Many patients with ER+/HER2- metastatic breast cancer who progress on endocrine therapy have tumors with ESR1 mutations, which drive resistance to standard treatments. It is estimated that nearly 308,000 new cases of breast cancer will be diagnosed in the United States in 2025, with approximately 70% of these being ER+/HER2- subtypes. Resistance to standard first-line treatments often emerges, leading to disease progression. ESR1 mutations, found in about 40% of patients in the second-line setting, are a significant cause of acquired resistance, complicating treatment options.

The VERITAC-2 trial demonstrated that vepdegestrant, an investigational oral PROTAC ER degrader, significantly improved progression-free survival in patients with ESR1 mutations compared to fulvestrant

The Pivotal Phase III VERITAC-2 clinical trial results presented at ASCO. A total of 624 patients were randomized to receive either vepdegestrant (n = 313) or fulvestrant (n = 311). Of these, 43.3% had ESR1-mutant tumors (n = 136 vepdegestrant; 134 fulvestrant). In patients with ESR1 mutations, progression-free survival (PFS) by blinded independent central review (BICR) was significantly longer with vepdegestrant compared to fulvestrant. Median PFS was 5.0 months with vepdegestrant versus 2.1 months with fulvestrant. In all patients, the difference in PFS by BICR was not statistically significant (384 events), with median PFS of 3.7 months for vepdegestrant versus 3.6 months for fulvestrant. Overall survival (OS) data were immature, with only 20% of the targeted events reached. Vepdegestrant was generally well tolerated in the trial, with a safety profile consistent.In the 619 treated patients, treatment-emergent adverse events (TEAEs) were predominantly Grade 1/2. Grade ≥3 TEAEs occurred in 23.4% of patients in the vepdegestrant arm compared to 17.6% in the fulvestrant arm. The most common TEAEs in the vepdegestrant arm included fatigue, increased ALT, increased AST, and nausea. TEAEs led to discontinuation of vepdegestrant in 2.9% of patients compared to 0.7% in the fulvestrant arm.

KOL insights: 

“Vepdegestrant is the first PROTAC [proteolysis targeting chimera] to be evaluated in a Phase III study. These results support vepdegestrant as a potential treatment option for previously treated patients with ESR1-mutant ER-positive, HER2-negative advanced breast cancer.”– Expert Opinion.

Conclusion: 

In ER-positive, HER2-negative advanced breast cancer (ABC), there is no clear standard of care for patients progressing after frontline endocrine therapy. Fulvestrant, a selective estrogen receptor degrader (SERD), is commonly used in second-line treatment, but it offers only modest PFS benefits after CDK4/6 inhibitors and endocrine therapy. Elacestrant has been approved for ESR1-mutated advanced or metastatic disease since 2023, though its PFS remains limited. 

Vepdegestrant, however, has shown a significant and clinically meaningful improvement in PFS compared to fulvestrant in patients with ESR1 mutations, establishing it as a potential oral treatment for this subset. While no PFS benefit was seen in the overall population, vepdegestrant was well tolerated with low discontinuation rates due to treatment-emergent adverse events (TEAEs). Vepdegestrant’s mechanism as a PROTAC, which degrades rather than just blocking disease-causing proteins like the estrogen receptor, represents a promising approach to overcoming resistance, especially in ESR1-mutated tumors. This novel class of therapy may offer more effective, longer-lasting treatment options for patients with advanced, hormone receptor-positive breast cancer. 

The VERITAC-2 results are promising and suggest that vepdegestrant could offer a much-needed treatment option for these patients, with a low incidence of burdensome GI effects that can meaningfully affect daily life. The companies plan to submit a New Drug Application (NDA) for vepdegestrant to the US Food & Drug Administration (FDA) in the second half of 2025.