Can vepdegestrant outperform elacestrant in the race for ESR1-mutant breast cancer dominance?

What is vepdegestrant’s mechanism and its edge over elacestrant?

Arvinas Inc. (NASDAQ: ARVN) and Pfizer Inc. (NYSE: PFE) have brought forward a potentially disruptive therapy in the form of vepdegestrant, an oral PROteolysis TArgeting Chimera (PROTAC) molecule designed to degrade the estrogen receptor (ER) in estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer. This investigational therapy targets both wild-type and mutant estrogen receptors, including the ESR1 mutation that is often responsible for endocrine therapy resistance. The mechanism of action—tethering the ER to an E3 ligase to initiate ubiquitination and subsequent proteasomal degradation—goes beyond the capabilities of traditional selective estrogen receptor degraders (SERDs), which simply bind and destabilize the receptor.

Elacestrant (marketed as Orserdu by Stemline Therapeutics), by comparison, is an oral SERD that binds to the ER and inhibits its transcriptional activity. While elacestrant was the first oral SERD approved by the U.S. Food and Drug Administration (FDA) in January 2023, vepdegestrant offers an entirely different modality that may translate into deeper and more durable responses, particularly in patients with ESR1 mutations.

How did vepdegestrant perform in the Phase 3 VERITAC-2 trial?

Vepdegestrant’s clinical credibility rests on the results of the Phase 3 VERITAC-2 trial, which enrolled 624 patients with ER+/HER2- advanced or metastatic breast cancer who had previously received cyclin-dependent kinase (CDK) 4/6 inhibitors and endocrine therapy. Among the ESR1-mutant subset, vepdegestrant reduced the risk of disease progression or death by 43% compared to fulvestrant, with a hazard ratio (HR) of 0.57 and a median progression-free survival (PFS) of 5.0 months versus 2.1 months for fulvestrant.

Other secondary endpoints were also met in the ESR1-mutant cohort. The clinical benefit rate (CBR) was 42.1% for vepdegestrant, compared to 20.2% with fulvestrant. The objective response rate (ORR) was 18.6% versus 4.0%. Overall survival (OS) data remain immature, with less than 25% of the required events accrued at the time of interim analysis. A New Drug Application (NDA) for vepdegestrant was submitted to the FDA in June 2025 under Fast Track designation, signaling regulatory momentum.

How does elacestrant compare based on EMERALD trial results?

Elacestrant was approved based on the results of the Phase 3 EMERALD trial, which randomized 477 postmenopausal women and men with ER+/HER2- advanced breast cancer who had received 1–2 prior endocrine therapies, including a CDK4/6 inhibitor. In the ESR1-mutant subgroup, which accounted for nearly half the cohort, elacestrant achieved a median PFS of 3.8 months versus 1.9 months for standard endocrine therapy, with a hazard ratio of 0.55. Among all patients regardless of mutation status, the median PFS was 2.8 months.

While elacestrant’s performance was sufficient for regulatory approval, especially given its oral formulation compared to injectable fulvestrant, its modest absolute PFS gain has been a point of discussion in the oncology community. Unlike vepdegestrant, which demonstrated numerical superiority over fulvestrant in a PROTAC-driven context, elacestrant’s efficacy is tightly linked to ESR1 mutation status and does not leverage targeted degradation.

How do the safety profiles of vepdegestrant and elacestrant compare?

Vepdegestrant demonstrated a favorable safety profile in the VERITAC-2 trial. Gastrointestinal adverse events were relatively low, with nausea, vomiting, and diarrhea occurring in fewer than 14% of patients. Fatigue was reported in 26.6% of patients, and Grade 4 treatment-emergent adverse events occurred in just 1.6% of those treated. Importantly, only 2.9% of patients discontinued treatment due to adverse events.

Elacestrant, while well-tolerated overall, has been associated with more frequent gastrointestinal issues, particularly nausea and fatigue, leading to some real-world discontinuation. In the EMERALD trial, nausea affected over 25% of patients. While both agents benefit from oral administration, vepdegestrant’s more favorable tolerability profile may improve adherence and quality of life in longer-term treatment settings.

What is the commercial potential of vepdegestrant versus elacestrant?

Elacestrant entered the market as the first oral SERD approved for ESR1-mutant metastatic breast cancer and has already begun establishing market share. However, its real-world uptake has been tempered by its modest PFS benefit and lack of differentiation in non-mutant patients.

In contrast, analysts forecast vepdegestrant to reach peak global sales of approximately $576 million by 2032 if approved and adopted broadly. The ESR1-mutant metastatic ER+/HER2- population in the United States alone is estimated to represent a $3 billion market, with room for multiple therapies. However, vepdegestrant’s superior efficacy and tolerability may allow it to secure first-mover advantage in the PROTAC category and potentially surpass elacestrant in market share.

For Arvinas, this represents a pivotal opportunity to anchor its PROTAC pipeline in a commercial setting. The Connecticut-based biotech has seen a rebound in investor sentiment following the VERITAC-2 data, although concerns persist over cash burn rates and capital efficiency. Pfizer, meanwhile, views vepdegestrant as a key piece in rebuilding its oncology portfolio following the waning impact of Ibrance.

Can vepdegestrant achieve long-term market leadership?

The answer may hinge on two factors: expansion into earlier lines of therapy and combination strategies. Elacestrant is currently exploring combination studies with CDK4/6 and PI3K inhibitors, but vepdegestrant’s PROTAC-based mechanism could offer synergistic advantages when paired with existing regimens. Physicians are likely to favor options with broad activity across ESR1 mutation subtypes and a lower burden of adverse effects.

Moreover, if vepdegestrant secures approval in 2025, it would be the first PROTAC therapy ever approved for oncology, creating a branding halo effect and ushering in broader adoption of protein degradation platforms. It could also catalyze follow-on investment into related programs at companies like Kymera Therapeutics, C4 Therapeutics, and Nurix Therapeutics.

What are the key limitations and unknowns?

While vepdegestrant shows stronger efficacy signals compared to elacestrant in ESR1-mutant patients, no head-to-head clinical trials have been conducted. Differences in trial design, comparator arms, and patient populations prevent definitive conclusions about superiority. Furthermore, long-term safety, resistance mechanisms, and real-world adherence patterns are still unknown for vepdegestrant.

Elacestrant benefits from first-mover advantage, deeper physician familiarity, and ongoing trials in broader populations. Vepdegestrant, though promising, must still prove its consistency across diverse care settings.

Future outlook: Are PROTACs poised to lead in endocrine resistance?

The broader oncology field is taking note of vepdegestrant’s trajectory. Should the FDA approve it by early 2026, its success may validate protein degradation as a therapeutic strategy beyond breast cancer. Pipeline efforts in prostate cancer, lymphoma, and even neurodegeneration are already exploring PROTAC applications.

In the narrower context of ESR1-mutant breast cancer, vepdegestrant appears well-positioned to overtake elacestrant based on efficacy, tolerability, and platform novelty. However, market penetration will depend on prescriber education, diagnostics integration, and payer support.

If these hurdles are cleared, vepdegestrant may not only outperform elacestrant but also redefine how resistance-driven cancer subtypes are treated.