Long-term effect of neoadjuvant denosumab treatment in high-risk early breast cancer (GeparX)

Link T, Reinisch M, Just M, Untch M, Filmann N, Stötzer O, Denkert C, Bjelic-Radisic V, Wimberger P, Thill M, Rhiem K, Huober J, Solbach C, Hanusch C, Engels K, Fasching P, Schneeweiss A, Nekljudova V, Holtschmidt J, Blohmer JU, Loibl S (2025)

Publication Type: Journal article

Publication year: 2025

Journal

ESMO Open BMJ Publishing Group

Book Volume: 10

Article Number: 105915

Journal Issue: 12

DOI: 10.1016/j.esmoop.2025.105915

Abstract

Background: In the GeparX trial (NCT02682693), neoadjuvant denosumab, in addition to either weekly or days 1 and 8 (d1,8) q22 nab-paclitaxel (nPac)-based chemotherapy, did not improve the pathological complete response (pCR) rate in early high-risk breast cancer patients, while the concomitantly applied weekly nPac regimen resulted in a significantly higher pCR rate compared with the interrupted regimen. Patients and methods: GeparX is a randomized, open-label, phase II study comparing neoadjuvant treatment with or without denosumab and two different nPac schedules. Invasive disease-free survival (iDFS), distant disease-free survival (DDFS), overall survival (OS), and locoregional recurrence-free interval (LRRFI) were considered as time-to-event endpoints. Results: After a median follow-up of 62.3 months, there was no statistically significant difference in iDFS [hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.62-1.21, P = 0.39], DDFS (HR 0.77, 95% CI 0.54-1.11, P = 0.16), LRRFI (HR 1.41, 95% CI 0.76-2.63, P = 0.28), and OS (HR 0.81, 95% CI 0.50-1.33, P = 0.41) between denosumab-treated and non-denosumab-treated patients. However, numerically fewer distant relapses occurred in patients with denosumab treatment (9.2% versus 13.8%). Denosumab treatment resulted in a significant risk reduction of 36% for distant relapse in the multivariate analysis (DDFS; HR 0.64, 95% CI 0.43-0.93, P = 0.02). There was no overall differential impact of the two neoadjuvant chemotherapy (NACT) regimens (nPac weekly or nPac d1,8 q22) on long-term outcome in the total study population. Triple-negative breast cancer (TNBC) patients without a pCR (non-pCR) had a significantly worse iDFS (HR 0.22, 95% CI 0.12-0.39, P < 0.0001), with a trend toward improved iDFS in those receiving weekly nPac at the 5-year landmark (iDFS rate at 60 months: 58.4% versus 72%). Conclusions: Denosumab as part of neoadjuvant therapy, although not improving the pCR rate, significantly reduced the risk of distant relapses. Other long-term outcome parameters did not differ between the treatment arms. TNBC patients, especially when not achieving pCR, seem to benefit from weekly nPac.

Authors with CRIS profile

Peter Fasching Professur für Translationale Frauenheilkunde und Geburtshilfe

Involved external institutions

Universitätsklinikum Heidelberg DE Germany (DE) Universitätsklinikum Frankfurt am Main (KGU) DE Germany (DE) GBG Forschungs GmbH (German Breast Group) DE Germany (DE) HELIOS Kliniken DE Germany (DE) Kantonsspital St.Gallen CH Switzerland (CH) Universitätsklinikum Carl Gustav Carus Dresden DE Germany (DE) Charité - Universitätsmedizin Berlin DE Germany (DE) Universitätsklinikum Mannheim / University Medical Centre Mannheim (Universitätsmedizin Mannheim) DE Germany (DE) Onkologische Schwerpunktpraxis Bielefeld DE Germany (DE) Universitätsklinikum Köln DE Germany (DE) Universitätsklinikum Gießen und Marburg (UKGM) DE Germany (DE) Rotkreuzklinikum München DE Germany (DE) Agaplesion Markus Krankenhaus DE Germany (DE)

How to cite

APA:

Link, T., Reinisch, M., Just, M., Untch, M., Filmann, N., Stötzer, O.,... Loibl, S. (2025). Long-term effect of neoadjuvant denosumab treatment in high-risk early breast cancer (GeparX). ESMO Open, 10(12). https://doi.org/10.1016/j.esmoop.2025.105915

MLA:

Link, T., et al. "Long-term effect of neoadjuvant denosumab treatment in high-risk early breast cancer (GeparX)." ESMO Open 10.12 (2025).

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