Vepdegestrant Improves PFS in ESR1-Mutated Breast Cancer

Breast cancer, female anatomy: © peterschreiber.media - stock.adobe.com

the risk of disease progression or death vs fulvestrant in patients with estrogen receptor 1-mutant (ESR1m),estrogen receptor–positive/HER2– advanced or metastatic breast cancer with disease progression after treatment with CDK 4/6 inhibitors and endocrine therapy, according to topline results from the phase 3 VERITAC-2 clinical trial (NCT05654623).¹

In the ESR1m subgroup, vepdegestrant met part of the primary study end point by significantly improving progression-free survival (PFS) vs fulvestrant, with a hazard ratio that surpassed the 0.60 threshold set by the study investigators. However, regarding the other component of the study’s primary end point, vepdegestrant treatment did lead to a statistically significant improvement in PFS in the intent-to-treat (ITT) population.

The study remains ongoing to evaluate the key secondary end point of overall survival (OS), which was not mature at the cutoff date for the analysis.

Regarding safety, the investigators determined that vepdegestrant was well tolerated in general, with no new safety signals emerging compared with previously reported studies.

The study investigators and developers of vepdegestrant plan to share the specific data from the trial at an upcoming medical meeting and discuss the findings with regulatory authorities.

“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 estrogen receptor 1 mutations,” John Houston, PhD, chairperson, CEO, and president at Arvinas, said in a press release. “We want to thank the patients and investigators who participated in this trial, and we look forward to sharing these data with health authorities as well as at a medical conference in 2025.”

VERITAC-2 Background

The global, open-label phase 3 VERITAC-2 trial evaluated the safety and efficacy of single-agent vepdegestrant in patients with ER+/HER2– advanced or metastatic breast cancer. Overall, there were 624 patients enrolled in the trial across 26 countries. Patients had previously been treated with a CDK4/6 inhibitor plus endocrine therapy.

Patients were randomized in a 1:1 ratio to treatment with oral vepdegestrant once daily for a 28-day continuous dosing cycle or fulvestrant delivered intramuscularly on days 1 and 15 of the first 28-day cycle and then on day 1 of each cycle starting with cycle 2.²

PFS per blinded independent central review in the intent-to-treat and ESR1m patient populations was the primary end point of the study, with OS being a key secondary end point.

Earlier this year, vepdegestrant received Fast Track designation from the FDA for use as a monotherapy in adult patients with ER+/HER2– advanced or metastatic breast cancer previously treated with endocrine-based therapy.³

“Patients with advanced ER+/HER2– 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 the 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.”

REFERENCES:

1. Arvinas and Pfizer Announce Positive Topline Results from Phase 3 VERITAC-2 Clinical Trial. Published online March 11, 2025. Accessed April 4, 2025. https://tinyurl.com/4u26e7tn

2. A study to learn about a new medicine called ARV-471 (PF-07850327) in people who have advanced metastatic breast cancer. (VERITAC-2). ClinicalTrials.gov. Updated September 21, 2023. Accessed April 4, 2025. https://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 5, 2024. Accessed April 4, 2025. http://tinyurl.com/4hp95z77