Vepdegestrant Hits PFS End Point in ESR1-Mutated, ER+/HER2– Metastatic Breast Cancer

Treatment with vepdegestrant (ARV-471) led to a statistically significant and clinically meaningful improvement in progression-free survival (PFS) vs fulvestrant (Faslodex) in patients with estrogen receptor (ER)–positive, HER2-negative advanced or metastatic breast cancer harboring an ESR1 mutation who experienced disease progression following previous treatment with CDK4/6 inhibitors and endocrine therapy.1

Of note, the PFS benefit associated with the investigational oral PROteolysis targeting chimera (PROTAC) ER degrader was observed only in patients harboring ESR1 mutations, where the hazard ratio exceeded the prespecified threshold of 0.60. The PFS improvement did not reach statistical significance in the intention-to-treat population.

“The first phase 3 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 ESR1 mutations,” John Houston, PhD, chairperson, chief executive officer, and president at Arvinas, stated in a news release.

At the time of the analysis, overall survival (OS) data—a key secondary end point—were not mature with less than a quarter of required events occurring for survival to be formally assessed. Regarding safety, vepdegestrant was generally well-tolerated with a safety profile consistent with previous data.

Full data from the topline analysis will be presented at a forthcoming medical conference and submitted to global health authorities.

The study included patients at least 18 years of age with ER-positive/HER2-negative, locoregional recurrent or metastatic breast cancer not amenable to surgical resection or radiation therapy who previously received 1 line of therapy with a CDK4/6 inhibitor therapy plus endocrine therapy in any setting and no more than 1 additional endocrine therapy.2 Patients needed to have radiological progression during or after the last line of therapy; a most-recent endocrine therapy duration of at least 6 months before disease progression; measurable disease per RECIST 1.1 criteria or non-measurable bone-only disease; and an ECOG performance status of 0 or 1.2

Patients were randomly assigned to two arms to either receive oral vepdegestrant at 200 mg daily (planned enrollment, n = 280), or intramuscular fulvestrant at 500 mg on days 1 and 15 of cycle 1 and day 1 on subsequent cycles (planned enrollment, n = 280); treatment was administered in 28-day cycles in each arm.3 Stratification factors included ESR1 mutation (yes or no) and visceral disease (yes or no).

The primary end points were PFS in the overall patient population and ESR1-mutant subpopulation; secondary end points included OS, overall response rate, duration of response, clinical benefit rate, safety, pharmacokinetics, patient-reported outcomes, and circulating tumor biomarkers.

“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, stated in a news release.1 “These data from VERITAC-2 support the potential of vepdegestrant to give patients whose tumors harbor ESR1 mutations additional time without disease progression, compared [with] fulvestrant.”

In February 2024, the FDA granted fast track designation to vepdestrant as a single agent for adult patients with ER–positive, HER2-negative locally advanced or metastatic breast cancer who previously received endocrine-based therapy.4

The phase 1/2 VERITAC study (NCT04072952) evaluated the safety of vepdegestrant plus palbociclib (Ibrance) in patients with locally advanced or metastatic ER-positive, HER2-negative breast cancer who were heavily pretreated (n = 46).5 Patients on the study were treated with daily oral doses of vepdegestrant at 180 mg (n = 2), 200 mg (n = 21; the recommended phase 3 dose), or 500 mg plus once-daily oral palbociclib at 125 mg for 21 days, followed by 7 days off treatment in the 28-day cycle.

References

1. Arvinas and Pfizer announce positive topline results from phase 3 VERITAC-2 clinical trial. News Release. Arvinas. March 11, 2025. Accessed March 11, 2025. https://ir.arvinas.com/news-releases/news-release-details/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 November 22, 2024. Accessed March 11, 2025. https://clinicaltrials.gov/study/NCT05654623
3. Hamilton EP, Ma C, De Laurentiis M, et al. VERITAC-2: a Phase III study of vepdegestrant, a PROTAC ER degrader, versus fulvestrant in ER+/HER2- advanced breast cancer. Future Oncol. 2024;20(32):2447-2455. doi:10.1080/14796694.2024.2377530
4. Arvinas and Pfizer’s vepdegestrant receives FDA fast track designation for the treatment of patients with ER+/HER2– metastatic breast cancer. News Release. Arvinas. February 6, 2024. Accessed March 11, 2025. https://ir.arvinas.com/news-releases/news-release-details/arvinas-and-pfizers-vepdegestrant-arv-471-receives-fda-fast
5. Arvinas and Pfizer announce interim data from phase 1b trial of vepdegestrant in combination with palbociclib (Ibrance) and plans to expand vepdegestrant development program. News Release. Pfizer. December 5, 2023. Accessed March 11, 2025. https://www.pfizer.com/news/press-release/press-release-detail/arvinas-and-pfizer-announce-interim-data-phase-1b-trial