Bisphosphonates In Prostate Cancer Care

Fracture-related hospitalisations in newly diagnosed high-risk localised or metastatic hormone-sensitive prostate cancer – a secondary post-hoc analysis study

Bone loss and increased fracture risk are often associated with treatments given for localised and metastatic prostate cancer.

ADT (androgen deprivation therapy) is a common systemic therapy used for prostate cancer. Its downside is that it can disturb normal bone remodelling leading to bone loss and a higher risk of osteoporosis and fractures.

The impact of treatment intensification on bone health and the risk of adverse events such as fractures has not been thoroughly examined. International guidelines (such as EAU) for men with hormone-sensitive prostate cancer, until recently, recommended routine risk assessment and consideration of bone protection only for patients at high risk of fracture.

STAMPEDE (funded by CRUK and the MRC-CTU) was a multi arm multistage trial which recruited men with high risk non metastatic (M0) or metastatic hormone sensitive prostate cancer (M1) between the years of 2005 and 2023.

This secondary post-hoc analysis study focuses on treatment intensification within the STAMPEDE trial and the use of docetaxel and/or zoledronic acid and their effects on the cumulative incidence and risk of fracture. This work was undertaken by a team at the Prostate Cancer UK Movember FASTMAN Centre of Excellence. Participants were randomised into 4 groups - ADT only as standard of care (SOC) or, SOC with zoledronic acid (ZA), docetaxel only, or docetaxel with zoledronic acid.

Linked healthcare systems data (HSD) for the trial participants through HES (Hospital Episode Statistics) and CRD (Civil Registrations of Death) for this study, facilitated long term assessment of fracture risk beyond the standard trial follow up. Trial therapies were discontinued after disease progression or intolerable adverse events.

The primary outcome measure for this secondary analysis was time to first fracture-related hospitalisation (FRH), defined from randomisation until the date of a hospital admission with a fracture diagnosis.

Discussion

Results from this study show a significant reduction in fracture risk with the addition of ZA in metastatic patients, but results for men with M0 disease were inconclusive.

The study investigators highlight that the definition of "fracture-related events" based on hospitalization records likely underestimates the actual fracture burden. It excludes non-hospitalized fractures, asymptomatic events found through imaging, and complications from radiotherapy or spinal cord compression, which are typically included in broader skeletal-related event (SRE) definitions used in trials. Nonetheless, they believe this definition captures a clinically significant subset of events linked to higher morbidity and greater healthcare resource use.

The inability to find a benefit of zoledronic acid in the M0 population may be due to the small sample size and the study's focus on fractures specifically leading to hospitalization, which potentially missed many other vertebral fractures that affect quality of life. Longer follow-up might reveal these effects more clearly. However, sensitivity analyses using procedure and primary diagnosis codes confirm that fractures were a major cause of hospitalization, with 81% requiring procedural intervention, contributing to increased morbidity.

Increasing age is also associated with a greater risk of fracture, suggesting that the real-world fracture incidence in patients with prostate cancer may be even higher than that reported in this study.

Even though reduction in fracture incidence with the addition of ZA to SOC ADT in M1 patients was observed, the existing SOC now includes upfront ARPI (Androgen Receptor Pathway Inhibitor) as part of doublet or triplet therapy, which may further increase fracture risk.

In conclusion, secondary analysis of the STAMPEDE trial using linked healthcare data shows a high incidence of fracture-related hospitalizations in both non-metastatic and metastatic patients. Treatment with zoledronic acid significantly lowers the fracture risk in those with metastatic disease, supporting the routine use of bone protective agents in standard care for metastatic prostate cancer.

“Funding for this type of sub-analysis can be hard to find. We're grateful that through the Prostate Cancer UK Movember FASTMAN Centre of Excellence we were able to analyse clinical trial data from the incredibly successful STAMPEDE trial linked with the rich resource of NHS health systems data.  Based on this new evidence, we are pleased to see that national and international guidelines have highlighted the pressing need to optimise bone health in prostate cancer patients starting hormone therapy and increasingly support routine use of bone protection agents to reduce fracture risk amongst patients with metastatic disease.”  

- Mr Ashwin Sachdeva, author and Clinical Senior Lecturer in Urology & Honorary Consultant Urological Surgeon at the University of Manchester