Addition of zoledronic acid to enzalutamide and androgen deprivation therapy in metastatic hormone-sensitive prostate cancer: the randomized phase II BONENZA trial

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.