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Pfizer, Arvinas’ Novel PROTAC ER Degrader Shows Significant Survival Benefit in ER+/HER2- Advanced Breast Cancer

Results from the Phase III VERITAC-2 trial demonstrated that vepdegestrant reduced the risk of disease progression or death by 43% in patients with ER+/HER2- advanced or metastatic breast cancer harboring ESR1 mutations.

Breast cancer with lymphatics, medically 3D illustration. Image Credit: Adobe Stock Images/Axel Kock

Image Credit: Adobe Stock Images/Axel Kock

Key Takeaways

  • Vepdegestrant Cuts Progression Risk by 43% in ESR1-Mutant Breast Cancer: In the Phase III VERITAC-2 trial, Arvinas and Pfizer’s vepdegestrant significantly reduced the risk of disease progression or death versus fulvestrant in patients with ER+/HER2- metastatic breast cancer with ESR1 mutations.
  • Improved Response Rates and Tolerability Profile: Patients treated with vepdegestrant showed higher clinical benefit and objective response rates, with low rates of serious adverse events (AEs) and minimal gastrointestinal AEs.
  • Potential Best-in-Class Therapy for Second-Line ESR1-Mutant Setting: Backed by promising efficacy and safety data, vepdegestrant is positioned as a strong candidate for regulatory submission in the second half of 2025.

Results from the Phase III VERITAC-2 trial show that vepdegestrant, an investigational oral PROTAC ER degrader developed by Arvinas and Pfizer, significantly improved progression-free survival (PFS) compared to fulvestrant in patients with ER+/HER2- advanced or metastatic breast cancer harboring ESR1 mutations. Full results from the study were presented at the American Society of Clinical Oncology Annual Meeting and simultaneously published in the New England Journal of Medicine.1

How Did Vepdegestrant Perform Compared to Fulvestrant in ESR1-Mutant Breast Cancer?

“Many patients with ER+/HER2- metastatic breast cancer who progress on endocrine therapy have tumors with ESR1 mutations, which drive resistance to standard treatments,” VERITAC-2 trial principal investigator Erika P. Hamilton, MD, director, breast cancer research, Sarah Cannon Research Institute, said in a press release. “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.”

VERITAC-2Trial Design and Patient Population

  • The global, randomized VERITAC-2 trial evaluated the efficacy and safety of vepdegestrant as a monotherapy compared to fulvestrant in 624 patients across 26 countries who previously received treatment with a CDK4/6 inhibitor plus endocrine therapy.
  • Patients were randomly assigned in a 1:1 ratio to receive oral vepdegestrant once daily for 28 days or fulvestrant, administered intramuscularly on days one and 15 during the first cycle, followed by the first day of each following cycle.
  • The primary endpoint of the study was PFS in the ESR1-mutation and intent-to-treat populations as determined by blinded independent central review.
  • A key secondary endpoint was overall survival (OS), while additional secondary endpoints included clinical benefit rate (CBR), objective response rate (ORR), and duration of response (DOR).

Efficacy Results in ESR1-Mutant Patients

  • Results show that vepdegestrant reduced the risk of disease progression or death by 43%.
  • Median PFS was 5.0 months in the vepdegestrant group and 2.1 months in the fulvestrant group.
  • In the broader intent-to-treat population, the PFS difference was not statistically significant.
  • CBR was 42.1% in the vepdegestrant group and 20.2% in the fulvestrant group.
  • ORR was 18.6% and 4% in the vepdegestrant and fulvestrant groups, respectively.
  • OS was immature at the time of data readout.
  • Median DOR was not reached in the study.

Safety and Tolerability Profile

  • Treatment-related adverse events (TEAEs) were mostly low grade, with grade 4 TEAEs reported in five patients in the vepdegestrant arm and nine patients in the fulvestrant arm.
  • The most common TEAEs were fatigue, increased alanine transaminase, and increased aspartate aminotransferase.
  • In 2.9% of patients taking vepdegestrant and 0.7% of patients taking fulvestrant, TEAEs led to treatment discontinuation.
  • Gastrointestinal AEs were infrequent and generally mild.1

Strategic Outlook and Regulatory Pathway

“Based on these strong data from VERITAC-2, we believe that vepdegestrant has the potential to be a best-in-class monotherapy treatment for patients in the second-line ESR1-mutant setting,” said John Houston, PhD, chairperson, CEO, president, Arvinas, in the press release. “We are excited to engage with regulatory authorities on next steps to potentially bring vepdegestrant to healthcare providers and their patients as swiftly as possible.”

Market Context and Disease Burden

According to the American Cancer Society, breast cancer is the most common form of the disease in women in the United States outside of skin cancers. It is estimated that by the end of 2025, there will be 316,950 new cases of invasive breast cancer and approximately 42,170 deaths. According to the companies, ER+/HER2- breast cancer accounts for approximately 70% of all cases.1

“Patients whose tumors harbor ESR1 mutations can face a poor prognosis, often experiencing rapid disease progression on endocrine therapy,” said Johanna Bendell, MD, chief oncology development officer, Pfizer, in the press release. “These results highlight the important role vepdegestrant may play in combating ESR1 mutation treatment resistance for these patients.”

References

1. Arvinas and Pfizer's Vepdegestrant Significantly Improves Progression-Free Survival for Patients with ESR1-Mutant, ER+/HER2- Advanced Breast Cancer. Pfizer. May 31, 2025. Accessed June 5, 2025. https://www.pfizer.com/news/press-release/press-release-detail/arvinas-and-pfizers-vepdegestrant-significantly-improves

2. Key Statistics for Breast Cancer. American Cancer Society. Accessed June 5, 2025. https://www.cancer.org/cancer/types/breast-cancer/about/how-common-is-breast-cancer.html

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