Vepdegestrant delivers Phase 3 success for Arvinas and Pfizer in ESR1-mutant breast cancer

Arvinas, Inc. (NASDAQ: ARVN) and Pfizer Inc. (NYSE: PFE) have reported detailed results from their Phase 3 VERITAC-2 clinical trial evaluating the investigational oral PROTAC therapy vepdegestrant in patients with estrogen receptor-positive, human epidermal growth factor receptor 2-negative (ER+/HER2-) advanced or metastatic breast cancer. The results, presented on May 31, 2025, at the American Society of Clinical Oncology (ASCO) Annual Meeting and published simultaneously in the New England Journal of Medicine, mark a significant advancement for patients harboring estrogen receptor 1 (ESR1) mutations—a subset known for resistance to standard endocrine therapies.

In this randomized global trial, vepdegestrant demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) for ESR1-mutant patients compared to fulvestrant. The oral PROTAC reduced the risk of disease progression or death by 43%, with a hazard ratio of 0.57 and a median PFS of 5.0 months versus 2.1 months for fulvestrant. While the intent-to-treat (ITT) population did not reach statistical significance, the subgroup benefit among ESR1-mutant patients positions vepdegestrant as a potential best-in-class treatment in this specific second-line setting.

What does the VERITAC-2 trial tell us about endocrine resistance?

The VERITAC-2 study (NCT05654623) evaluated 624 patients with ER+/HER2- metastatic breast cancer whose disease progressed after prior treatment with CDK4/6 inhibitors and endocrine therapy. Approximately 43% of patients were confirmed to have ESR1 mutations—genomic alterations associated with reduced responsiveness to traditional selective estrogen receptor degraders (SERDs) such as fulvestrant.

Vepdegestrant, developed jointly by Arvinas and Pfizer since their collaboration began in July 2021, is a PROTAC-based therapy designed to harness the ubiquitin-proteasome pathway to degrade the estrogen receptor, thereby overcoming ESR1-driven endocrine resistance. According to Dr. Erika P. Hamilton, principal investigator at the Sarah Cannon Research Institute, the data suggest that vepdegestrant offers both clinical efficacy and a favorable safety profile, an important consideration for patients with limited therapeutic options.

How does vepdegestrant compare to fulvestrant across efficacy endpoints?

In ESR1-mutant patients, investigator-assessed and blinded independent central review (BICR) confirmed that vepdegestrant delivered superior efficacy across multiple parameters. In addition to the 2.9-month increase in PFS, the clinical benefit rate (CBR) was more than double that of fulvestrant at 42.1% versus 20.2%, respectively. The objective response rate (ORR) was 18.6% for vepdegestrant compared to 4.0% for fulvestrant, with a corresponding odds ratio of 5.45.

Although overall survival (OS) data remain immature, with fewer than 25% of required events reported, these initial efficacy signals have been viewed positively by analysts and oncology stakeholders, who have long awaited a targeted therapy capable of addressing this resistance mechanism.

What is the safety profile of vepdegestrant in this patient population?

From a tolerability perspective, vepdegestrant showed a safety profile that supports further clinical use. Grade 4 treatment-emergent adverse events (TEAEs) were less common in the vepdegestrant arm (1.6%) compared to fulvestrant (2.9%). The most frequently observed TEAEs with vepdegestrant included fatigue (26.6%), elevated alanine transaminase (14.4%), and elevated aspartate aminotransferase (14.4%). Gastrointestinal adverse events were low in both frequency and severity, with nausea (13.5%), vomiting (6.4%), and diarrhea (6.4%) being the most noted.

Discontinuation due to adverse events occurred in 2.9% of patients receiving vepdegestrant versus 0.7% in the fulvestrant cohort. Despite this slight increase, the overall safety and ease of oral administration could provide vepdegestrant with a competitive edge in real-world clinical settings.

What does this mean for Arvinas and Pfizer’s oncology pipeline?

For Arvinas, the results reinforce confidence in its proprietary PROTAC platform, which aims to degrade rather than inhibit disease-causing proteins. Vepdegestrant now emerges as a leading asset in the company’s pipeline, which also includes investigational therapies for lymphoma and neurodegenerative disorders.

Pfizer, on the other hand, is leveraging this collaboration to bolster its oncology portfolio, which spans antibody-drug conjugates, bispecific antibodies, and now targeted protein degraders. With oral SERDs such as elacestrant and amcenestrant generating mixed clinical outcomes in recent trials, vepdegestrant’s differentiated mechanism and efficacy profile may offer Pfizer a route to deeper penetration in the ER+/HER2- metastatic breast cancer market.

Sentiment analysis: How markets are reacting to Arvinas and Pfizer post-VERITAC-2

The market reaction to the VERITAC-2 Phase 3 trial results has been mixed but directionally constructive, especially for Arvinas Inc. (NASDAQ: ARVN), which is more directly exposed to the clinical success of vepdegestrant. As of June 6, 2025, Arvinas shares traded at $7.36, marking a sharp year-over-year decline of nearly 75% from $27.70. However, following the public release of the vepdegestrant data at ASCO, the stock jumped 8.7% intraday, reflecting renewed optimism about its lead pipeline candidate’s regulatory and commercial potential.

Despite the positive trial outcome, analyst views remain divided. Guggenheim lowered its price target from $32 to $16 but reiterated a “Buy” rating. Wedbush downgraded the stock to “Neutral,” citing capital constraints and broader market sentiment, with a reduced target of $12. Jefferies Financial Group maintained a cautious stance with a $10 target, classifying the stock as “Hold.” Across the board, the average analyst price target now sits at $20.29, with a “Moderate Buy” consensus.

Institutionally, Arvinas remains widely held. Approximately 94.6% of its float is owned by institutional investors, including RTW Investments and Opaleye Management. However, financial caution persists due to a cash burn of over $250 million in the trailing twelve months, nearly 48% of its market cap. While the biotech firm’s net margin stands at 43.9% and ROE at 13.6%, many investors are awaiting more clarity on funding before increasing exposure. For now, most fund managers and sell-side desks appear to support a “Hold” strategy, pending regulatory progress or partnership announcements tied to vepdegestrant.

Pfizer Inc. (NYSE: PFE), the co-development partner, has seen more muted equity impact. The stock closed at $23.35 on June 6, 2025—down 18.3% year-on-year from $28.58. Institutional interest remains healthy, with ownership at 68.4%. Over the past 12 months, institutional inflows totaled $13.78 billion, while outflows reached $11.49 billion, reflecting portfolio rebalancing amid broader large-cap pharma repricing.

Despite recent challenges in its oncology and vaccine portfolios, Pfizer continues to attract long-term investors with its $8 billion net income and $63.6 billion revenue. Dividend stability and strong free cash flow have cemented its “Hold” status for most institutional desks. While vepdegestrant’s success strengthens Pfizer’s oncology narrative, analysts view it as one piece of a broader pipeline mosaic rather than a primary valuation driver.

What are the next regulatory and clinical steps for vepdegestrant?

The focus now turns to regulatory engagement and potential approval pathways. The U.S. Food and Drug Administration has already granted Fast Track designation for vepdegestrant as a monotherapy in ER+/HER2- breast cancer post-endocrine therapy. This designation may expedite review and facilitate communication between the sponsors and regulatory bodies.

Beyond the NDA submission, ongoing development will likely include expansion trials exploring combination strategies with CDK4/6 inhibitors or PI3K pathway agents, as well as potential frontline applications. Investigators are also watching for updated OS data, which could influence final regulatory and reimbursement outcomes.

How big is the addressable market for vepdegestrant?

Globally, an estimated 2.3 million new breast cancer cases were diagnosed in 2022, with ER+/HER2- accounting for roughly 70% of all cases. In the United States alone, over 300,000 new breast cancer cases are expected in 2025. Approximately 30% of women with early-stage disease will eventually develop metastases, and ESR1 mutations are found in nearly 40% of these second-line or later patients. That translates to a large, underserved patient population in urgent need of new treatment options.

If vepdegestrant gains approval, it could emerge as the preferred therapy for patients whose disease has progressed after CDK4/6 inhibition and endocrine treatment, especially those harboring ESR1 mutations.