Addition of Docetaxel to Androgen-Deprivation Therapy Improves Survival in Metastatic Prostate Cancer
In the phase III E3805 trial reported in The New England Journal of Medicine, Sweeney et al found that chemohormonal therapy with docetaxel plus androgen-deprivation therapy produced a significant 13.6-month increase in median overall survival vs androgen-deprivation therapy alone in men with metastatic prostate cancer.
Study Details
In this open-label trial, 790 patients were randomly assigned between July 2006 and December 2012 to receive standard androgen-deprivation therapy alone (n = 393) or combined with docetaxel 75 mg/m2 every 3 weeks for six cycles (n = 397). Patients receiving docetaxel were premedicated with 8 mg of dexamethasone at 12, 3, and 1 hour before docetaxel infusion.
Stratification factors included age, Eastern Cooperative Oncology Group (ECOG) performance status, planned use of combined androgen blockade for more than 30 days, use of zoledronic acid or denosumab (Xgeva), duration of prior adjuvant androgen-deprivation therapy, and high volume (visceral metastases or four or more bone lesions with at least one beyond the vertebral bodies and pelvis) vs low volume of metastatic disease. Patients were enrolled by ECOG-ACRIN, Southwest Oncology Group, Alliance for Clinical Trials in Oncology, and NRG Oncology. The primary endpoint was overall survival.
The androgen-deprivation therapy plus docetaxel and androgen-deprivation therapy alone groups were generally balanced for age (median 64 and 63 years), race (87% and 84% white, 10% and 9% black), ECOG performance status (0 for 70% and 69%, 1 for 29% in both), metastasis volume (high in 66% and 64%), visceral metastases (14% and 17%), Gleason score (7 in 24% and 21%, 8–10 in 61% and 62%), median prostate-specific antigen (PSA) level (50.9 and 52.1 ng/mL), prior treatment (no local therapy in 73% in both, radiation in 7% and 8%, prostatectomy in 20% and 19%), adjuvant androgen-deprivation therapy (4.5% and 4.1%), median time from start of androgen-deprivation therapy to randomization (1.2 and 1.3 months), and no receipt of androgen-deprivation therapy before randomization (13% in both).
At a planned interim analysis in October 2013, 53% of planned full overall survival information had been obtained, and prespecified criteria for significance had been met. The current report includes data with a cutoff date for survival of December 23, 2013, representing a median follow-up of 28.9 months. All other data reflect the data base as of December 23, 2014.
Improved Overall Survival and Reduced Progression
Overall, 86% of patients in the combination group completed six cycles of docetaxel. Median overall survival was 57.6 months in the androgen-deprivation therapy plus docetaxel group vs 44.0 months in the androgen-deprivation therapy–alone group (hazard ratio [HR] = 0.61, P < .001).
Benefit was more pronounced among patients with high-volume disease, with a median overall survival of 49.2 vs 32.2 months (HR = 0.60, P < .001). At the time of analysis, median overall survival had not been reached among patients with low-volume disease in either group (HR = 0.60, 95% confidence interval = 0.32–1.13). A survival benefit of combined treatment was detected in all analyzed subgroups.
Median time to castration-resistant disease (biochemical, symptomatic, or radiographic progression) was 20.2 vs 11.7 months (HR = 0.61, P < .001), and median time to clinical progression was 33.0 vs 19.8 months (HR = 0.61, P < .001). PSA level < 0.2 ng/mL was achieved at 12 months in 27.7% vs 16.8% of patients (P < .001).
After progression, 54 patients in the combination group and 137 patients in the androgen-deprivation therapy–alone group received docetaxel, 57 and 37 received cabazitaxel (Jevtana), and 29 and 27 received mitoxantrone or platinum chemotherapy. Hormonal therapy with abiraterone (Zytiga) or enzalutamide (Xtandi) was received by 105 and 104 and with an antiandrogen or ketoconazole by 80 and 91. Immunotherapy with sipuleucel-T (Provenge) was received by 22 and 19. Radiotherapy was received by 69 and 79. Overall, 150 and 187 patients received at least one agent shown to prolong overall survival in metastatic castration-resistant prostate cancer, and 71 and 83 received at least two agents.
Adverse Events
Among patients in the combination group, 16.7% had grade 3 and 12.6 had grade 4 adverse events. The most common grade 3 adverse events were fatigue (4.1%), febrile neutropenia (3.8%), and neutropenia (3.1%); the most common grade 4 events were neutropenia (9.0%) and febrile neutropenia (2.3%). Grade 3 or 4 infection with neutropenia occurred in 2.3%, grade 3 or 4 allergic reaction occurred in 2.1%, grade 3 sensory neuropathy occurred in 0.5%, and grade 3 motor neuropathy occurred in 0.5%. Grade 3 or 4 thromboembolism occurred in three patients (< 1%). One patient (0.3%) died of sudden death, considered possibly related to docetaxel treatment.
The investigators concluded: “[T]he combination of standard [androgen-deprivation therapy] and six cycles of docetaxel resulted in significantly longer overall survival than that with standard [androgen-deprivation therapy] alone in men with hormone-sensitive metastatic prostate cancer. The clinical benefit at this early analysis was more pronounced among patients with a higher burden of disease.
Christopher Sweeney, MB, BS, of Dana-Farber Cancer Institute, is the corresponding author of The New England Journal of Medicine article.
The study was funded by the National Cancer Institute and others. Sanofi provided docetaxel and a grant to ECOG-ACRIN. For full disclosures of the study authors, visit www.nejm.org.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
