Vepdegestrant Meets PFS Primary End Point in ESR1m ER+/HER2– Breast Cancer

The safety profile of vepdegestrant in ER–positive/HER2– breast cancer was consistent with its observed profile in previous studies.

Vepdegestrant (ARV-471) monotherapy elicited a statistically significant progression-free survival (PFS) vs fulvestrant (Faslodex) in patients with ESR1-mutant advanced or metastatic breast cancer who experienced disease progression after treatment with CDK4/6 inhibitors and endocrine therapy, according to news release from the drug’s developer, Arvinas Inc.¹

In February 2024, vepdegestrant monotherapy was granted fast track designation as a treatment for adults with estrogen receptor (ER)–positive/HER2–negative advanced or metastatic breast cancer previously treated with endocrine therapy.

Data from the phase 3 VERITAC-2 trial (NCT05654623) revealed that the prespecified target HR for PFS of 0.60 was exceeded in the ESR1m population. Additionally, the trial did not reach statistical significance in PFS improvement with vepdegestrant vs fulvestrant in the intent-to-treat population.

Overall survival (OS) data were immature at the time of analysis, with less than 25% of the required number of events having occurred. The trial will continually assess OS as a secondary end point and data from the phase 3 VERITAC-2 trial will be submitted for presentation at a medical meeting later this year. Additionally, these data will be shared with global regulatory authorities to support regulatory filings.

“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 at Pfizer Oncology, said in the press release.¹ “These data from the phase 3 VERITAC-2 trial support the potential of vepdegestrant to give patients whose tumors harbor ESR1 mutations additional time without disease progression, compared to fulvestrant.”

Patients enrolled on the phase 3 VERITAC-2 trial were randomly assigned 1:1 to receive either daily oral vepdegestrant on a 28-day continuous dosing schedule or fulvestrant.² Fulvestrant was dosed intramuscularly on days 1 and 15 of cycle 1 and then day 1 of each 28-day cycle thereafter.

The primary end point of the study was progression-free survival (PFS). Secondary end points included OS, objective response rate, duration of response, and safety.

Vepdegestrant is being developed as an investigational, orally bioavailable proteolysis targeting chimera (PROTAC) protein degrader targeting the ER. It is currently being assessed as both a monotherapy and in combination therapies across multiple ER–positive/HER2–negative metastatic breast cancer indications.

Patients were permitted for enrollment if they had recurrent ER-positive/HER2– advanced or metastatic breast cancer not amenable to curative treatment with surgery or radiation therapy. Additionally, patients must have responded to prior hormonal or endocrine therapy, have received at least 1 prior line of CDK4/6 inhibitor therapy, and must not have received any more than 2 endocrine therapies. Additionally, patients with ECOG performance status scores were permitted for enrollment, and patients must be willing to provide bone and tumor tissue.

Exclusion criteria included those with advanced, symptomatic visceral spread at risk of life-threatening complications; those previously treated with vepdegestrant, fulvestrant, elacestrant (Orserdu), mTOR, PI3K, or AKT pathway inhibitors or PARP inhibition, or other investigational agents; those treated with prior chemotherapy for advanced/metastatic disease; those with inadequate liver, kidney and bone marrow function; those with brain metastases; and those with concomitant illnesses.

“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, chief executive officer and president at Arvinas, stated in the news release.¹ “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.”

References

1. Arvinas and Pfizer announce positive topline results from phase 3 VERITAC-2 clinical trial. News release. Arvinas Inc. March 11, 2025. Accessed March 12, 2025. https://tinyurl.com/4cba6tj7
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 12, 2025. https://tinyurl.com/3x9ajujy