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PROTAC ER Degraders
PROTAC ER Degraders in ER-Positive/HER2-Negative MBC Progressing After Endocrine Therapy: Latest Updates From SABCS 2025

Released: February 20, 2026

Adrienne G. Waks
Adrienne G. Waks, MD
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Key Takeaways
  • PROTAC ER degraders are an emerging novel class of highly effective therapeutic options for ER-positive/HER2-negative MBC with a potential use in recurrent ESR1-mutated MBC.
  • Recently presented subgroup analyses from VERITAC-2 suggest vepdegestrant shows benefit compared with fulvestrant for patients with ER-positive/HER2-negative ESR1-mutated breast cancer including those who received previous CDK4/6 inhibitors ≥12 months and with detected PIK3CA/AKT/PTEN genetic alterations.

The current standard first-line treatment for estrogen receptor (ER)–positive/HER2-negative advanced or metastatic breast cancer (MBC) remains endocrine therapy (ET) with a CDK4/6 inhibitor. However, development of ET resistance mechanisms, such as mutation in the estrogen receptor-1 gene (ESR1), remain a critical challenge in the management of ER-positive/HER2-negative MBC. ESR1 mutations are a prominent mechanism of resistance that develop during or following treatment with ET. These mutations can lead to constitutive activation of ERs despite estrogen depletion, which enables tumor progression. ESR1 mutations are detected in approximately 4% of patients receiving first-line treatment for ER-positive/HER2-negative MBC and in approximately 40% of such patients after progression on aromatase inhibitors.

The oral selective estrogen receptor degraders (SERD) elacestrant and imlunestrant are available options for patients with ER-positive/HER2-negative MBC who relapse during or following treatment with ET. Elacestrant is indicated for the treatment of postmenopausal women or adult men with ER-positive/HER2-negative, ESR1-mutated advanced or metastatic breast cancer with disease progression following at least 1 line of ET. Imlunestrant is indicated for treatment of adults with ER-positive/HER2-negative, ESR1-mutated advanced or metastatic breast cancer with disease progression following at least 1 line of ET. However, an unmet need remains, particularly in patients with ESR1-mutant tumors and disease progression following oral SERDs.

Proteolysis-targeting chimera (PROTAC) ER degraders are an emerging novel class of highly effective therapeutic options for ER-positive/HER2-negative MBC with a potential use in recurrent ESR1-mutated MBC. Compared to other ER inhibitors, including oral SERDs, PROTAC ER degraders may potentially be more efficient at inducing ER-target degradation. Vepdegestrant is a selective oral PROTAC ER degrader that targets both wild-type and mutated ER. Vepdegestrant binds to ER and an E3 ubiquitin ligase to directly induce ubiquitination-based proteasomal degradation of the ER. SERDs, on the other hand, induce ER immobilization and/or conformational changes, indirectly recruiting the ubiquitin-proteasome system. 

The phase III VERITAC-2 trial compared activity of vepdegestrant vs fulvestrant in patients with ER-positive/HER2-negative MBC, including patients with ESR1 mutations (40%). Approximately 70% of patients in the study had visceral disease, 18% had bone-only disease, and approximately 80% had received 1 prior line of systemic therapy (including all patients previously receiving a CDK4/6 inhibitor). Investigators were able to show progression-free survival (PFS) benefit with vepdegestrant compared with fulvestrant in patients whose tumors harbored an ESR1 mutation (median PFS: 5.0 vs 2.1 months; HR: 0.57; 95% CI: 0.42-0.77; 2-sided P <.001). 

An update from the VERITAC-2 trial was presented at the 2025 San Antonio Breast Cancer Symposium (SABCS) annual meeting. In that report, investigators looked at the efficacy of vepdegestrant compared with fulvestrant by menopausal status in the ESR1-mutated population specifically. The median PFS in patients with premenopausal or perimenopausal status with vepdegestrant vs fulvestrant was 4.5 vs 2.1 months (HR: 0.48; 95% CI: 0.24-0.95) and in patients with postmenopausal status it was 5.0 vs 2.0 months (HR: 0.60; 95% CI: 0.43-0.85).

Investigators also looked at the median PFS for vepdegestrant compared with fulvestrant by duration of prior CDK4/6 inhibitor (<12 months, ≥12 months, and ≥18 months). In the <12 months group, median PFS for vepdegestrant vs fulvestrant was 3.6 vs 2.4 months (HR: 0.94; 95% CI: 0.48-1.84); in the ≥12 months group it was 5.5 vs 2.0 months (HR: 0.51; 95% CI: 0.37-0.73); and in the ≥18 months group it was 7.4 vs 2.1 months (HR: 0.45; 95% CI: 0.30-0.69).

At SABCS 2025 investigators from the VERITAC-2 trial also reported outcomes for vepdegestrant vs fulvestrant by presence of liver metastases and by presence or absence of PIK3CA/AKT/PTEN alteration also within the ESR1-mutated population. In the patient subgroup with liver metastases, median PFS for vepdegestrant vs fulvestrant was 2.2 vs 1.9 months (HR: 0.50; 95% CI: 0.33-0.75) and 7.4 vs 3.7 months (HR: 0.60; 95% CI: 0.38-0.94) for those without liver metastases. Looking at the patient subgroup with PIK3CA/AKT/PTEN alteration, median PFS was 3.7 vs 3.0 months (HR: 0.70; 95% CI: 0.44-1.12) and for the subgroup without PIK3CA/AKT/PTEN alteration, the median PFS was 5.0 vs 2.0 months (HR: 0.54; 95% CI: 0.36-0.80).

Regarding safety, there were no unexpected adverse events (AEs) observed with vepdegestrant vs fulvestrant. Most AEs reported were grade 1/2. Fatigue was the most common grade 1/2 treatment-emergent AE with vepdegestrant compared with fulvestrant, (27% vs 16%) followed by liver enzyme elevation (ALT: 14% vs 10%; AST 14% vs 10%) and nausea (13% vs 9%). Of importance, QT prolongation was more common with vepdegestrant vs fulvestrant and was seen in 10% and 1% of patients, respectively.

The phase III VERITAC-3 is a large, randomized phase III trial looking at vepdegestrant plus palbociclib vs letrozole plus palbociclib in patients with ER-positive/HER2-negative locally advanced and unresectable or MBC with no prior treatment in the advanced setting. That trial aims to enroll approximately 1000 patients. The primary endpoint is PFS, and secondary endpoints include quality of life, overall response rate, duration of response, clinical benefit rate, and overall survival. The rationale for the use of palbociclib instead of other CDK4/6 inhibitors stems from concerns about QT prolongation and challenges associated with combining vepdegestrant with other CDK4/6 inhibitors also with risk of QT prolongation (ribociclib). 

Your Thoughts
What are the unmet needs for your patients with ER-positive/HER2-negative locally advanced or metastatic breast cancer, particularly if also harboring ESR1 or other genetic alterations? Join the discussion by leaving us a comment. Visit the program page to watch a recording from the live webinar associated with this discussion.

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