Docetaxel should be added at initiation of standard of care treatment in men with prostate cancer; however, no evidence of survival improvement was seen with zoledronic acid therefore it is not recommended as part of standard of care for this patient population. These results were published online first in the journal The Lancet.
Standard of care treatment for advanced prostate cancer since the 1940s is long-term hormone therapy. A randomized controlled trial using a multiarm, multistage platform design, STAMPEDE (ClinicalTrials.gov, NCT00268476; ControlledTrials.com, ISRCTN78818544), comparison tested adding zoledronic acid, docetaxel, or both to standard of care vs. standard of care alone. The trial recruited men with high-risk, locally advanced, metastatic, or recurrent prostate cancer who were beginning first-line long-term hormone therapy.
Stratified randomization (via minimization) assigned 2962 men (median age 65 years [IQR 60-71]) 2:1:1:1 to four study groups: standard of care only (SOC-only; control), standard of care plus zoledronic acid (SOC + ZA), standard of care plus docetaxel (SOC + Doc), or standard of care plus zoledronic acid and docetaxel (SOC + ZA + Doc).
Standard of care was hormone therapy for 2 years; men with N0M0 disease were encouraged, then mandated after November 2011, to undergo radiotherapy. Men with node-positive nonmetastatic (N+M0) disease were offered optional radiotherapy. Zoledronic acid (4 mg) was given for 6 3-weekly cycles, then 4-weekly until 2 years. Docetaxel (75 mg/m2) was given for 6 3-weekly cycles with prednisolone 10 mg daily. Treatment allocation was not blinded. Primary outcome measure was overall survival.
Among the participants, 1817 (61%) had M+ disease, 448 (15%) had N+/X M0, and 697 (24%) had N0M0. Six percent (165) of the men had previously received local therapy, median prostate-specific antigen was 65 ng/mL (IQR 23-184), and median follow-up was 43 months (IQR 30-60).
Median overall survival was 71 months (IQR 32 to not reached) for SOC-only, not reached (32 to not reached) for SOC + ZA (hazard ratio [HR] 0.94, 95% confidence interval [CI]: 0.79-1.11; P=.450), 81 months (41 to not reached) for SOC + Doc (HR 0.78, 95% CI: 0.66-0.93; P=.006), and 76 months (39 to not reached) for SOC + ZA + Doc (HR 0.82, 95% CI: 0.69-0.97; P=.022). No evidence of heterogeneity in treatment effect, for any of the treatments, was seen across prespecified subsets. Grade 3 to 5 adverse events were reported for 399 (32%) patients in the SOC arm, 197 (32%) in the SOC + ZA arm, 288 (52%) in the SOC + Doc arm, and 269 (52%) in the SOC + ZA + Doc arm.
No evidence of survival improvement was seen with zoledronic acid, and the researchers therefore do not recommend including it in standard of care. However, survival improvement was seen with adding docetaxel at initiation of long-term hormone therapy. Although this was accompanied with an increase in adverse events, the researchers recommend including docetaxel as part of the standard of care for appropriately selected patients.
The following provided funding for this study: Cancer Research UK, Medical Research Council, Novartis, Sanofi-Aventis, Pfizer, Janssen, Astellas, NIHR Clinical Research Network, Swiss Group for Clinical Cancer Research.
1. James ND, Sydes MR, Clarke NW, et al. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial [published online ahead of print December 21, 2015]. Lancet. doi:10.1016/S0410-6736(15)01037-5.