A Recently Published Analysis May Provide New Guidance on Therapy to Prevent Skeletal-Related Events in Oncology Patients

Note: The following is a writing exercise I completed recently. I thought it was interesting so I decided to post it here.

Results from the analysis of three phase 3 trials suggest that denosumab is superior to zoledronic acid (ZA) in the context of preventing skeletal-related events (SREs) in patients with a history of bone metastasis from various advanced cancers.

The article, published in the European Journal of Cancer, analyzed previously published trials data and included 5543 patients from over 320 medical centers in more than 30 countries. Included were patients with breast cancer, prostate cancer and other solid tumors.

All 3 studies were identically designed, double blind, double dummy phase 3 trials. Patients were randomized to receive either denosumab 120 milligrams subcutaneously every 4 weeks (Q4W) or 4 milligrams of intravenous ZA Q4W (doses of ZA were adjusted for creatinine clearance per the prescribing information).

Patients were divided into subgroups including Eastern Cooperative Oncology Group performance status (ECOG PS), bone metastasis location, bone metastasis number, visceral presence/absence, and urinary N-telopeptide level. The primary endpoint evaluated was time to first on-study SRE and a secondary endpoint was time to first and subsequent on-study SREs. 

According to the published results of the analysis, denosumab reduced the risk of both first SRE (assessed using a Cox proportional hazard model) across all subgroups as well as first and subsequent SREs (assessed using an Anderson-Gill model) in all subgroups. There was no statistically significant difference between subgroups.

It is important to note that patients with multiple myeloma were excluded along with patients with a creatinine clearance of less than 30 ml/min, life expectancy less than 6 months, or patients currently receiving oral/intravenous bisphosphonate treatment for bone metastases.

The previous studies referenced do not necessarily provide the same compelling evidence that the authors present in this article. One previous study showed non-inferiority as opposed to the other 2, which claimed superiority. Multiple authors of the manuscript have received honoraria and/or served as consultants and advisors for the study sponsor, Amgen Inc. 

An interesting finding from the 3 trials that may warrant further consideration is the increased occurrence of hypocalcemia and osteonecrosis of the jaw with denosumab vs. ZA. This suggests there are other factors to consider and that ultimately, therapy selection should be patient specific and based on all related evidence from the currently available literature.