Introduction and objective
Long-term ADT is recommended for men with mHSPC: bone loss and increased fracture risk are known complications. The STAMPEDE trial compared ADT±docetaxel (Doc)±zoledronic acid (ZA): adding ZA did not improve overall survival (OS) but long-term effects of bisphosphonate treatment on skeletal health was not formally collected as part of the trial. Accessible, high quality, routinely-collected healthcare data (RCHD) enables analysis of outcome data beyond standard trial follow-up to evaluate long-term treatment toxicity and clinical efficacy of ZA as a bone protective agent in mHSPC. The Hospital Episode Statistics (HES) database provides RCHD for patients in England and Wales.
Methods
HES data up to 2018 were obtained for patients (pts) randomised 2:1 between ADT (Arm A) and ADT+ZA (Arm B), or ADT+Doc (Arm C) or ADT+Doc+ZA (Arm E). ZA (4 mg) was six 3-weekly cycles, then 4-weekly for 2 years. Clinical fracture events were identified using a bespoke pre-specified coding framework of International Classification of Diseases (ICD 10) diagnosis and Classification of Interventions and Procedures (OPCS 4) procedure codes. Multivariate Cox regression models were developed to adjust for age, N stage, WHO performance status, Gleason score and NSAID use to determine impact of ZA on fracture risk.
Results
Connected datasets were available for 2,145 eligible pts (796 M0, 1,349 M1) of 2,962 (72%). Overall, 5-year fracture incidence was 6.4%; higher in M1 pts (9.6% in M1 vs 2.1% in M0, p<0.0001), and lower amongst M1 pts allocated ZA (4.55% with ZA vs 12.9% without ZA, p<0.0001) (Figure 1). ZA significantly reduced fracture risk in M1 pts (HR 0.36, 95% CI 0.22-0.57, p<0.0005) but not in M0 pts (HR 0.67, 95% CI 0.32-1.39, p=0.28).
Conclusions
By accessing RCHD, we evaluated long-term fracture events amongst patients in STAMPEDE. Fracture rates were clinically notable in M1 and reduced significantly in pts allocated ZA with ADT±Doc. These data support using bone protective agents to reduce clinically significant fractures in mHSPC.