VERITAC-2 Trial Shows Vepdegestrant Significantly Improves Survival in ESR1-Mutant Breast Cancer

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Data from the Phase III VERITAC-2 trial (NCT05654623) found that vepdegestrant (ARV-471) monotherapy produced a significant improvement in progression-free survival (PFS) compared to fulvestrant treating patients with estrogen receptor 1-mutant (ESR1m) advanced or metastatic breast cancer. However, the therapy was not found to achieve statistical significance among the overall intent-to-treat (ITT) patient population.^1,2

“Patients with advanced ER-positive/HER2-negative metastatic breast cancer face significant clinical challenges, with limited treatment options following disease progression and the development of resistance to available endocrine therapies,” Megan O’Meara, MD, interim chief development officer, Pfizer Oncology, said in a press release. “These data from VERITAC-2 support the potential of vepdegestrant to give patients whose tumors harbor ESR1 mutations additional time without disease progression, compared to fulvestrant."¹

Vepdegestrant is a novel oral PROteolysis Targeting Chimera (PROTAC) ER degrader co-developed by Arvinas and Pfizer. In February 2024, the FDA granted Fast Track designation (FTD) to vepdegestrant (ARV-471) monotherapy for adult patients with ER-positive/HER2-negative locally advanced or metastatic breast cancer who received prior treatment with an endocrine-based therapy.³ The FTD was based on findings from the Phase I/II VERITAC trial (NCT04072952).

Preclinical data found that vepdegestrant monotherapy produced ER degradation up to 97% in cancer cells across multiple ER-driven xenograft models. Administration of vepdegestrant both with or without a CDK4/6 inhibitor was found to increase antitumor activity compared with standard fulvestrant.

Vepdegestrant is also being evaluated in combination with Ibrance (palbociclib) in the first-line setting for the ongoing lead-in cohort of the Phase III VERITAC-3 clinical trial. Additionally, the drug is being considered in combination with Verzenio (abemaciclib), Kisqali (ribociclib), samuraciclib, everolimus, and with the novel CDK4 inhibitor, PF-07220060.

Trial Design

The global, randomized VERITAC-2 trial is being conducted at sites in 26 countries. Investigators are analyzing the efficacy and safety of vepdegestrant as a monotherapy compared to fulvestrant in patients with ER-positive/HER2-negative advanced or metastatic breast cancer who received prior treatment with a CDK4/6 inhibitor plus endocrine therapy.

A total of 624 patients were randomly assigned to receive oral vepdegestrant once daily on a 28-day continuous dosing schedule or to receive fulvestrant intramuscularly on days one and 15 of cycle one and on day one of each 28-day cycle starting from day one of cycle two. The trial’s primary endpoint is PFS in both the ITT population and ESR1m population as determined by blinded independent central review, with a key secondary endpoint of overall survival (OS).

Vepdegestrant achived the primary endpoint showing a statistically significant and clinically meaningful PFS improvement compared to fulvestrant in the ESR1m patient population. These data were above the pre-specified target hazard ratio of 0.60 among this patient group. These results did not carry over to the ITT population, falling short of statistical significance for PFS.

OS data were not mature when the analysis was conducted, as fewer than one-quarter of the required number of events occurred. As such, investigators will continue their analysis of OS for the trial’s secondary endpoint.

In terms of safety, vepdegestrant showed a tolerable profile with no new safety signals reported. Detailed findings from the trial will presented at a medical meeting later in 2025 and submitted to regulatory authorities for a potential filing.

“The first Phase III data readout for a PROTAC degrader represents a significant achievement and these data show that vepdegestrant has the potential to provide clinically meaningful outcomes for thousands of patients with metastatic breast cancer whose tumors harbor estrogen receptor 1 mutations,” John Houston, PhD, chairperson, CEO, and president, Arvinas, said in the release.¹

References

1. Arvinas and Pfizer Announce Positive Topline Results from Phase 3 VERITAC-2 Clinical Trial. News release. Pfizer. March 11, 2025. Accessed March 21, 2025. https://www.pfizer.com/news/press-release/press-release-detail/arvinas-and-pfizer-announce-positive-topline-results-phase

2. 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. Updated March 13, 2025. Accessed March 21, 2025. https://www.clinicaltrials.gov/study/NCT05654623

3. 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 March 21, 2025. https://ir.arvinas.com/news-releases/news-release-details/arvinas-and-pfizers-vepdegestrant-arv-471-receives-fda-fast