Additional Evidence For Use of Zoledronic Acid In Metastatic CRPC Patients

Zoledronic acid lengthens time to first symptomatic skeletal-related event in men with bony metastatic castration-resistant prostate cancer

medwireNews: Primary phase III findings from the TRAPEZE trial support the addition of zoledronic acid (ZA) to life-prolonging regimens for men with metastatic castration-resistant prostate cancer (CRPC).

The results, published in JAMA Oncology, include follow-up data for at least 12 months for 757 patients who were randomly assigned to receive up to 10 cycles of docetaxel alone, or with ZA, docetaxel with a single dose of strontium-89, or docetaxel with ZA and strontium-89.

Patients given ZA had a significantly longer interval until first symptomatic skeletal-related event (SRE) than those not assigned to receive the bisphosphonate, at a median of 13.6 versus 11.2 months and a hazard ratio (HR) of 0.78, after adjusting for confounding factors.

ZA was also associated with a significant 30% reduction in the overall number of symptomatic SREs compared with no ZA therapy, report Nicholas James, from University Hospital Birmingham NHS Foundation Trust in the UK, and co-investigators.

And analysis of the distribution of symptomatic SREs suggested that ZA was associated with a 50% reduction in the most severe types of events, such as fracture, spinal cord compression and bone surgery.

Nevertheless, ZA failed to produce a significant benefit in the primary endpoint of clinical progression-free survival (CPFS), defined as time from randomisation to the occurrence of progressive pain, symptomatic SREs or death, or the secondary endpoint of overall survival.

“Although commonly prescribed in the United States, Canada, and several other countries, the use of ZA and also denosumab remains controversial in the United Kingdom and elsewhere owing to doubts about the clinical relevance of the radiological SREs in the licensing trials, particularly the question of whether additional bone protection is relevant in patients receiving life-prolonging CRPC therapy, such as chemotherapy or new generation hormone therapies”, the researchers write.

By overcoming these concerns by using a clinical endpoint for SRE, however, they believe that the TRAPEZE results “support the use of ZA in the context of at least 1 life-prolonging CRPC therapy (ie, docetaxel)”.

The investigators also report that Cox regression analysis suggested that strontium-89 had a significant and “moderate effect” on CPFS, with a HR of 0.85, although the radioisotope had no significant impact on overall survival or other secondary endpoints.

However, the researchers note the development of radium-223, with a similar uptake mechanism to strontium-89 but a “more intense and localized radiation dose”.

Acknowledging that radium-223 has been associated with both improved overall survival and symptomatic SREs in clinical trials, they suggest that strontium-89 “probably has now been superseded with the recent license for radium-223.”


James ND, Pirrie SJ, Pope AM, et al. Clinical outcomes and survival following treatment of metastatic castrate-refractory prostate cancer with docetaxel alone or with strontium-89, zoledronic acid, or both. The TRAPEZE randomized clinical trial. JAMA Oncol 2016; Advance online publication 21 January.doi:10.1001/jamaoncol.2015.5570

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