toward improved event-free survival (HR, 0.56; 95% CI, 0.26-1.17).
The DESTINY-Breast05 trial was a head-to-head comparison of adjuvant T-DXd against trastuzumab emtansine (T-DM1) in patients with high-risk, HER2-positive, early breast cancer with residual invasive disease after neoadjuvant treatment. Interim analysis data were presented at ESMO.
After a median study duration of 29.9 months for T-DXd (n=818) and 29.7 months for T-DM1 (n=817), the T-DXd arm had 51 (6.2%) IDFS events and the T-DM1 arm had 102 (12.5%) events (HR, 0.47; 95% CI, 0.34-0.66; P < .0001). Similarly, the T-DXd arm had 52 (6.4%) DFS events while the T-DM1 arm had 103 (12.6%) events (HR, 0.47; 95% CI, 0.34-0.66; P < .0001). The analysis also found T-DXd was associated with a clinically meaningful improvement in brain metastasis-free interval (HR, 0.64; 95% CI, 0.35-1.17).
At present, it is unclear whether the neoadjuvant approach from DESTINY-Breast11 or the adjuvant approach from DESTINY-Breast05 is more optimal. Regardless, the doctors agreed that managing side effects of T-DXd, especially interstitial lung disease, is crucial for this curative-intent population.
T-DXd Plus Pertuzumab Versus THP
Previously, the DESTINY-Breast09 trial found a PFS benefit with first-line T-DXd plus pertuzumab versus THP in patients with HER2-positive advanced or metastatic breast cancer. During the ESMO session, additional data were presented for disease subgroups stratified by de novo or recurrent, HR-positive or HR-negative, and PIK3CA-mutated or PIK3CA-unmutated disease.
Between the T-DXd plus pertuzumab arm (n=383) and THP arm (n=387), approximately 52% of patients had de novo disease, approximately 54% had HR-positive disease, and approximately 31% had detectable PIK3CA mutation. Concurrent ET was used in 13.5% and 38.8% of patients with HR-positive disease in the T-DXd and THP groups, respectively. T-DXd plus pertuzumab demonstrated clinically meaningful improvements in both ORR and median duration of response (DOR) compared with THP for all disease subgroups, according to the presentation.
Given the toxicities associated with T-DXd, Dr. Kaklamani said she might consider using T-DXd plus pertuzumab for the first 6 months of treatment to maximize response, and then switch to a more tolerable maintenance regimen, potentially trastuzumab, pertuzumab, CDK4/6 inhibitor, and aromatase inhibitor based on the PATINA trial.
First-Line TNBC Therapy With Sacituzumab Govitecan in ASCENT-03
The ASCENT-03 trial evaluated first-line therapy with sacituzumab govitecan versus chemotherapy in patients with advanced triple negative breast cancer (TNBC) ineligible for PD-L1 inhibitors because of comorbidities or prior exposure. Primary findings were presented during the Congress.
At a median follow-up of 13.2 months, sacituzumab govitecan significantly improved median PFS at 9.7 months compared with chemotherapy at 6.9 months (HR, 0.62; 95% CI, 0.50-0.78; P < .0001). The ORR and median DOR were 48.4% (95% CI, 42.4-54.4) and 12.2 months (95% CI, 9.7-13.8) with sacituzumab govitecan compared with 45.5% (95% CI, 39.6-51.6) and 7.2 months (95% CI, 5.7-8.4) with chemotherapy, respectively.
“I’ve moved my ADCs into the first-line setting in TNBC since the ASCENT-04 presentation and the press release of ASCENT-03,” said Dr. Kaklamani. “I think we should be considering doing that now and definitely when these drugs get approved in the first-line setting.”
Dato-DXd Results for TNBC From TROPION-Breast02
The TROPION-Breast02 trial randomized patients with locally recurrent inoperable or metastatic TNBC ineligible for immunotherapy to receive first-line therapy with either datopotamab deruxtecan (Dato-DXd) or investigator’s choice of chemotherapy.
After a median follow-up of 27.5 months, the Dato-DXd arm had a median OS of 23.7 months (95% CI, 19.8-25.6) compared with 18.7 months (95% CI, 16.0-21.8) in the chemotherapy arm (HR, 0.79; 95% CI, 0.64-0.98; P = .0291). The median PFS was 10.8 months (95% CI, 8.6-13.0) with Dato-DXd versus 5.6 months (95% CI, 5.0-7.0) with chemotherapy (HR, 0.57; 95% CI, 0.47-0.69; P < .0001). Additionally, the ORR was 62.5% with Dato-DXd versus 29.3% with chemotherapy, and median DORs were 12.3 months (95% CI, 9.1-15.9) and 7.1 months (95% CI, 5.6-8.9), respectively.
When selecting between different ADCs, toxicities and dosing schedule are major drug characteristics to consider. “It’s hard to pick between these two agents, but both are going to be used in the first-line setting which is huge for our patients,” Dr. Kaklamani said.