Pfizer and Arvinas Report Mixed Results in Landmark Phase 3 Trial of PROTAC Degrader for Breast Cancer

Pfizer and Arvinas have announced mixed results from the first-ever phase 3 trial of a PROteolysis TArgeting Chimera (PROTAC) degrader, vepdegestrant, in patients with ER+/HER2- advanced or metastatic breast cancer. The oral estrogen receptor (ER) degrader failed to meet its primary endpoint of improved progression-free survival (PFS) in the intent-to-treat population but showed promise in a specific subgroup of patients.

Trial Results and Implications

The phase 3 VERITAC-2 study evaluated vepdegestrant against AstraZeneca's Faslodex (fulvestrant) in 624 patients who had previously received CDK 4/6 inhibitors and endocrine therapy. While the drug did not demonstrate an overall PFS benefit, it exceeded the prespecified target hazard ratio of 0.6 in patients whose tumors harbor estrogen receptor 1 (ESR1) mutations.

Dr. Megan O'Meara, interim chief development officer for Pfizer's oncology unit, stated, "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."

The companies reported that vepdegestrant was generally well-tolerated, with a safety profile consistent with previous studies. However, overall survival data, a secondary endpoint, was not yet available due to insufficient events at the time of analysis.

Market Response and Future Plans

The mixed results had a significant impact on Arvinas' stock, which plummeted 50% to $8.60 per share following the announcement. Despite this setback, both Pfizer and Arvinas remain optimistic about the drug's potential.

Dr. John Houston, CEO of Arvinas, emphasized the significance of the trial, stating, "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."

The companies plan to present detailed trial data at an upcoming medical meeting and intend to share the results with global regulatory authorities to potentially support regulatory filings. Additionally, Pfizer and Arvinas have announced plans to combine vepdegestrant with Pfizer's investigational CDK4 inhibitor atirmociclib in a phase 3 trial later this year.

Industry Implications and Expert Analysis

Analysts at Evercore ISI suggest that the results may be "likely sufficient for approval in ESR1m patients, but not dramatic." They added that this outcome "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."

The VERITAC-2 trial results mark a significant milestone in the development of PROTAC degraders, a novel class of therapeutics designed to recruit the ubiquitin proteasome system to degrade specific protein targets. While the overall results were mixed, the potential benefit observed in patients with ESR1 mutations may pave the way for more targeted approaches in breast cancer treatment.