PROTAC vs SERD: Is protein degradation the future of endocrine resistance treatment?

The clinical oncology landscape for estrogen receptor-positive, human epidermal growth factor receptor 2-negative (ER+/HER2-) advanced breast cancer is witnessing a disruptive transition with the emergence of PROteolysis TArgeting Chimera (PROTAC) therapies. Arvinas Inc. (NASDAQ: ARVN) and Pfizer Inc. (NYSE: PFE) are at the forefront of this paradigm shift with vepdegestrant, a PROTAC estrogen receptor degrader that is now being positioned as a post-CDK4/6 treatment option for patients with ESR1-mutant breast cancer.

The traditional class of endocrine therapies—selective estrogen receptor degraders (SERDs)—has long been the cornerstone of ER+ breast cancer treatment, particularly in metastatic settings. However, limitations in bioavailability, injection-based delivery, and growing endocrine resistance have prompted the development of alternative approaches, including oral SERDs like elacestrant and investigational candidates such as amcenestrant. Vepdegestrant introduces a fundamentally different mechanism, one that not only blocks but actively eliminates the estrogen receptor through proteasomal degradation. The Phase 3 VERITAC-2 results presented at ASCO 2025 suggest that this new approach could significantly alter the standard of care in endocrine-resistant settings.

How do PROTACs work differently from traditional SERDs?

Conventional SERDs function by binding to the estrogen receptor and inducing a conformational change that marks the receptor for degradation. Fulvestrant, the injectable reference standard, has demonstrated clinical benefit, but its slow onset of action and inconsistent bioavailability have encouraged the search for more effective oral alternatives. Oral SERDs such as elacestrant aim to address these limitations while retaining the fundamental mechanism of ER modulation and degradation.

PROTACs, by contrast, use a bifunctional molecule that links a ligand targeting the estrogen receptor to another ligand that recruits an E3 ubiquitin ligase. This results in the ubiquitination and subsequent proteasomal degradation of the target protein. Vepdegestrant is the first ER-targeting PROTAC to reach Phase 3 in oncology and, more notably, the first to demonstrate statistically significant clinical benefit in ESR1-mutant breast cancer patients.

In essence, while SERDs disrupt estrogen signaling by degrading ER directly, PROTACs hijack the body’s intracellular degradation machinery to eliminate ER altogether, which may improve efficacy and reduce the likelihood of resistance mutations accumulating downstream.

Comparing trial results: Vepdegestrant vs elacestrant and amcenestrant

Arvinas and Pfizer’s vepdegestrant gained widespread attention after results from the Phase 3 VERITAC-2 trial showed a 43% reduction in the risk of disease progression or death compared to fulvestrant in ESR1-mutant patients. Median progression-free survival (PFS) was 5.0 months versus 2.1 months in the fulvestrant arm. The objective response rate (ORR) was 18.6% compared to 4.0% for fulvestrant, while the clinical benefit rate (CBR) doubled at 42.1%. Importantly, this was achieved in the second-line setting following CDK4/6 inhibitor and endocrine therapy failure—a notoriously difficult subgroup to treat.

In comparison, elacestrant, an oral SERD developed by Radius Health and approved in 2023, demonstrated a median PFS of 8.6 months versus 1.9 months in ESR1-mutant patients in the Phase 3 EMERALD trial. However, the benefit in the overall population was less pronounced, and the trial was powered specifically for the ESR1-mutant subgroup. Amcenestrant, developed by Sanofi, failed to meet the primary endpoint in the AMEERA-5 trial and was withdrawn from further development.

While elacestrant showed a higher PFS numerically, differences in patient populations, trial designs, and comparator arms make head-to-head comparison speculative. Notably, vepdegestrant remains the only PROTAC to show positive Phase 3 data in this setting, offering a mechanism that could bypass common resistance pathways associated with standard SERDs.

Safety and tolerability: How do patients fare across modalities?

Vepdegestrant’s safety profile has been a core strength of the program. In VERITAC-2, rates of gastrointestinal-related adverse events were low, with nausea at 13.5%, vomiting and diarrhea each at 6.4%. Grade 4 treatment-emergent adverse events occurred in just 1.6% of patients, and discontinuation rates were 2.9%. Fatigue was the most common adverse event, but liver enzyme elevations were limited and manageable.

Elacestrant similarly exhibited a favorable safety profile, although nausea was more common, affecting over 25% of patients in some cohorts. The oral route of administration offers greater convenience compared to fulvestrant’s monthly intramuscular injections. Amcenestrant, although discontinued, had demonstrated an acceptable safety profile with no significant toxicity red flags. However, efficacy remains the defining metric for market adoption.

How are investors reacting to vepdegestrant’s Phase 3 results?

For Arvinas, vepdegestrant could be a transformative product. Following the release of full Phase 3 data, shares of Arvinas rose 8.7% on June 6, 2025, though the stock remains down significantly from its 2023 highs. Analysts from Guggenheim and Jefferies maintain a “Moderate Buy” consensus, with an average price target of $20.29. Institutional ownership exceeds 94%, though concerns persist around capital needs due to a reported $250 million annual cash burn.

Pfizer, while less directly impacted by vepdegestrant’s performance given its broader oncology and vaccine portfolio, views the product as a strategic addition to its post-Ibrance breast cancer pipeline. The New York-based pharmaceutical giant retains robust institutional inflows and maintains its dividend position, suggesting that investors view vepdegestrant as part of a long-term oncology rebuild rather than a primary growth driver.

Commercial forecasts for vepdegestrant estimate peak sales of around $576 million by 2032, assuming FDA approval in 2025 and moderate uptake in the ESR1-mutant segment. For comparison, elacestrant was expected to generate peak sales north of $400 million based on earlier modeling. However, vepdegestrant’s differentiated mechanism and broader developmental potential may unlock additional value in combination settings and earlier lines of therapy.

Is protein degradation the new standard in endocrine resistance?

The field of endocrine therapy is increasingly embracing biomarker-driven segmentation, and ESR1 mutation status is emerging as a critical decision-making factor. As diagnostics like Guardant360 and FoundationOne expand accessibility to ESR1 mutation testing, oncologists are better equipped to tailor treatment regimens post-CDK4/6 inhibition.

While SERDs like elacestrant offer an improvement over fulvestrant, they may still be vulnerable to emerging resistance mechanisms. PROTACs like vepdegestrant offer a more aggressive strategy—eliminating the estrogen receptor entirely rather than merely degrading it. This could reduce clonal evolution and potentially extend treatment durability.

Analysts suggest that if PROTACs continue to show efficacy with minimal toxicity, they could become a new foundational class in endocrine oncology. Future data from combination trials, as well as ongoing studies in earlier settings, will determine whether PROTACs like vepdegestrant can fully displace oral SERDs in the treatment paradigm.

Future outlook: What comes next in the PROTAC vs SERD race?

Arvinas and Pfizer have confirmed their intent to file a New Drug Application (NDA) for vepdegestrant with the U.S. Food and Drug Administration in the second half of 2025. Fast Track designation has already been granted, positioning the candidate for expedited review.

Meanwhile, other PROTAC developers such as Kymera Therapeutics and C4 Therapeutics are progressing oncology-focused programs, though none have reached Phase 3 in breast cancer. If approved, vepdegestrant would be the first commercialized PROTAC therapy in oncology, setting the stage for broader clinical adoption of targeted protein degradation platforms.

The future of endocrine resistance treatment may well depend on the ability of PROTACs to combine high specificity with systemic tolerability. Whether vepdegestrant becomes the standard of care or a niche option remains to be seen—but its Phase 3 success has already signaled a shift in what oncologists expect from next-generation endocrine therapies.