Data presented at the 2025 ESMO Congress showed that per the EORTC QLQ-C30 Global Health Status/QOL questionnaire, vepdegestrant (n = 127) led to a median time to definitive deterioration (TTDD) of 12.0 months (95% CI, 6.7-15.8) vs 4.8 months (95% CI, 3.9-8.6) with fulvestrant (n = 129; HR, 0.60; 95% CI, 0.40-0.91; P = .015). Per the EQ-5D-5L VAS, the median TTDD with vepdegestrant was 9.2 months (95% CI, 6.5-not evaluable [NE]) vs 5.8 months (95% CI, 3.8-8.3) with fulvestrant (HR, 0.59; 95% CI, 0.39-0.89; P = .012).
Moreover, spanning all functioning domains of the EORTC QLQ-C30 and QLQ-BR23, the risk of clinically meaningful definitive deterioration was numerically lower with vepdegestrant compared with fulvestrant; 5 of the 7 domains had risk reductions that were determined to be statistically significant. With regard to physical functioning, the median TTDD with vepdegestrant was 14.4 months (95% CI, 8.4-NE) vs NE (95% CI, 4.6-NE) with fulvestrant (HR, 0.79; 95% CI, 0.50-1.26; P = .326). In terms of role functioning, the median TTDD was 14.0 months (95% CI, 6.5-NE) and 5.7 months (95% CI, 3.8-NE), respectively (HR, 0.64; 95% CI, 0.42-0.97; P = .031).
With regard to emotional functioning, the respective median TTDD was 14.4 months (95% CI, 10.2-NE) and NE (95% CI, 6.0-NE; HR, 0.57; 95% CI, 0.35-0.93; P = .023). With regard to cognitive functioning, the median TTDD with vepdegestrant was 12.0 months (95% CI, 9.5-NE) vs 10.9 months (95% CI, 4.7-NE) with fulvestrant (HR, 0.53; 95% CI, 0.33-0.84; P = .006). In terms of social functioning, the median TTDD was 14.0 months (95% CI, 9.5-NE) and 4.7 months (95% CI, 4.0-8.3), respectively (HR, 0.52; 95% CI, 0.34-0.81; P = .003). The median TTDD for body image with vepdegestrant was NE (95% CI, 12.2-NE) vs NE (95% CI, 5.4-NE) with fulvestrant (HR, 0.42; 95% CI, 0.23-0.77; P = .004). Lastly, the median TTDD with regard to future perspective in the respective arms was 17.0 months (95% CI, 10.0-NE) and 10.3 months (95% CI, 5.6-NE; HR, 0.62; 95% CI, 0.36-1.04; P = .069).
Risk of clinically meaningful definitive deterioration in pain was also found to be significantly lower with vepdegestrant compared with fulvestrant across all assessed pain measures, including the BPI-SF and EORTC QLQ-C30. Per BPI-SPF, the median TTDD with vepdegestrant for item 3 “worst pain” was NE (95% CI, 14.4-NE) vs NE (95% CI, 4.6-NE) with fulvestrant (HR, 0.49; 95% CI, 0.29-0.83; P = .007). With regard to pain severity, the median TTDD with the respective approaches were also NE (95% CI, NE-NE) and NE (95% CI, 6.5-NE; HR, 0.55; 95% CI, 0.31-0.97; P = .036). In terms of pain interference, the median TTDD with vepdegestrant was 14.4 months (95% CI, 14.0-NE) vs NE (95% CI, 6.8-NE) with fulvestrant (HR, 0.57; 95% CI, 0.32-1.00; P = .048).
Lastly, the risk of clinically meaningful deterioration was numerically lower with vepdegestrant vs fulvestrant across all symptom domains of the EORTC QLQ-C30 and QLQ-BR23 questionnaires, with significant reductions observed with regard to pain, dyspnea, and constipation. Specifically, the median TTDD with vepdegestrant for pain was 9.5 months (95% CI, 6.5-16.1) vs 4.6 months (95% CI, 2.9-8.3) with fulvestrant (HR, 0.64; 95% CI, 0.43-0.96; P = .030). For dyspnea, the median TTDD in the respective arms was 17.0 months (95% CI, 8.4-NE) and NE (95% CI, 5.1-NE; HR, 0.56; 95% CI, 0.34-0.92; P = .020). For constipation, the median TTDD was 16.1 months (95% CI, 16.1-NE) with vepdegestrant vs 10.3 months (95% CI, 5.6-NE) with fulvestrant (HR, 0.57; 95% CI, 0.33-0.97; P = .035).
“To our knowledge, vepdegestrant is the first estrogen receptor degrader to demonstrate statistically significant delays in risk of clinically meaningful deterioration across multiple PRO measures relative to standard-of-care endocrine therapy in patients with ESR1-mutated ER-positive, HER2-negative advanced breast cancer,” Mario Campone, MD, PhD, of Institut de Cancérologie de l’Ouest Angers-Nantes, in Saint-Herblain, France, said in a presentation of the data. “These patient-reported findings, together with the demonstrated clinical efficacy and favorable safety profile, support the clinical value of vepdegestrant for [this patient population.]”
What Did VERITAC-2 Examine, and What Prior Data Have Been Reported?
The study enrolled patients with ER-positive, HER2-negative advanced or metastatic breast cancer who received 1 line of therapy with a CDK4/6 inhibitor plus endocrine therapy who were administered no more than 1 additional line of endocrine therapy, received their most recent endocrine therapy for at least 6 months, and who had not previously received a selective ER degrader such as fulvestrant or elacestrant (Orserdu).2 Patients were at least 18 years of age and were naive to chemotherapy in the advanced or metastatic settings. They were required to have experienced radiological disease progression during or following their most recent line of treatment.
Participants were randomly assigned 1:1 to receive oral vepdegestrant at 200 mg once daily (n = 313) or intramuscular fulvestrant at 500 mg on days 1 and 15 of cycle 1, then on day 1 of subsequent cycles (n = 311). Patients were stratified based on ESR1 mutational status (yes vs no) and whether they had visceral disease (yes vs no).
The trial’s primary end point was progression-free survival (PFS) per blinded independent central review (BICR) in the ESR1-mutated subgroup and the overall population. Overall survival (OS) represented a key secondary end point, and other objectives included clinical benefit rate (CBR), overall response rate (ORR), and safety.
Data showed that in those with ESR1-mutated disease, the median PFS with vepdegestrant (n = 136) was 5.0 months (95% CI, 3.7-7.4) vs 2.1 months (95% CI, 1.9-3.5) with fulvestrant (n = 134), translating to a 42% reduction in the risk of disease progression or death (HR, 0.58; 95% CI, 0.43-0.78; P < .001). In all patients, the median PFS with vepdegestrant (n = 313) and fulvestrant (n = 311) was 3.8 months (95% CI, 3.7-5.3) and 3.6 months (95% CI, 2.6-4.0), respectively (HR, 0.83; 95% CI, 0.69-1.01; P = .07).
In June 2025, a new drug application was submitted to the FDA seeking approval of vepdegestrant for use in patients with ER-positive, HER2-negative advanced or metastatic breast cancer and ESR1 mutations who had prior exposure to endocrine-based therapy.3
At the 2025 ESMO Congress, PRO assessments done in the ESR1-mutated subgroup were shared.1
What Instruments Were Leveraged to Evaluate PROs in VERITAC-2?
The PRO population comprised 256 patients who had ESR1-mutated disease; 127 of these patients received vepdegestrant and 129 received fulvestrant. The EORTC QLQ-C30 questionnaire evaluated clinically meaningful changes in symptoms like fatigue, pain, nausea or vomiting, dyspnea, insomnia, appetite loss, constipation, and diarrhea; physical, role, emotional, cognitive and social functioning; and overall perception of health or wellbeing associated to cancer and its treatment. The EORTC QLQ-BR23 evaluated systemic therapy adverse effects, breast symptoms, arm symptoms, and upset by hair loss; as well as body image, sexual functioning, sexual enjoyment, and future perspective. The 5Q-5D-5L visual analog scale examined generic measure of health-related QOL health state. Lastly, the BPI-SF examined change in pain at its worst in the last 24 hours; pain over the last 24 hours at its worst, least, average, and currently; and pain interference with normal activity, mood, walking capabilities, normal work, relations with other people, sleep, and life enjoyment.
“Longitudinal analysis of change from baseline was assessed using mixed model repeated measures [MMRM] analysis,” Campone said, adding that “TTDD was estimated using established thresholds for clinically meaningful change.”
For all the questionnaires, PRO completion rates for both arms were higher than 80% through cycle 16. Moreover, baseline PRO scores were comparable between the groups and indicated good functioning and low symptom burden. Based on MMRM analyses of change from baseline, PRO scores were found to be consistently maintained and to be comparable between the groups throughout the study.
Disclosures: Campone disclosed receipt of honoraria from Novartis, Eli Lilly, and GTI. He serves as a consultant or advisor for Novartis, SERVIER, Menarini, Sanofi, Eli Lilly, Pfizer, AstraZeneca/MedImmune, AbbVie, Pierre Fabre, Accord Healthcare, Sandoz-Novartis, Seattle Genetics, and Daiichi Sankyo Europe GmbH. Research funding was received from Novartis and travel support was provided by Novartis, AstraZeneca, and Pfizer.
References
- Campone M, De Laurenetiis M, Hu X, et al. Patient-reported outcomes with vepdegestrant vs fulvestrant in patients with estrogen receptor-positive, Human Epidermal Growth Factor Receptor 2-negative advanced breast cancer in the phase 3 VERITAC-2 trial. Presented at: 2025 ESMO Congress; October 17-21, 2025; Berlin, Germany. Abstract 489MO.
- Campone M, De Laurentiis M, Jhaveri K, et al. Vepdegestrant, a PROTAC estrogen receptor degrader, in advanced breast cancer. N Engl J Med. 2025;393(6):556-568. doi:10.1056/NEJMoa2505725
- Arvinas announces submission of new drug application to U.S. FDA for vepdegestrant for patients with ESR1-mutated ER+/HER2- advanced or metastatic breast cancer. News release. Arvinas. June 6, 2025. Accessed October 27, 2025. https://ir.arvinas.com/news-releases/news-release-details/arvinas-announces-submission-new-drug-application-us-fda
