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PROTAC ER Degraders
Thoughts on Emerging PROTAC ER Degraders for Patients With Advanced HR+/HER2- Metastatic Breast Cancer

Released: October 01, 2025

Rita Nanda
Rita Nanda, MD
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Key Takeaways
  • Despite recent approvals of new therapies for HR-positive/HER2-negative metastatic breast cancer (mBC) including oral SERDs and PI3K/AKT/mTOR inhibitors, a need for novel therapies remains.
  • Vepdegestrant, a novel PROTAC ER degrader, shows promise as single agent and in combination with palbociclib in patients with previously treated ER-positive/HER2-negative ESR1-mutant mBC.
  • Clinical development of PROTAC ER degraders could benefit from analysis of optimal sequencing with oral SERDs to better understand efficacy and safety of these agents in the context of the current treatment paradigm.

The general approach to managing patients with metastatic hormone receptor–positive/HER2-negative (HR+/HER2-) advanced or metastatic breast cancer (mBC) is to exhaust endocrine-based therapy (ET) before moving on to chemotherapy or antibody–drug conjugates. In the first-line setting, treatment options are often informed by what the patient received previously as adjuvant treatment for early-stage disease and how long they received that therapy. In patients with newly diagnosed mBC, an aromatase inhibitor (AI) plus a CDK4/6 inhibitor is currently the most used approach. If they have recurred on adjuvant ET plus a CDK4/6 inhibitor, this can be a more challenging situation. At this point, we pursue genomic testing preferably using a liquid biopsy and next-generation sequencing (NGS) to gain an understanding of the genetic profile of the disease.   

Current Unmet Needs in HR+/HER2- Advanced Breast Cancer
Despite clinical advancements within the last decade for patients with HR+/HER2- mBC, those treated with second-line treatment options such as the injectable selective estrogen receptor degrader (SERD) fulvestrant in combination with a CDK4/6 inhibitor often experience disease progression due to resistance mutations in the ESR1 gene. ESR1 mutations are identified in approximately 4% of patients undergoing first-line treatment for HR+/HER2- mBC and approximately 40% of patients who experience disease progression on ET.

Optimal Timing for Assessing ESR1 Mutations in Patients Progressing on AI + CDK4/6 Inhibitor
A liquid biopsy and tumor sequencing are often performed at the time of metastatic disease diagnosis. A liquid biopsy might also be warranted at the time of disease progression on initial therapy for advanced/metastatic disease. Based on the trials leading to CDK4/6 inhibitor approvals (PALOMA, MONALEESA, and MONARCH) the median time on ET therapy with a CDK4/6 inhibitor is approximately 20‑24 months. However, there are patients who may progress much more rapidly. Patients with rapid progression on ET are often suspected of not being endocrine sensitive and, depending on disease burden (eg, visceral metastases, high-volume of disease), the treating healthcare professional (HCP) might consider moving on to chemotherapy as the next line of therapy. However, for most patients with early progression with adjuvant therapy—and maybe also for any patient with progression on first-line therapy between 6 and 12 months—experts often consider rechallenge with another line of ET (ie, bone-only disease). That said, if patients are rapidly progressing through ET, even if it is bone-only, moving on to chemotherapy or ADC might be a better option.

These limitations spurred the development of oral SERDs with better bioavailability and superior ER-degrading potential than the injectable SERD, fulvestrant. In patients with ESR1 mutation, elacestrant, an oral SERD, is an option for the treatment of men and postmenopausal women with ER+/HER2- ESR1-mutated advanced or mBC with disease progression on at least 1 line of ET. Its approval was supported by results from the phase III EMERALD trial of elacestrant vs investigator’s choice of standard of care (SoC) ET in patients with ER+/HER2- mBC. In EMERALD, elacestrant yielded improved median progression-free survival (PFS) vs SoC ET in the overall population (HR: 0.70; P = .0018) and in patients with ESR1-mutated disease (HR: 0.50; P = .0005).

The oral SERD imlunestrant was also recently approved for the treatment of adults with ER+/HER2- ESR1-mutated advanced or mBC whose disease progressed after at least 1 line of ET based on data from the phase III EMBER trial where imlunestrant was shown to significantly improve median PFS compared with fulvestrant or exemestane (5.5 vs 3.8 months; HR: 0.62; P =.0008). Thus, for patients with ESR1 mutations, and more recently PI3K/AKT/PTEN alterations, biomarker-driven options are often good alternatives. Unfortunately, patients with ESR1 mutations ultimately relapse on elacestrant.

Emerging Novel Agents in HR+/HER2- Advanced Breast Cancer
We would often favor a clinical trial over SoC if the patient is interested and there is a clinical trial available that we can offer to them. New agents under development for the treatment of HR+/HER2- advanced breast cancer and disease progression on ET plus CDK4/6 inhibitor, including in patients with an ESR1 mutation, are the PROTAC ER degraders.

How PROTAC ER Degraders Differ From Oral SERDs
Oral SERDs bind selectively to the estrogen receptor, prevent signaling, and lead to indirect receptor degradation, including in ER receptors with an ESR1 mutation. The PROTAC ER degrader vepdegestrant is composed of a linker that connects the targeting moiety (ER receptor's ligand) and an E3 ligase recruiting segment leading to proteasomal degradation by the ubiquitin proteosome system. Different from other ER-receptor targeting mechanisms, the event-driven action of PROTAC ER degraders enables iterative degradation of ERs, allowing these novel agents to overcome limitations associated with occupancy-based inhibitors. Of note, PROTAC ER degraders can also be recycled to repeat the process on additional receptors.

Although the mechanisms of action for oral SERDs and PROTAC ER degraders are different, we must think about the efficacy data and how they apply to the patient populations that we see in our clinics.

Available Data for PROTAC ER Degraders
The phase I/II VERITAC trial evaluated oral vepdegestrant at 200 mg/daily or 500 mg/daily alone or in combination with palbociclib in postmenopausal women with confirmed ER+/HER2- advanced breast cancer and measurable disease per RECIST v1.1. In the phase I dose-expansion portion of the trial, investigators showed that vepdegestrant was safe and well tolerated in 71 patients and yielded a clinical benefit rate of 38% overall, including in patients with ESR1 mutation. The optimal vepdegestrant dose for safety and efficacy in the phase II portion of the study was determined to be 200 mg/daily. In the combination arm of VERITAC evaluating vepdegestrant plus palbociclib we saw a clinical benefit rate of 63% for all patients and 72.4% in patients with ESR1 mutations, and median PFS of approximately 11.0 and 14 months, respectively. Common adverse events with vepdegestrant 200 mg/daily included fatigue (22.9%), hot flush (20.0%), and arthralgia (11.4%), with minimal discontinuations due to toxicity (5.7%).

More recently, the phase II VERITAC-2 trial evaluated oral vepdegestrant 200 mg/daily vs injectable fulvestrant 500 mg in adults with ER+/HER2- advanced or mBC who had 1 prior line of CDK4/6 inhibitor plus ET and at least 1 additional line of ET, with the most recent ET given for ≥6 months before disease progression. Patients were not eligible for VERITAC-2 enrollment if they had previous chemotherapy or SERD. In the overall patient population, the median PFS with oral vepdegestrant vs fulvestrant did not reach statistical significance (3.7 vs 3.6 months; P = .07). However, in patients with ESR1 mutation, oral vepdegestrant yielded improved median PFS improvement (5.0 vs 2.1 months; 2-sided P <.001) vs injectable fulvestrant. In combination with palbociclib, neutropenia was the most prominent adverse event with 100% of patients experiencing any grade of neutropenia followed by any grade fatigue (62%) and decrease platelets (52%).

These studies were designed with disadvantages. VERITAC did not include oral SERDs as previously allowed therapy, and in VERITAC-2 the active comparator was an injectable SERD and did not allow any previous SERD (either injectable or oral). These limitations are notable because the data do not help determine the best sequencing of these agents. At present, we do not have data regarding the efficacy or safety of a PROTAC ER degrader following an oral SERD or vice versa. However, with the caveat that cross-trial comparisons can be misleading and should be taken with some level of skepticism, data for the oral SERDs elacestrant and PROTAC ER degrader vepdegestrant do appear to be similar regarding equivalency vs an injectable SERD in the overall population. In addition, both are superior to injectable fulvestrant in patients who have ESR1-mutated ER+/HER2- advanced or mBC.

As other oral SERDs and PROTAC inhibitors become available, healthcare professionals will have to decide which class of agents they are going to use based on the patient and disease characteristic and shared decision-making.

Although PROTAC ER degraders are not yet available as an option for patients with HR+/HER2- advanced or mBC, the potential benefits to clinical practice if available 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 the potential for combining with targeted therapies such as CDK4/6 inhibitors.
  • Oral administration: As oral agents, PROTACs provide a more convenient alternative to intramuscular SERDs such as fulvestrant, enhancing patient adherence.

Ongoing Trials or PROTAC ER Degraders
The open-label, global, multicenter, randomized, phase III VERITAC-3 study is evaluating vepdegestrant in combination with palbociclib vs letrozole plus palbociclib in 1130 patients with ER+/HER2- locoregionally recurrent or mBC with no prior treatment in the advanced setting and no prior treatment in any setting with CDK4/6 inhibitor, fulvestrant, elacestrant, or other investigational ER degraders or antagonists, and no disease recurrence during or within 12 months after completing ET (NCT05909397). Like the other VERITAC trials, the limitation of VERITAC-3 is that we are not generally using palbociclib in the first-line setting because of lack of survival benefit with palbociclib. However, what I think would be most valuable from this trial will be the assessment of the safety of the combined agents (vepdegestrant plus palbociclib).

Vepdegestrant is also being evaluated in a phase I/II trial as combination therapy with PF-07220060 (atirmociclib), an investigational potent selective CDK4 inhibitor, in patients with advanced disease not amenable for surgical resection with curative intent or mBC (NCT06206837).

Looking Ahead: Future of HR-Positive mBC Treatment
HR+/HER2- advanced/mBC is the most common form of breast cancer with several therapies recently becoming available and many more under development. This is an area of constant knowledge expansion with new information available every few months. I encourage my breast oncology colleagues to join me and my colleague Adrienne Waks, MD, in exploring the changing landscape for the treatment of HR+/HER2- advanced/mBC, including an opportunity to learn about some of the newer emerging agents such as PROTAC ER degraders and their implications for clinical practice in the horizon.

Your Thoughts
What are your challenges and questions related to your everyday care of patients with ER+/HER2- mBC? Join the discussion by leaving us a comment. Visit the program page and register for upcoming live webinar associated with this discussion.

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