Vepdegestrant Outperforms Fulvestrant in PFS for ESR1-Mutant Advanced Breast Cancer

Vepdegestrant shows significant clinical activity and a favorable safety profile in ESR1-mutant HER2-negative, ER-positive metastatic breast cancer vs fulvestrant.

Results from the phase 3 VERITAC-2 trial (NCT05654623) shared at the 2025 ASCO Annual Meeting showed that vepdegestrant (ARV-471) demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared with fulvestrant (Faslodex) in pretreated patients with ESR1-mutant estrogen receptor (ER)–positive, HER2-negative advanced or metastatic breast cancer.1

At a median follow-up of 7.4 months in the vepdegestrant arm (n = 136) and 6.0 months in the fulvestrant arm (n = 134), the median PFS was 5.0 months (95% CI, 3.7-7.4) and 2.1 months (95% CI, 1.9-3.5), respectively (stratified HR, 0.57; 95% CI, 0.42-0.77; 2-sided P < .001). At the time of the analysis, 58% of PFS events had occurred in the vepdegestrant arm vs 71% in the fulvestrant arm; treatment was ongoing in 33% and 12% of patients, respectively. The 6-month PFS rates with vepdegestrant and fulvestrant were 45.2% (95% CI, 36.1%-53.9%) and 22.7% (95% CI, 15.1%-31.2%), respectively.

Blinded independent central review (BICR)-assessed PFS did not show a substantial improvement with vepdegestrant vs fulvestrant in the all-comer population (HR, 0.83; 95% CI, 0.68-1.02; P = .07).

“Vepdegestrant is the first PROTAC [proteolysis targeting chimera] to be evaluated in a phase 3 study,” lead study author Erika Hamilton, MD, said in a press briefing ahead of the meeting. “These results support vepdegestrant as a potential treatment option for previously treated [patients with] ESR1-mutant ER-positive, HER2-negative advanced breast cancer.”

Setting the Stage for VERITAC-2

There is no agreed-upon standard of care for patients with ER-positive, HER2-negative advanced breast cancer following progression on frontline endocrine therapy. Fulvestrant is a selective estrogen receptor degrader (SERD) that is typically given in the second line even though it is associated with modest PFS benefit following progression on CDK4/6 inhibition and endocrine therapy.

Since January 2023, elacestrant (Orserdu) has become an option for postmenopausal women or adult men with ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer with disease progression following at least one line of endocrine therapy. However, median PFS remains limited.2 

Vepdegestrant is a selective, oral PROTAC ER degrader that targets the mutant and wild-type ER.1 In the first-in-human phase 1/2 trial (NCT04072952), vepdegestrant was well tolerated and active, with a clinical benefit rate (CBR) of 51.2% (95% CI, 35.1%-67.1%) in heavily pretreated patients with ESR1-mutant ER-positive, HER2-negative advanced breast cancer who had received a median of 3 (range, 0-7) prior lines of therapy in the metastatic setting.3

In February 2024, the FDA granted fast track designation to vepdegestrant for the treatment of patients with ER-positive, HER2-negative locally advanced or metastatic breast cancer previously treated with endocrine-based therapy.4 

Seeking confirmation of benefit in the VERITAC-2 trial, investigators enrolled patients at least 18 years of age with ER-positive, HER2-negative advanced or metastatic breast cancer that developed radiological progression during or after the last line of therapy.1 Prior therapy consisted of 1 line of endocrine therapy and a CDK4/6 inhibitor, and no more than 1 additional line of endocrine therapy. Patients must have been exposed to the most recent line of endocrine therapy for at least 6 months, and prior chemotherapy for advanced or metastatic disease or a SERD like fulvestrant or elacestrant was not allowed.

Eligible patients were randomly assigned 1:1 to 200 mg of oral vepdegestrant once daily (n = 313) or 500 mg of intramuscular fulvestrant on days 1 and 15 of cycle 1, and day 1 of subsequent cycles. Treatment cycles were 28 days. Patients were stratified by ESR1 status (mutated vs not) and visceral disease (yes vs no).

The primary end point was BICR-assessed PFS in the ESR1-mutant and all-comer populations. Secondary end points were overall survival (OS), CBR and objective response rate (ORR) by BICR, and adverse effects (AEs).

Hamilton noted that approximately 80% of patients had received 1 prior line of therapy and around 20% had received 2 prior lines of therapy in the advanced or metastatic setting.

Vepdegestrant Sails Through Secondary End Point Verification of Benefit

With respect to the secondary end points of the trial, vepdegestrant (n = 121) more than doubled the CBR compared with fulvestrant (n = 119) in the ESR1-mutant population, at 42.1% vs 20.2%, respectively (odds ratio [OR], 2.88; 95% CI, 1.57-5.39; P < .001). The ORR was 18.6% with vepdegestrant (n = 97) vs 4.0% with fulvestrant (n = 100; OR, 5.45; 95% CI, 1.69-22.73; P = .001). The median duration of response was not reached.

Safety was evaluated in all-treated patients who received vepdegestrant (n = 312) and fulvestrant (n = 307) and was generally well tolerated.

“Vepdegestrant demonstrated a favorable safety profile, evidenced by few AEs [< 5%] leading to dose reduction or discontinuation,” Hamilton said.

Any-grade treatment-emergent AEs (TEAEs) occurred in 87% of patients on vepdegestrant (grade ≥3, 23%) vs 81% of those on fulvestrant (grade ≥3, 18%). Serious AEs occurred in 10% and 9% of patients on vepdegestrant and fulvestrant, respectively. TEAEs leading to discontinuation and dose reduction occurred in 3% and 2% of cases, respectively, in the vepdegestrant arm. Only 1% of patients in the fulvestrant arm required treatment discontinuation because of a TEAE. Treatment-related AEs also occurred in the vepdegestrant (any grade, 57%; grade ≥3, 8%) and fulvestrant (any grade, 40%; grade ≥3, 3%) arms.

Any-grade TEAEs that occurred in at least 10% of patients in the vepdegestrant and fulvestrant arms, respectively, were fatigue (27%; 16%), alanine aminotransferase increase (14%; 10%), aspartate aminotransferase increase (14%; 10%), nausea (13%; 9%), anemia (12%; 8%), neutropenia (12%; 5%), back pain (11%; 7%), arthralgia (11%; 11%), and decreased appetite (11%; 5%).

No treatment-related deaths occurred.

“OS analyses remain immature, and follow-up is ongoing,” Hamilton concluded.

Putting the Results in Context

“This is a very exciting study,” Jane L. Meisel, MD, professor in the Departments of Hematology and Medical Oncology and Gynecology & Obstetrics, and codirector of Breast Medical Oncology at Emory University School of Medicine in Georgia, said. “This drug is something that we think is going to be a very exciting option potentially for patients with previously treated, ESR1-mutant ER-positive, HER2-negative advanced breast cancer. There are a lot of exciting things happening in this space, so seeing what the overall survival analyses show will be interesting and how this compares with some of the other things that we [have]. We all look forward to that. This is a very exciting option, and the first of its kind in terms of being a PROTAC as opposed to other mechanisms of action, so [there’s] a lot to think about, and exciting data to see.”

Disclosures: No disclosures were shown for Hamilton.

References

1. Hamilton E, De Laurentiis M, Jhaveri K, et al. Vepdegestrant, a PROTAC estrogen receptor (ER) degrader, vs fulvestrant in ER-positive/human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer: results of the global, randomized, phase 3 VERITAC-2 study. J Clin Oncol. 2025;43(suppl 17):LBA1000. doi:10.1200/JCO.2025.43.17_suppl.LBA1000
2. FDA approves elacestrant for ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer. FDA. January 27, 2023. Accessed May 28, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-elacestrant-er-positive-her2-negative-esr1-mutated-advanced-or-metastatic-breast-cancer
3. Schott AF, Hurvitz S, Ma C, et al. GS3-03 ARV-471, a PROTAC estrogen receptor (ER) degrader in advanced ER-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer: phase 2 expansion (VERITAC) of a phase 1/2 study. Cancer Res. 2023;83(suppl 5):GS3-03. doi:10.1158/1538-7445.SABCS22-GS3-03
4. Arvinas and Pfizer’s vepdegestrant (ARV-471) receives FDA fast track designation for the treatment of patients with ER+/HER2- metastatic breast cancer. News release. Arvinas, Inc. February 6, 2024. Accessed May 28, 2025. https://www.pfizer.com/news/announcements/arvinas-and-pfizers-vepdegestrant-arv-471-receives-fda-fast-track-designation