Increased Survival and Toxicity With Docetaxel, No Benefit of Zoledronic Acid, When Added to First-Line Hormone Therapy in Prostate Cancer

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Docetaxel treatment should become part of standard of care for adequately fit men commencing long-term hormone therapy.
— Nicholas D. James, BSc, MBBS, PhD, and colleagues

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As reported in The Lancet by Nicholas D. James, BSc, MBBS, PhD, of the University of Warwick, and colleagues, survival results of the STAMPEDE trial, which used a multiarm, multistage seamless phase II/III design, provide little evidence of benefit of zoledronic acid and showed increased survival and toxicity with docetaxel when added to first-line long-term hormone therapy in patients with high-risk locally advanced, metastatic, or recurrent prostate cancer.1

Study Details

In the open-label trial, 2,962 men with newly diagnosed metastatic, node-positive, or high-risk locally advanced disease from more than 100 UK and Swiss sites who had planned long-term hormone therapy were randomly assigned (2:1:1:1) between October 2005 and March 2013 to receive standard of care consisting of hormone therapy for at least 2 years (n = 1,184), standard of care plus zoledronic acid (n = 593), standard of care plus docetaxel (n = 592), or standard of care with both zoledronic acid and docetaxel (n = 593). Hormone therapy had to be started at no more than 12 weeks prior to randomization and consisted of gonadotropin-releasing hormone agonists or antagonists or, between 2006 and 2011, oral antiandrogens alone in patients with nonmetastatic disease.

Radiotherapy at 6 to 9 months after randomization was encouraged in patients with N0, M0 disease until November 2011 and then mandated. Radiotherapy was optional in patients with N+, M0 disease.

Zoledronic acid was given at 4 mg for six 3-weekly cycles and then in 4-weekly cycles until 2 years. Docetaxel was given at 75 mg/m2 for six 3-weekly cycles with prednisolone at 10 mg daily. The primary outcome measure was overall survival. Pairwise comparisons of investigational groups vs the control group had 90% power at a 2.5% one-sided α for a hazard ratio (HR) of 0.75, requiring approximately 400 deaths in the control group.

Patients had a median age of 65 years. Overall, 94% of patients were newly diagnosed, with 1,738 (62%) of 2,797 newly diagnosed patients and 79 (48%) of 165 patients with recurrent disease having metastatic disease at entry (61% overall); 448 (15%) had N+/X, M0 disease, and 697 (24%) had N0, M0 disease. The median prostate-specific antigen level was 65 ng/mL, 71% of patients had a Gleason score of 8 to 10, and 6% had received previous local therapy. Radiotherapy was reported for 25% to 27% of patients, including 57% to 63% of those with nonmetastatic disease.

Overall Survival

Median follow-up was 43 months (interquartile range [IQR] = 30–60 months). There were 415 deaths in the control group, with 347 (84%) due to prostate cancer. Median overall survival was 71 months (IQR = 32 months to not reached) in the standard-of-care group, not reached (IQR = 32 months to not reached) in the zoledronic acid group (HR = 0.94, 95% CI = 0.79–1.11, P = .450), 81 months (IQR = 41 months to not reached) in the docetaxel group (HR = 0.78, 95% CI = 0.66–0.93, P = .006), and 76 months (IQR = 39 months to not reached) in the zoledronic acid–plus-docetaxel group (HR = 0.82, 95% CI = 0.69–0.97, P = .022). Five-year survival was 55%, 57%, 63%, and 60% in the four groups, respectively.

There was no evidence of heterogeneity in treatment effect for any of the treatments across prespecified subsets. Among patients with metastatic disease at entry, median survival was 45 months in the standard-of-care group, 46 months (HR = 0.93, P = .416) in the zoledronic acid group, 60 months (HR = 0.76, P = .005) in the docetaxel group, and 55 months (HR = 0.79, P = .015) in the zoledronic acid–plus-docetaxel group. Five-year survival was 39%, 43%, 50%, and 46%. Data for the nonmetastatic group were immature at the time of reporting.

Failure-Free Survival and Prostate Cancer Mortality

Median failure-free survival was 20 months in the standard-of-care group vs 22 months in the zoledronic acid group (HR = 0.92, P = .198), 37 months in the docetaxel group (HR = 0.61 = P = .413 × 10-13), and 36 months in the zoledronic acid–plus-docetaxel group (HR = 0.62, P = .134 × 10-12). Five-year failure-free survival was 28%, 31%, 38%, and 34%.

At the time of analysis, 978 men had died, 809 (83%) due to prostate cancer. Among men who died, prostate cancer was the cause of death in 86% of men with metastatic disease at entry and 68% of men with nonmetastatic disease. Compared with standard of care alone, risk of prostate cancer mortality was reduced in the docetaxel group (HR = 0.79, P = .019) and the zoledronic acid–plus-docetaxel group (HR = 0.78, P = .013) but not in the zoledronic acid group (HR = 0.95, P = .613).

Adverse Events

Grade ≥ 3 adverse events occurred in 32% of patients in the standard-of-care group (with endocrine disorders, occurring in 12%, being the most common), 32% in the zoledronic acid group (endocrine disorders in 12%), 52% in the docetaxel group (febrile neutropenia in 15%, neutropenia in 12%, endocrine disorders in 10%), and 52% of the zoledronic acid–plus-docetaxel group (febrile neutropenia in 14%, neutropenia in 12%, endocrine disorders in 12%, general disorder—eg, lethargy, fever, asthenia—in 11%). Osteonecrosis of the jaw was reported in 2% of the zoledronic acid group and 4% of the zoledronic acid–plus-docetaxel group.

Fine-Tuning Treatment of High-Risk Prostate Cancer

  • The addition of docetaxel but not zoledronic acid to first-line hormone therapy was associated with increased overall survival.
  • The addition of docetaxel was associated with improved failure-free survival and prostate cancer mortality.

Of eight deaths considered at least possibly related to study treatment, seven (due to neutropenic sepsis in four patients, pneumocystis pneumonia in one, interstitial pneumonitis in one, and pneumonia in one) occurred in the zoledronic acid–plus-docetaxel group and one (due to neutropenic sepsis) occurred in the docetaxel group.

The investigators concluded: “Zoledronic acid showed no evidence of survival improvement and should not be part of standard of care for this population. Docetaxel chemotherapy, given at the time of long-term hormone therapy initiation, showed evidence of improved survival accompanied by an increase in adverse events. Docetaxel treatment should become part of standard of care for adequately fit men commencing long-term hormone therapy.”

Matthew R. Sydes, MSc, of the Medical Research Council Clinical Trials Unit at University College London, is the corresponding author for The Lancet article. ■

Disclosure: The study was funded by Cancer Research UK, Medical Research Council, Novartis, Sanofi-Aventis, Pfizer, Janssen, Astellas, National Institute for Health Research Clinical Research Network, and Swiss Group for Clinical Cancer Research. For full disclosures of the study authors, visit


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. Lancet 387:1163-1177, 2016.