Phase III results were announced for Arvinas and Pfizer’s first-in-class investigational oral PROteolysis TArgeting Chimera (PROTAC) ER degrader this week showing it was only effective in people with advanced or metastatic breast cancer with an estrogen receptor 1-mutant in their tumor.
Although the drug, vepdegestrant, met its primary endpoint in the population with an estrogen receptor 1-mutant, it did not meet this goal in the larger “intention to treat” population leading to a large drop in Arvinas share price after the announcement.
Estrogen receptor 1 mutants are rare in untreated breast cancer, but more common in metastatic, endocrine therapy-resistant cancers, where 10–50% of cases can have these mutations.
This trial is important, as vepdegestrant is the most advanced of the PROTAC candidate drugs to date. PROTAC degraders use the cell’s natural protein degradation machinery to target cancer by marking pathogenic proteins for proteasomal destruction.
These drug candidates are thought to potentially have a number of advantages over current cancer therapies because their unique mechanism of action allows them to target previously undruggable proteins, they also have the potential to be very selective and overcome drug resistance as they are effective against mutations or overexpression that render inhibitors ineffective and also have good catalytic efficiency.
Arvinas, a biotech company based in New Haven, CT, was founded in 2013 and was initially the sole developer of vepdegestrant. In 2021, Pfizer partnered with Arvinas to develop the drug further after promising Phase I results.
In this study, the researchers tested vepdegestrant monotherapy versus fulvestrant in 626 adults with estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced or metastatic breast cancer whose disease progressed following prior treatment with cyclin-dependent kinase (CDK) 4/6 inhibitors and endocrine therapy.
According to a press statement from the companies, the primary endpoint was an improvement in progression free survival in the intent to treat and estrogen receptor 1-mutant populations, with a secondary endpoint of overall survival.
In the estrogen receptor 1-mutant group, progression free survival was improved by over 40% (preset hazard ratio of 0.60), meeting the primary endpoint specifications, but this goal was not met in the larger “intent to treat” population that also included people without this specific mutation.
No major safety concerns were reported and the statement reported that the safety profile was in line with that of earlier studies.
These results are topline results and the trial is continuing. No results for overall survival have been shared to date, as less than a quarter of the required number of events have occurred.
“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,” said John Houston, chairperson, CEO, and president at Arvinas, in a press statement.
“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,” added Megan O’Meara, MD, interim chief development officer, Pfizer Oncology.
The companies stated that the broader, more detailed results of the trial will be shared at a later date.
