Which Class of ER Degrader Is Better?

Medscape

01-06-2025

Vepdegestrant, an investigational estrogen receptor (ER) degrader, known as a proteolysis-targeting chimera (PROTAC ), outshone the commonly used selective estrogen receptor degrader (SERD) fulvestrant in a phase 3 trial of second-line treatment for a subset of patients with breast cancer.
The VERITAC-2 trial included patients with ER-positive/human epidermal growth factor receptor 2-negative (ER+/HER2-), locally advanced or metastatic disease who had failed prior treatment with cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors and endocrine therapy, and no exposure to chemotherapy in the advanced setting.
Only a subset of the study cohort, those with estrogen receptor 1-mutant disease, experienced a statistically significant and clinically meaningful improvement in progression-free survival (PFS) when treated with vepdegestrant compared with patients treated with fulvestrant.
'These results support vepdegestrant as a potential monotherapy treatment option for patients with previously treated ESR1 -mutant ER+/HER2- advanced breast cancer,' said lead author Erika P. Hamilton, MD, a medical oncologist and director of Breast Cancer and Gynecologic Cancer Research at Sarah Cannon Research Institute, Nashville, Tennessee, during a press conference for the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting. The findings were simultaneously published in the New England Journal of Medicine .
Vepdegestrant is not approved by the US Food and Drug Administration, but received fast-track status in February 2024 as monotherapy for this patient population. It is the first and only PROTAC ER degrader to be evaluated in a phase 3 clinical trial in breast cancer. PROTACs represent a novel class of therapeutic agents that harness the proteasome to selectively degrade target proteins.
'There's no established consensus for patients getting treatment in the second-line setting after progression on endocrine therapy and a CDK 4/6 inhibitor,' explained Hamilton. 'One of the mainstays of our treatment really has been fulvestrant, which clearly has some challenges. First, it's administered intramuscularly, and second, in a post-CDK 4/6 landscape, we know that progression-free survival is very short — on the order of less than 2 months.'
Besides fulvestrant, the oral SERD elacestrant was FDA-approved in January 2023, and other oral SERDs are in development, she noted.
Trial Design
The new trial included 624 patients with advanced ER+/HER2- disease that had progressed following one or two lines of endocrine therapy and a CDK 4/6 inhibitor.
'They could not have received fulvestrant already or chemotherapy, and patients had to have benefited from their previous line of endocrine therapy for at least 6 months to enter the study,' Hamilton noted.
Study participants were also stratified by the presence or absence of visceral disease, as well as the presence of an ESR1 mutation (n = 270). Such mutations are a common cause of acquired resistance found in approximately 40% of patients in the second-line setting, according to a press release from the drug developer.
Patients were randomly assigned 1:1 to 28-day treatment cycles of either 200 mg oral vepdegestrant once daily, or 500 mg intramuscular fulvestrant on day 1 and day 15 of the first cycle, and then on day 1 of each subsequent cycle.
The primary endpoint was PFS by blinded, independent central review, first in patients with ESR1 mutations and then in the entire cohort.
Key secondary endpoints were overall survival, objective response rate, and clinical benefit rate, which was defined as the rate of confirmed clinical or partial response at any time, or stable disease, nonclinical response, or nonprogressive disease for at least 24 weeks.
Vepdegestrant vs Fulvestrant
The study met its key primary endpoint, showing a median PFS of 5.0 months with vepdegestrant compared with 2.1 months with fulvestrant (hazard ratio [HR] 0.57; P < .001) in the 270 patients with ESR1 mutations. At 6 months, twice as many patients in the vepdegestrant arm remained progression-free compared with those in the fulvestrant arm (45.2% vs 22.7%). However, this primary endpoint was not significantly different between groups when calculated for the entire patient population (HR, 0.83; P = .07).
For the key secondary endpoints, among patients with ESR1 mutations, the clinical benefit rate was more than double in patients receiving vepdegestrant (42.1% vs 20.2%). Similarly, the objective response rate was more than four times higher (18.6% vs 4%)
Commenting in a press release, ASCO breast cancer expert Jane Lowe Meisel, MD, said that although the trial found that vepdegestrant worked better than fulvestrant in patients with ESR1 mutations, 'on average, patients did not have prolonged responses on either agent, highlighting the need for combination therapies and continued development in this space.' Meisel is co-director of Breast Medical Oncology at the Winship Cancer Institute of Emory University School of Medicine in Atlanta, Georgia.
'Overall survival was very immature at the time of this analysis, with only 20% of the anticipated events occurring,' added lead investigator Hamilton.
Treatment-emergent adverse events (TEAEs) led to discontinuation in 3% of patients taking vepdegestrant and 1% of patients taking fulvestrant. TEAEs leading to dose reductions occurred in 2% of the vepdegestrant group and none in the fulvestrant group.
The three most common AEs of any grade were fatigue (27% in vepdegestrant group, 16% fulvestrant group) and increased aspartate aminotransferase and alanine aminotransferase levels of any grade (14% vepdegestrant group, 10% fulvestrant group).
Oral SERDS vs Vepdegestrant Side Effects
Compared to oral SERDs, vepdegestrant has a favorable side effect profile, Hamilton said.
'Oral SERDs have prominent GI side effects as their most frequent side effect.' But, across all grades, rates of both vomiting and diarrhea were only 6% with vepdegestrant.
GI side effects tend to be more common, 'in the 30% or 40% range with oral SERDs,' she told Medscape Medical News .
Study discussant William John Gradishar, MD, emphasized the importance of reducing side effects.
' Vepdegestrant now joins a growing list of drugs that perform better than current standard of care monotherapy' in the ESR1 -mutant population, he noted in the session.
But the reality is that most of these drugs are being developed to be used in combination with targeted therapies, 'and increased toxicity can be expected with doublet therapy…Quality of life measures as experienced and reported by patients are critical, and even modest changes in symptom and functional domains should not be minimized,' said Gradishar, professor of breast oncology at Northwestern University Feinberg School of Medicine, Chicago, Illinois.
'Vepdegestrant has demonstrated compelling preclinical activity and encouraging early clinical data supporting its efficacy in degrading ER,' said Albert Grinshpun, MD, in an interview with Medscape Medical News .
Grinshpun, head of the Breast Cancer Service at Shaare Zedek Medical Center and The Hebrew University, Jerusalem, Israel, said his initial takeaway from the study is that 'vepdegestrant now stands alongside other oral SERDs, such as elacestrant and imlunestrant, in demonstrating superiority over fulvestrant, specifically in the context of ESR1­ -mutant [disease].'
'Importantly, the treatment landscape for patients progressing on CDK 4/6 inhibitors is rapidly evolving, with a growing shift toward combination therapies rather than fulvestrant monotherapy,' he said. 'In my view, vepdegestrant has established itself as a promising endocrine backbone for future combination strategies. Its favorable toxicity profile makes it particularly well-suited for pairing with a range of targeted agents or even antibody-drug conjugates, including inhibitors of PIK3CA and KAT6 , in the pursuit of more effective therapeutic regimens.'
The study was jointly funded by Arvinas Estrogen Receptor, Inc. and Pfizer.
Hamilton disclosed consulting or advisory roles with Accutar Biotechnology (Inst), Arvinas (Inst), AstraZeneca (Inst), Circle Pharma (Inst), Daiichi Sankyo (Inst), Ellipses Pharma (Inst), Entos (Inst), Fosun Pharma (Inst), Genentech/Roche (Inst), Gilead Sciences (Inst), Janssen (Inst), Jazz Pharmaceuticals (Inst), Jefferies (Inst), Johnson & Johnson (Inst), Lilly (Inst), Medical Pharma Services (Inst), Mersana (Inst), Novartis (Inst), Olema Pharmaceuticals (Inst), Pfizer (Inst), Stemline Therapeutics (Inst), Tempus (Inst), Theratechnologies (Inst), Tubulis GmbH (Inst), Verascity Science (Inst), and Zentalis (Inst).
Hamilton has also received research funding from AbbVie (Inst), Accutar Biotech (Inst), Acerta Pharma (Inst), ADC Therapeutics (Inst), Akeso Biopharma (Inst), Amgen (Inst), Aravive (Inst), ArQule (Inst), Artios (Inst), Arvinas (Inst), AstraZeneca (Inst), AtlasMedx (Inst), BeiGene (Inst), Black Diamond Therapeutics (Inst), Bliss Biopharmaceutical (Inst), Boehringer Ingelheim (Inst), Bristol-Myers Squibb (Inst), Cascadian Therapeutics (Inst), Clovis Oncology (Inst), Compugen (Inst), Context Therapeutics (Inst), Cullinan Oncology (Inst), Curis (Inst), CytomX Therapeutics (Inst), Daiichi Sankyo (Inst), Dana-Farber Cancer Institute (Inst), Dantari (Inst), Deciphera (Inst), Duality Biologics (Inst), eFFECTOR Therapeutics (Inst), Eisai (Inst), Ellipses Pharma (Inst), Elucida Oncology (Inst), EMD Serono (Inst), Fochon Pharmaceuticals (Inst), Fujifilm (Inst), G1 Therapeutics (Inst), Genentech/Roche (Inst), Gilead Sciences (Inst), H3 Biomedicine (Inst), Harpoon (Inst), Hutchison MediPharma (Inst), Immunogen (Inst), Immunomedics (Inst), Incyte (Inst), Infinity Pharmaceuticals (Inst), Inspirna (Inst), InventisBio (Inst), Jacobio (Inst), K-Group Beta (Inst), Karyopharm Therapeutics (Inst), Kind Pharmaceuticals (Inst), Leap Therapeutics (Inst), Lilly (Inst), Loxo (Inst), Lycera (Inst), MabSpace Biosciences (Inst), Macrogenics (Inst), MedImmune (Inst), Mersana (Inst), Merus (Inst), Millennium (Inst), Molecular Templates (Inst), Myriad Genetics (Inst), Novartis (Inst), Nucana (Inst), Olema Pharmaceuticals (Inst), OncoMed (Inst), Oncothyreon (Inst), ORIC Pharmaceuticals (Inst), Orinove (Inst), Orum Therapeutics (Inst), Pfizer (Inst), PharmaMar (Inst), Pieris Pharmaceuticals (Inst), Pionyr (Inst), Plexxikon (Inst), Prelude Therapeutics (Inst), ProfoundBio (Inst), Radius Health (Inst), Regeneron (Inst), Relay Therapeutics (Inst), Repertoire Immune Medicines (Inst), Rgenix (Inst), Seagen (Inst), Sermonix Pharmaceuticals (Inst), Shattuck Labs (Inst), Silverback Therapeutics (Inst), Stem CentRx (Inst), Stemline Therapeutics (Inst), Sutro Biopharma (Inst), Syndax (Inst), Syros Pharmaceuticals (Inst), Taiho Pharmaceutical (Inst), TapImmune Inc. (Inst), Tesaro (Inst), Tolmar (Inst), Torque (Inst), Treadwell Therapeutics (Inst), Verastem (Inst), Zenith Epigenetics (Inst), and Zymeworks (Inst).
Meisel disclosed consulting or advisory roles with AstraZeneca, GE Healthcare, Genentech, Novartis, Olema Oncology, Pfizer, SeaGen, Sermonix Pharmaceuticals, and Stemline, and research funding from AstraZeneca (Inst), Olema Oncology (Inst), Pfizer (Inst), Seagen (Inst), and Sermonix Pharmaceuticals (Inst).
Grinshpun disclosed honoraria from GSK, Lilly, Novartis, and AstraZeneca, and travel from Roche, Pfizer, and AstraZeneca.
Gradishar disclosed consulting or advisory roles with AstraZeneca , Genentech/Roche, Gilead Sciences, Merck, Novartis, Pfizer.