Meta-analysis of effects of zoledronic acid (ZOL) on survival in metastatic bone disease (MBD): Survival in patients with high bone turnover

Abstract

20562 Background: ZOL is an integral component of therapy for patients (pts) with MBD to reduce the risk of skeletal-related events (SREs) and preserve physical function. Recent reports suggest that pts with high N-telopeptide of type I collagen (NTX) levels that normalize during therapy have improved survival compared with persistently high NTX (Lipton A, et al. Oncologist 2007, Cancer 2008). In this study we evaluate the outcomes of pts included in 3 placebo (PLA)-controlled trials of ZOL in solid tumors. Methods: Pts with MBD from solid tumors were included in randomized trials of ZOL (4 or 8/4 mg every 3–4 wk; n = 1071) vs PLA (n = 571) in addition to standard cancer therapies. Baseline NTX and bone-specific alkaline phosphatase (BALP) levels were available for 1345 pts (218 breast, 608 prostate, 519 other). Relative risks (RR) of death and associated 95% confidence intervals (CI) for ZOL vs PLA in the entire population (ITT), all pts with NTX and BALP data, and those ≥ and < the upper limits of normal (ULN) for NTX (64 nmol/mmol creatinine [Cr]) or BALP (146 IU/L) were assessed using a Cox regression model. Results: Survival was similar between treatment groups in the ITT population. However, although there was not statistically significant heterogeneity between the different bone marker groups, pts with NTX ≥ ULN who were treated with ZOL had significantly longer survival compared with PLA (Table 1). Further exploratory subset analyses revealed a 26.4% reduction in the risk of death for ZOL vs PLA among pts with especially high NTX levels (NTX > 100 nmol/mmol Cr [n = 498; RR = 0.736; 95% CI = 0.592, 0.916; P = .006]). Conclusions: The relationships between normalization of high baseline NTX at 3 mo and survival have been described previously. For the first time, this exploratory analysis investigates the effects of ZOL on survival in pts based on baseline bone turnover rates associated with MBD. Potential survival benefits are currently being investigated in multivariate models of the pooled dataset. Population ZOL, n PLA, n RR 95% CI P ITT 1071 571 0.939 0.828, 1.064 .323 Marker data 866 466 0.924 0.801, 1.067 .283 NTX < ULN 351 180 1.137 0.880, 1.469 .328 NTX ≥ ULN 518 286 0.828 0.696, 0.985 .034 BALP < ULN 304 162 1.039 0.795, 1.358 .781 BALP ≥ ULN 567 302 0.882 0.744, 1.046 .148 Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Novartis Pharmaceuticals Inc. Novartis Pharmaceuticals Inc. Novartis Pharmaceuticals Inc. Novartis Pharmaceuticals Inc. Novartis Pharmaceuticals Inc. Novartis Pharmaceuticals Inc. Novartis Pharmaceuticals Inc. - Speaker’s Bureau