The clinical benefit [of standard androgen-deprivation therapy and docetaxel] at this early analysis was more pronounced among patients with a higher burden of disease.
—Christopher J. Sweeney, MBBS, and colleagues
In a phase III trial (E3805) reported in The New England Journal of Medicine, Christopher J. Sweeney, MBBS, of Dana-Farber Cancer Institute, Boston, and colleagues 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.1
Dr. Sweeney emphasized to The ASCO Post, “The data are relevant for patients who are fit for chemotherapy.”
In this open-label trial, 790 patients were randomized 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 6 cycles (n = 397). Patients receiving docetaxel were premedicated with dexamethasone 8 mg 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 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%), and visceral metastases (14% and 17%). The groups were also generally balanced for Gleason score, median prostate-specific antigen (PSA) level (50.9 and 52.1 ng/mL), prior treatment, adjuvant androgen-deprivation therapy, median time from start of androgen-deprivation therapy to randomization, and no receipt of androgen-deprivation therapy before randomization.
At a planned interim analysis in October 2013, 53% of overall survival information had been obtained, and prespecified criteria for significance had been met. The current report included data with a cutoff date for survival of December 23, 2013, representing a median follow-up of 28.9 months. All other data reflected the database as of December 23, 2014.
Improved Overall Survival
Overall, 86% of patients in the combination group completed 6 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 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 in the androgen-deprivation therapy–alone group received docetaxel, 57 and 37 patients received cabazitaxel (Jevtana), and 29 and 27 patients received mitoxantrone or platinum chemotherapy. Hormonal therapy with abiraterone (Zytiga) or enzalutamide (Xtandi) was received by 105 and 104 patients, respectively, and with an antiandrogen or ketoconazole by 80 and 91 patients, respectively.
Immunotherapy with sipuleucel-T (Provenge) was received by 22 patients in the combination group and 19 patients in the androgen-deprivation therapy–alone group. Radiotherapy was received by 69 and 79 patients, respectively. 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 patients received at least two such agents.
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 from 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.” ■
Disclosure: 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.
1. Sweeney CJ, Chen YH, Carducci M, et al: Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med 373:737-746, 2015.
Sweeney et al reported on the results of a seminal phase III trial (E3805) of chemohormonal therapy vs androgen-deprivation therapy in metastatic hormone-sensitive prostate cancer in a recent issue of The New England Journal of Medicine,1 and the study is summarized in this issue of The ASCO Post....