A pragmatic, randomised, multicentre trial comparing 4-weekly vs. 12-weekly administration of bone-targeted agents (denosumab, zoledronate or pamidronate) in patients with bone metastases

Abstract

Background: Defining the optimal dosing interval of bone-targeted agents (BTAs), such as denosumab (DN) and bisphosphonates, for patients (pts) with bone metastases remains an important clinical question. We performed a pragmatic randomised trial comparing the non-inferiority of 12- vs. 4-weekly BTAs in pts with breast and prostate cancer. We present data from the breast cohort. Methods: Breast cancer pts who were either BTA-naïve, or already receiving, DN, zoledronate (ZA) or pamidronate (PAM) were eligible. They were randomised to their chosen BTA every 12- or 4-weeks for one year. The primary endpoint was Health Related Quality of Life (HRQL) (EORTC-QLQ-C30 Functional Domain-Physical Subdomain). Secondary endpoints included: pain (EORTC-QLQ-BM22-pain domain), Global Health Status (EORTC-QLQ-C30), symptomatic skeletal event (SSE) rates and SSE-free survival (composite of time to first SSE and time to death). Adverse events and toxicity were also compared. Results: Of 160 breast cancer pts, 79 (49.4%) were randomised to 12- and 81 (50.6%) to 4-weekly therapy. 64 pts (40%) were BTA naïve. BTAs included; DN (n=60, 37.5%), ZA (n=48, 30%) or PAM (n=52, 32.5%). Study-reported outcomes showed no significant difference in change from baseline in: HRQL-physical domain (median [range]: 0 [-87,20] vs. 0 [-66,53]), pain (median [range]: 0 [-80,33] vs. 0 [-27,20]), Global Health Status (median [range]: 0 [-67,50] vs. 0 [-50,42]) between the 12- and 4- weekly arms, respectively. Five (6%) and 7 (9%) pts had an SSE within 2 years and 1- year SSE-free survival was 65% (95% CI:52-75%) and 80% (69-88%) in the 12- and 4- weekly arms, respectively. Changes in dosing schedules were more common in the 4- weekly arm (17% vs 31%). Results were similar for subgroup analyses for BTA naïve and pre-treated pts, and for pts receiving DN, ZA or PAM. Conclusions: The findings of this trial are consistent with those previously reported for de-escalating ZA. This trial also included pts receiving de-escalated DN and PAM. While the results of the REDUSE trial are awaited, the data presented would suggest that de-escalation of commonly used BTAs is a reasonable treatment option.