Vepdegestrant was the first PROTAC to be evaluated in a phase 3 clinical trial.
Compared with fulvestrant (Faslodex; AstraZeneca), vepdegestrant (ARV-471; Arvinas, Pfizer) demonstrated statistically significant and clinically meaningful improvement in progression-free survival (PFS) in pretreated patients with ESR1-mutated estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer. The findings were presented at the 2025 American Society of Clinical Oncology Annual Meeting, which was held in Chicago, Illinois.1
Trial Name: A Study to Learn About a New Medicine Called Vepdegestrant (ARV-471, PF-07850327) in People Who Have Advanced Metastatic Breast Cancer (VERITAC-2)
ClinicalTrials.gov ID: NCT05654623
Sponsor: Pfizer
Completion Date (Estimated): May 15, 2028
Vepdegestrant is an oral proteolysis-targeting chimera (PROTAC) ER degrader that has previously shown positive clinical activity and tolerability in a phase 1/2 clinical trial in pretreated patients with advanced breast cancer. It is the first PROTAC to be evaluated in a phase 3 clinical trial, according to the investigators. This trial, a randomized, open-label, multicenter study called VERITAC-2 (NCT05654623)2, enrolled 624 patients aged 18 years and older who received 1 prior line of a CDK4/6 inhibitor plus endocrine therapy and at least 1 additional line of endocrine therapy who were randomly assigned to receive either vepdegestrant (n = 313; 200 mg orally once daily continuously) or fulvestrant (n = 311; 500 mg intramuscularly on days 1 and 15 of cycle 1, then day 1 of subsequent cycles).1,2
The primary end point was PFS as assessed by blinded independent central review in patients with an ESR1 mutation, as well as in all patients. The key secondary end point was overall survival (OS), with others being objective response rate, duration of response, clinical benefit rate, and number of participants experiencing treatment-emergent and serious adverse events (AEs).1,2
In an interview with Pharmacy Times®, VERITAC-2 investigator Erika Hamilton, MD, director of breast cancer research and executive chair of the Breast Cancer Research Executive Committee, Sarah Cannon Research Institute, discussed the study as well as its findings and the implications. She explained why vepdegestrant’s PROTAC mechanism of action and pharmacologic properties might influence resistance patterns that are often seen with other endocrine therapies.3
“A lot of times people want to group the PROTAC with the selective estrogen receptor degrader (SERD), and it's true that both of them are working to degrade the ER, but they do so in different ways,” she explained. “What's unique about vepdegestrant, a proteolysis-targeting chimera, is that it binds the estrogen receptor on 1 side, and then the other side binds e3 ligase. When e3 ligase is brought into close proximity with the ER, this leads to ubiquitination and, ultimately, recruiting the proteasome to kind of 'chomp up' the ER and spit it out. There may be some advantages in certain mechanisms of resistance where this is advantageous for us.”3
The findings demonstrated that PFS was significantly longer (5.0 months [95% CI, 3.7–7.4]) with vepdegestrant than with fulvestrant (2.1 [95% CI, 1.9–3.5]) among patients with ESR1 mutations (HR = 0.57 [95% CI, 0.42–0.77]; P = .0001). Conversely, PFS in all patients was not considered significantly different (HR = 0.83 [95% CI, 0.68–1.02]; P = .0358) in the respective groups (vepdegestrant: 3.7 months [95% CI, 3.6–5.3]; fulvestrant: 3.6 months [95% CI, 2.2–3.8]). At the time of this analysis, OS data were immature (20% of targeted events in all patients).1
Of note, AEs were relatively minor in severity. In 619 treated patients, treatment-emergent AEs (TEAEs) were mostly grades 1 or 2, with grades 3 or higher TEAEs occurring in approximately 23.4% and 17.6% of patients in the vepdegestrant and fulvestrant groups, respectively. The most common TEAEs in these respective treatment arms were fatigue (26.6% vs 15.6%), increased alanine transaminase (14.4% vs 9.8%) and aspartate aminotransferase (14.4% vs 10.4%), and nausea (13.5% vs 8.8%).1
“We saw only 3% of patients discontinue vepdegestrant, and we saw only 2% have to dose reduce. So, [this is] really an indication that this was well-tolerated. Our top 3 [AEs] were grade 1 fatigue, essentially, and we also saw nausea and [aspartate transaminase and alanine transaminase] elevations, but across all grades, this was only in the low teens,” Hamilton said.3
The findings of VERITAC-2 support vepdegestrant as a potential oral treatment option for previously treated patients with ESR1-mutated ER+/HER2- advanced breast cancer. Hamilton noted that its oral formulation allows for easier administration and that in addition to anticipating conversations with regulatory authorities about a possible approval, vepdegestrant also has the potential to be looked at in other settings, whether as a monotherapy or part of a combination regimen.1,3
“Vepdegestrant also has the potential to be looked at in other settings, either in combination since it's an endocrine backbone that can easily combine with other drugs, whether those are PI3 kinase inhibitors or CDK4/6 inhibitors [and so on]. We could also imagine this being brought up into earlier lines in combination with CDK4/6 in the first-line setting or even in the adjuvant setting,” Hamilton said.
“Essentially, in the second line, post-CDK4/6 setting, there's not a consensus of what therapies to use. Previously, fulvestrant was really one of our mainstays, and [it] has some disadvantages [such as] the intramuscular administration," Hamilton continued. "Specifically, across multiple randomized trials, we now see that fulvestrant has a PFS of 2 months or less, and so, really, it's not good enough for our patients. And so, this is why the VERITAC-2 trial was born.”3
