Endocrine therapy remains the backbone of treatment for estrogen receptor–positive (ER+), HER2-negative advanced breast cancer. However, resistance to endocrine therapies inevitably develops, particularly after exposure to aromatase inhibitors and CDK4/6 inhibitors. The emergence of novel estrogen receptor–directed agents aims to overcome this resistance and extend the durability of endocrine control. Vepdegestrant (ARV-471, PF-07850327) represents a next-generation approach to estrogen receptor targeting, leveraging targeted protein degradation rather than receptor antagonism alone.
Vepdegestrant is currently being evaluated in the Phase III VERITAC-2 trial, which compares the drug directly with fulvestrant in patients with ER-positive, HER2-negative advanced breast cancer who have progressed after prior endocrine-based therapy. This study positions vepdegestrant at a critical point in the treatment sequence, where therapeutic options are limited and resistance biology dominates clinical outcomes.
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Mechanism of Action: Estrogen Receptor Degradation via PROTAC Technology
Vepdegestrant is an oral selective estrogen receptor degrader (SERD) developed using PROTAC (proteolysis-targeting chimera) technology. Unlike traditional SERDs such as fulvestrant, which bind and destabilize the estrogen receptor, PROTACs actively recruit the cell’s ubiquitin–proteasome system to induce targeted degradation of the estrogen receptor protein.
At the molecular level, vepdegestrant simultaneously binds the estrogen receptor and an E3 ubiquitin ligase, forming a ternary complex that marks the receptor for proteasomal degradation. This results in near-complete elimination of estrogen receptor protein, including mutant forms such as ESR1 ligand-binding domain mutations, which are a well-recognized driver of endocrine resistance after aromatase inhibitor exposure. Preclinical studies demonstrated that vepdegestrant achieves deeper and more sustained ER suppression than fulvestrant, providing a strong biological rationale for its clinical development.
Rationale for Development After CDK4/6 Inhibitors
The widespread adoption of CDK4/6 inhibitors in combination with endocrine therapy has significantly improved outcomes in ER-positive metastatic breast cancer. However, most patients eventually experience disease progression. Post-CDK4/6 inhibitor progression is frequently characterized by ER pathway reactivation, often mediated by ESR1 mutations, ligand-independent signaling, or altered co-regulatory networks.
Fulvestrant has been a standard option in this setting, but its intramuscular administration, incomplete receptor degradation, and limited efficacy in ESR1-mutant disease highlight the need for more potent ER-directed agents. Vepdegestrant was designed specifically to address these limitations by providing oral administration, systemic exposure, and robust ER degradation, potentially translating into improved disease control.
VERITAC-2 Trial: Study Design and Key Data
The clinical efficacy and safety of vepdegestrant are being evaluated in VERITAC-2, a Phase III, randomized, open-label, multicenter trial designed to directly compare vepdegestrant with fulvestrant in patients with estrogen receptor–positive, HER2-negative advanced breast cancer whose disease progressed after prior endocrine-based therapy.
The trial enrolled adult patients with recurrent or metastatic disease that was not amenable to curative surgery or radiation. All participants were required to have estrogen receptor–positive disease, reflecting continued endocrine sensitivity, and must have received one prior line of CDK4/6 inhibitor therapy in combination with endocrine therapy for advanced disease. Up to one additional line of endocrine therapy for advanced disease was permitted, aligning the study population with contemporary post–CDK4/6 clinical practice.
Participants were randomized in a 1:1 ratio to receive either oral vepdegestrant (ARV-471, PF-07850327) administered once daily on a continuous 28-day dosing schedule, or intramuscular fulvestrant, administered on Days 1 and 15 of Cycle 1 and then every 28 days thereafter. Treatment in both arms continued until radiographic disease progression, unacceptable toxicity, or treatment discontinuation for other protocol-defined reasons.
The primary endpoint of VERITAC-2 is progression-free survival (PFS), defined as the time from randomization to first documented disease progression or death from any cause, whichever occurs first. Disease progression is assessed by blinded independent central review (BICR) according to RECIST version 1.1, with radiographic evaluations performed every 8 weeks during the first 48 weeks and every 12 weeks thereafter. This endpoint reflects the trial’s central objective of determining whether deeper estrogen receptor degradation with vepdegestrant can prolong disease control compared with fulvestrant.
Key secondary endpoints include overall survival, objective response rate, duration of response, and clinical benefit rate, all assessed by BICR using RECIST 1.1 criteria. These measures provide a comprehensive assessment of tumor response, durability of benefit, and long-term outcomes in a population with limited endocrine treatment options.
The trial also incorporates an extensive evaluation of patient-reported outcomes and quality of life, including health status measured by the EQ-5D-5L, disease-related quality of life assessed by the EORTC QLQ-C30 and QLQ-BR23, and symptom burden evaluated using the Brief Pain Inventory. These assessments are conducted longitudinally throughout treatment to capture both change from baseline and time to deterioration, recognizing the importance of tolerability and symptom control in advanced breast cancer.
Safety assessments include the incidence of treatment-emergent adverse events, serious adverse events, laboratory abnormalities, and electrocardiographic monitoring, including QT interval evaluation. Pharmacokinetic analyses of plasma vepdegestrant concentrations are also performed to characterize exposure over time.
Collectively, the VERITAC-2 trial is designed to determine whether the enhanced estrogen receptor degradation achieved by vepdegestrant translates into meaningful clinical benefit compared with fulvestrant, while maintaining an acceptable safety and quality-of-life profile in patients with ER-positive, HER2-negative advanced breast cancer.
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Efficacy Endpoints and Clinical Meaning
The primary endpoint of VERITAC-2 is progression-free survival (PFS), assessed by blinded independent central review (BICR) using RECIST v1.1 criteria. This endpoint reflects the clinical priority of delaying disease progression in a population with limited endocrine sensitivity.
Key secondary endpoints include overall survival, objective response rate, duration of response, and clinical benefit rate, providing a comprehensive assessment of both tumor control and durability of benefit. Importantly, the trial also incorporates extensive patient-reported outcomes, including quality-of-life assessments using EQ-5D-5L, EORTC QLQ-C30, and QLQ-BR23 instruments, recognizing that tolerability and symptom control are critical considerations in long-term endocrine therapy.
Safety and Tolerability Considerations
Safety evaluation in VERITAC-2 includes treatment-emergent adverse events, serious adverse events, laboratory abnormalities, and electrocardiographic monitoring, including QT interval assessment. The oral administration of vepdegestrant offers a potential advantage over intramuscular fulvestrant in terms of patient convenience, but long-term safety data are essential to establish its role in chronic therapy.
Early-phase clinical experience with vepdegestrant suggested a manageable safety profile, with adverse events largely consistent with endocrine therapy and limited off-target toxicity. The Phase III trial will be pivotal in determining whether enhanced ER degradation translates into improved efficacy without compromising tolerability.
Quality of Life as a Central Outcome
A notable feature of the VERITAC-2 trial is its comprehensive evaluation of quality-of-life endpoints, including pain, functional status, and disease-related symptoms. As patients with advanced ER-positive breast cancer often remain on therapy for prolonged periods, maintaining quality of life is as important as prolonging progression-free survival.
The inclusion of validated instruments such as the Brief Pain Inventory and EORTC questionnaires reflects a growing emphasis on patient-centered outcomes in oncology drug development. Demonstrating preserved or improved quality of life compared with fulvestrant would further strengthen the clinical value proposition of vepdegestrant.
Potential Impact on the Treatment Landscape
If VERITAC-2 demonstrates superior progression-free survival with acceptable safety, vepdegestrant could redefine the standard of care for patients with ER-positive, HER2-negative advanced breast cancer after CDK4/6 inhibitor progression. Its oral administration and mechanistic advantages over fulvestrant position it as a potential foundational endocrine therapy in later-line settings.
Beyond its direct comparison with fulvestrant, vepdegestrant also opens the door to combination strategies, including pairing with CDK4/6 inhibitors, PI3K inhibitors, or novel targeted agents. Its ability to degrade mutant estrogen receptor variants may be particularly relevant as molecular profiling becomes increasingly integrated into treatment selection.
Conclusion
Vepdegestrant represents a significant evolution in estrogen receptor targeting, shifting from receptor antagonism to active protein degradation. Through the VERITAC-2 Phase III trial, vepdegestrant is being rigorously tested against fulvestrant in a clinically relevant population that reflects modern treatment sequencing.
As resistance to endocrine therapy remains a central challenge in ER-positive advanced breast cancer, agents capable of deeper and more durable estrogen receptor suppression are urgently needed. The results of VERITAC-2 will be closely watched, as they may establish vepdegestrant as a new standard endocrine option and further validate PROTAC technology as a transformative platform in oncology drug development.
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Written by Armen Gevorgyan, MD