Abstract
Background
Zoledronic acid (ZA) in combination with androgen deprivation therapy (ADT) has never proved additional activity in patients with advanced prostate cancer. However, conventional imaging is poorly reliable in monitoring disease response of metastatic bone lesions.
Methods
BonEnza is a randomized phase II multicenter clinical trial designed to compare activity of ADT plus Enzalutamide (E) plus/minus ZA in term of bone response rate by Whole-Body Diffusion-Weighted Magnetic Resonance Imaging (WB-DW-MRI). From February 2018 to June 2021, 126 patients with metastatic hormone-sensitive prostate cancer (mHSPC) and bone metastasis at bone scan were enrolled. Patients were randomized in a 1:1 to receive E 160 mg OD orally alone (E arm) or in combination with ZA 4 mg intravenously every 4 weeks (EZ arm). Primary endpoint of the study was overall response rate (ORR) in bone metastases, secondary endpoints were ORR with conventional imaging, progression free survival (PFS) and overall survival (OS). A logistic model was used to evaluate the association between treatment arm and ORR.
Results
After a median follow-up of 31.9 months, according to an intent to treat analysis, the ORR was superimposable in both arms: 69.8% (95% Confidence Interval [CI]: 57.5–79.9%), Odds Ratio: 1.00 (95%CI 0.47–2.15; p > 0.9). No advantage in favor of EZ arm over E arm emerged either in terms of PFS (Hazard Ratio [HR] 0.77, 95%CI 0.44–1.37; p = 0.4) or OS (HR 1.09; 95%CI 0.54–2.2; p = 0.8). A main limitation of this study was the inability of WB-DW-MRI to evaluate disease response in 17 patients.
Conclusions
ZA did not improve bone response rate to E plus ADT in mHSPC patients. WB-DW-MRI is a reliable technique to evaluate the response of prostate cancer bone metastases to systemic therapy.
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Data availability
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
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Acknowledgements
FZ is supported by an AIRC fellowship Italy Post-Doc ID 29854-2023.
Funding
This research was partially funded by an investigator sponsored research grant from Astellas (grant number IT-72-RG-33/ISR004983). The funder had no role in design and conduct of the study, collection, management, analysis, and interpretation of the data and in preparation, review, or approval of the manuscript.
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ADV: Investigation, Resources, Data Curation, Validation, Writing—Original Draft, Visualization, Project Administration. FV: Investigation, Resources, Writing—Review & Editing, Project Administration. AZ: Investigation, Resources, Writing—Review & Editing. GP: Investigation, Resources, Writing—Review & Editing. PS: Investigation, Writing—Review & Editing. GDC: Investigation, Resources, Writing—Review & Editing. NDM: Resources, Writing—Review & Editing. SF: Investigation, Writing—Review & Editing. SZ: Resources, Writing—Review & Editing. CM: Investigation, Resources, Writing—Review & Editing. EL: Investigation, Resources, Writing—Review & Editing. AR: Investigation, Resources, Writing—Review & Editing. MR: Resources, Writing—Review & Editing. SC: Formal analysis, Methodology, Resources, Validation, Writing—Review & Editing. FZ: Investigation, Writing—Review & Editing. GC: Software, Methodology, Writing—Review & Editing. NS: Resources, Writing—Review & Editing. RM: Conceptualization, Resources, Writing—Review & Editing. DF: Resources, Writing—Review & Editing. AB: Conceptualization, Resources, Validation, Writing—Review & Editing, Supervision, Project Administration, Funding acquisition.
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Dalla Volta, A., Valcamonico, F., Zivi, A. et al. Addition of zoledronic acid to enzalutamide and androgen deprivation therapy in metastatic hormone-sensitive prostate cancer: the randomized phase II BONENZA trial. Prostate Cancer Prostatic Dis (2025). https://doi.org/10.1038/s41391-025-00975-8
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DOI: https://doi.org/10.1038/s41391-025-00975-8
