Pfizer and Arvinas’ estrogen receptor (ER) degrader has failed a key part of its first phase 3 test, although the companies have pointed to success in a subpopulation to suggest the therapy still has a path to regulators.
The drug in question, called vepdegestrant, is an oral PROteolysis TArgeting Chimera (PROTAC) ER degrader. The phase 3 study assessed vepdegestrant against AstraZeneca’s hormone med Faslodex in 624 patients with ER+/HER2- advanced or metastatic breast cancer who had already tried CDK 4/6 inhibitors and endocrine therapy.
There was a lot riding on the trial, which the companies had touted as the first-ever phase 3 readout for a PROTAC therapy. But vepdegestrant was unable to show an improvement in progression-free survival (PFS) in the intent-to-treat population, Pfizer and Arvinas revealed in a March 11 release.
The study's primary endpoint was PFS or death due to any cause, according to ClinicalTrials.gov. No specification by patient population is made in the federal database, but a Pfizer spokesperson told Fierce Biotech that the main measure is in the intent-to-treat and estrogen receptor 1 mutant populations, as determined by a blinded independent central review.
Based on that, the companies are pointing to PFS in patients whose tumors have an estrogen receptor 1 mutation, in which the prespecified target hazard ratio of 0.6 was exceeded.
Investors didn’t appear to buy this silver lining, sending Arvinas’ stock down 50% to $8.60 per share as of 10 a.m. ET Tuesday morning, falling from a Monday closing price of $17.56.
The companies were not yet able to share overall survival rates—the study’s secondary endpoint—as less than a quarter of the required number of events had occurred at time of analysis. Vepdegestrant was “generally well tolerated and its safety profile was consistent with what has been observed in previous studies,” they said.
The companies didn’t share any other detailed trial data today, instead saying these would be presented at a medical meeting later this year as well as “shared with global regulatory authorities to potentially support regulatory filings.”
“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,” Arvinas’ CEO John Houston, Ph.D., said in the release.
“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, M.D., interim chief development officer for Pfizer's oncology unit, said in the 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,” O’Meara added.
Analysts at Evercore ISI said today’s readout would be “likely sufficient for approval in ESR1m patients, but not dramatic.”
“This would set Arvinas up well for sliding into upcoming 2L+ combos based on fulvestrant, but rules out one of their main avenues for clear differentiation versus other next-gen SERDs,” added the analysts, who branded this “clearly a mixed result.”
The aim of vepdegestrant is to recruit the ubiquitin proteasome system to degrade the ER. Pfizer got in on the action back in 2021, and the companies have previously announced plans to combine vepdegestrant with Pfizer's investigational CDK4 inhibitor atirmociclib in a phase 3 trial this year.