One thing I have noticed at some of the support groups I run is that there seems to be a very uneven distribution of when men start taking Zoledronic Acid (ZA).

Hormone therapy (ADT) has many negative side effects and the loss of bone mineral density (thinning of the bones) that ZA (and similar drugs) is designed to slow is the standard of care. Additionally, ZA will decrease the risk of developing skeletal-related events (SREs) in men with castrate resistant prostate cancer and bone metastases.

At the 2013 Genitourinary Cancers Symposium there was an abstract that described a phase III study that evaluated efficacy and safety of earlier treatment with ZA in men with castration-sensitive metastatic prostate.

The trial, CALGB 90202 was a randomized, double-blinded, placebo-controlled phase III trial in men with castration-sensitive prostate cancer and bone metastases who had initiated androgen deprivation therapy within six months of study entry.

The subject men were randomized 1:1 in blinded manner to receive ZA (4 mg intravenously every 4 weeks) or placebo (P). After progression to CRPC, all men were crossed over to open-label ZA.

The primary endpoint was time to first SRE. Target sample size was 680. Time to SRE was defined as interval between date of randomization and date of first SRE (radiation to bone, or clinical fracture, or surgery to bone, or death due to prostate cancer). With 470 SRE events, the log-rank test has 88% power to detect a 23% decrease in hazard rate of SRE event assuming a one-sided type I error rate of 0.05.

The study was discontinued prematurely after the corporate supporter withdrew study drug supply. Primary analysis was based on the stratified log-rank statistic adjusting on the stratification factors following observation of 284 SREs (60% of total events).

Results: Between June 2004 and April 2012, 645 men were randomly assigned to ZA or P. Median time to first SRE was 32.5 months in the ZA group and 29.8 months in the P group (hazard ratio (HR) 0.96

[0.76-1.22]; stratified log-rank P=0.74).

A total of 271 deaths were observed; median follow-up time for surviving patients was 24.4 months (20.6, 28.3). Overall survival was similar between groups (HR= 0.89 [0.70-1.14]; stratified P=0.34).

Rates of grade 3 or higher adverse events were similar between groups (15% vs. 12% in ZA and P).

Conclusions: In men with castration-sensitive prostate cancer and bone metastases, early treatment with ZA was not associated with lower risk for SREs or death, even with the early termination of the study which limits its statistical power. Given that ZA comes with its own side effects it is not advantageous to start a protocol of ZA while you remain hormone sensitive.

Clinical trial information: NCT00079001

J Clin Oncol 31, 2013 (suppl 6; abstr 27)
Matthew Raymond Smith, Susan Halabi, Charles J. Ryan, Walter Michael Stadler, Arif Hussain, Nicholas J. Vogelzang, Ralph J. Hauke, Ben L. Sanford, Eric Jay Small, Alliance; Massachusetts General Hospital Cancer Center, Boston, MA; Alliance Statistical and Data Center/Duke University Medical Center, Durham, NC; USCF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA; University of Chicago, Chicago, IL; University of Maryland, Baltimore, MD; Comprehensive Cancer Centers of Nevada, Las Vegas, NV; University of Nebraska Medical Center, Omaha, NE; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA

Joel T Nowak, M.A., M.S.W.