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PROTAC ER Degraders in ER+/HER2- MBC Progressing After Endocrine Therapy: Emerging Mechanisms and Implications for Clinical Practice on the Horizon

Released: January 21, 2025

Expiration: January 20, 2026

Erika P. Hamilton
Erika P. Hamilton, MD
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Key Takeaways
  • Novel proteolysis-targeting chimeras (PROTACs) are molecules that enable effective degradation of both wild-type and mutant estrogen receptors (ERs).
  • The PROTAC ER degrader vepdegestrant in combination with CDK4/6 inhibitors demonstrates promise in previously treated patients with ER+/HER2- ESR1-mutant MBC.

Proteolysis-targeting chimera (PROTAC) estrogen receptor (ER) degraders are emerging as a novel class of highly effective therapeutic options for ER-positive, HER2-negative (ER+/HER2-) metastatic breast cancer (MBC). PROTAC ER degraders are designed to address resistance mechanisms that limit the efficacy of traditional endocrine therapies (ETs), offering the potential to improve clinical outcomes for patients with heavily pretreated and/or endocrine-resistant MBC.

The Current Landscape of ET in ER+/HER2- MBC
The current standard first-line treatment for ER+/HER2- MBC consists of ET with CDK4/6 inhibitors. However, development of ET resistance mechanisms remains a critical challenge in MBC therapy. ESR1 mutations, for example, are a prominent mechanism of resistance that develop during or following treatment with ET. These mutations can lead to constitutive activation of ERs despite estrogen depletion or receptor blockade, which enables tumor progression. ESR1 mutations are detected in approximately 4% of patients receiving first-line treatment for ER+/HER2- MBC and in approximately 40% of such patients after progression on ET. Despite much progress in the last several years, patients still progress on second-line options such as the injectable selective estrogen receptor degrader (SERD) fulvestrant in combination with a CDK4/6 inhibitor.

Recently, the FDA approved the oral SERD elacestrant for men and postmenopausal women with ER+/HER2-, ESR1-mutant MBC who relapse after ≥1 line of ET (1 line with CDK4/6 inhibitor) based on positive data from the phase III EMERALD study showing improved progression-free survival (PFS) with elacestrant compared with ET (8.6 vs 2.1 mo; HR: 0.466). Although elacestrant has provided disease survival benefit in patients with advanced MBC, particularly in ESR1-mutant tumors, an unmet need persists for novel strategies in those with disease progression.

Mechanisms and Advantages of PROTAC ER Degraders
PROTAC ER degraders represent an innovative approach to targeting the ER. Unlike SERDs, which block ER function and facilitate its degradation indirectly, PROTAC ER degraders actively recruit cellular machinery to ubiquitinate and degrade the ER protein via proteasomes. This event-driven pharmacology enables iterative degradation of ERs, allowing PROTACs to overcome limitations associated with occupancy-based inhibitors; these PROTACs can then be recycled to repeat the process on additional receptors.

The potential benefits of PROTAC ER degraders in clinical practice include:

  • Activity in ESR1-mutant tumors: PROTACs demonstrate efficacy in both wild-type and ESR1-mutant tumors, addressing a key mechanism of endocrine resistance.
  • Combination potential: their unique mechanism of action suggests potential combinability with targeted therapies such as CDK4/6 and mTOR inhibitors.
  • Oral administration: as oral agents, PROTACs provide a more convenient alternative to intramuscular SERDs such as fulvestrant, enhancing patient adherence.

Clinical Evidence for Vepdegestrant  
Vepdegestrant (ARV-471) is a PROTAC ER degrader currently in late-stage development. In the VERITAC phase I/II trial, vepdegestrant demonstrated encouraging activity either as monotherapy or in combination with the CDK4/6 inhibitor palbociclib.

  • Monotherapy: among patients with heavily pretreated disease who were treated with 200 mg/day dosing of vepdegestrant, the clinical benefit rate was 37.1% and 47.4% and median PFS was 3.5 and 5.7 months in the overall population and ESR1-mutated population, respectively. Vepdegestrant monotherapy demonstrated a favorable safety profile, with most treatment-emergent adverse events (AEs) being mild (grade 1/2). Common AEs with vepdegestrant 200 mg/daily in VERITAC included fatigue (22.9%), hot flush (20.0%), and arthralgia (11.4%), with minimal discontinuations due to toxicity (5.7%).
  • Combination with palbociclib: when combining vepdegestrant and palbociclib, patients achieved a clinical benefit rate of 63.0% and 72.4% and median PFS of 11.2 and 13.7 months, respectively, for all patients and those with ESR1-mutant disease, suggesting a relative improvement over ET in this setting. In combination with palbociclib, neutropenia was the most prominent AE with 100% of patients experiencing any grade of neutropenia followed by fatigue (62%) and decrease platelets (52%) during vepdegestrant 200 mg/daily cotreatment.

Additional reports reinforce the potential of PROTAC ER degraders as a potential new treatment option for patients with HR+/HER2- MBC. This includes extended efficacy in ESR1-mutant tumors: vepdegestrant’s PFS was sustained across broader ESR1-mutant cohorts, highlighting its role as a precision therapy in molecularly defined populations. We are also awaiting results for a few phase III trials with this agent. The phase III VERITAC-2 trial is comparing vepdegestrant monotherapy vs fulvestrant in patients with ER+/HER2- MBC after 1 line of prior treatment with CDK4/6i + ET and ≤1 additional line of ET, and results of this trial are expected soon. The initial lead-in data is also expected from the global, randomized phase III VERITAC-3 trial comparing first-line vepdegestrant plus palbociclib vs letrozole plus palbociclib in endocrine-sensitive patients with ER+/HER2- MBC. In addition, a new phase III trial assessing vepdegestrant in combination with an investigational CDK4 inhibitor, atirmociclib, is currently planned for 2025.

Data from a phase I, first-in-human, open-label, 3+3 dose escalation study of AC699, another novel PROTAC ER degrader, revealed impressive response rates of 56% in ESR1-mutant tumors (23% in all patients) with a favorable safety profile. All treatment-related AEs were grade 1 or 2, including nausea (11%), fatigue (6%), and hot flushes (14%). There were few grade ≥3 treatment-emergent AEs, no dose limiting toxicities, and no AC699-related serious AEs.

A Look Into the Future: Challenges and Opportunities
Despite their promise, challenges remain in the development and implementation of PROTACs including:

  • Biomarker development: refining predictive biomarkers beyond ESR1 mutations will be critical to optimizing patient selection and maximizing therapeutic benefit.
  • Combination toxicity: although PROTAC ER degraders such as vepdegestrant have shown excellent tolerability, long-term safety in combination with other agents requires further validation.

PROTAC ER degraders represent a paradigm shift in the treatment of ER+/HER2- MBC. By addressing resistance mechanisms and enabling innovative combination strategies, PROTAC ER degraders have the potential to redefine ET and address an unmet need for HR+/HER2- ESR1-mutant disease following progression to oral SERDs, offering renewed hope for patients with this challenging disease. We await further data from ongoing clinical trials to further validate the potential integration of PROTAC ER degraders into practice.

Your Thoughts?
How do you see PROTAC ER degraders fitting into your current treatment paradigm for ER+/HER2- MBC? Visit the program page, watch videos from a breast oncology expert, and download the slides associated with this discussion.

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