A recent secondary analysis of the STAMPEDE phase 3 trial, published in the Annals of Oncology, sheds new light on the significant risk of fractures faced by men with high-risk localized or metastatic hormone-sensitive prostate cancer (mHSPC) undergoing androgen deprivation therapy (ADT).

The analysis focused on 2,140 patients from England enrolled in the STAMPEDE trial, with linked healthcare data available for 2,042 (96%) of them, 734 with non-metastatic (M0) and 1,308 with metastatic (M1) prostate cancer.

These patients were randomized to receive standard-of-care ADT alone or ADT combined with zoledronic acid, docetaxel (with prednisolone), or both.

The researchers employed flexible parametric competing risks models to estimate the 5- and 10-year cumulative incidence of fractures and to calculate subdistribution hazard ratios, accounting for competing risks like death, which is particularly relevant in metastatic disease.

The results revealed a high burden of fractures associated with ADT.
For men with non-metastatic prostate cancer treated with ADT alone, the 5-year cumulative incidence of fracture-related hospitalizations was 11% (95% CI, 8–15%), rising to 26% (95% CI, 20–33%) by 10 years.
For those with metastatic disease, the 5-year incidence was even higher at 23% (95% CI, 19–28%).

Zoledronic acid, administered as six 3-weekly cycles of 4 mg followed by 4-weekly cycles for two years, significantly reduced fracture risk in M1 patients, with a subdistribution hazard ratio of 0.73 (95% CI, 0.55–0.97; p=0.015). This suggests that zoledronic acid, which inhibits osteoclast-mediated bone resorption, can stabilize bones weakened by both ADT and metastatic lesions.

However, no significant benefit was observed in M0 patients, where the hazard ratio was 0.88 (95% CI, 0.59–1.32; p=0.549). This difference may be due to the absence of bone metastases in M0 patients, where ADT-induced bone loss is the primary driver of fracture risk, potentially requiring different or longer-term interventions to show a protective effect.Docetaxel, a chemotherapeutic agent, showed no clear impact on fracture risk in either group, with p-values of 0.570 for M0 and 0.264 for M1 patients.

The study also found no interaction between docetaxel and zoledronic acid in reducing fractures, indicating that the bone-protective effect is driven primarily by zoledronic acid in metastatic cases. These findings have important implications for clinical practice.

The significant reduction in fracture risk with zoledronic acid in M1 patients supports its routine use in this group, aligning with its established role in preventing skeletal-related events in metastatic prostate cancer.

The study’s strengths include its large sample size and use of real-world healthcare data, which provide a robust picture of fracture risk over time. The long-term follow-up, particularly the 10-year data for M0 patients, adds valuable insight into the persistent skeletal effects of ADT. However, limitations exist. The analysis was restricted to patients in England, which may limit generalizability to other healthcare systems with different ADT or bone health management practices. Additionally, the study does not detail the types of fractures (e.g., vertebral, hip) or their clinical severity, which could influence treatment decisions.

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