Early Docetaxel, ADT Combo Increases Survival in Advanced Prostate Cancer

Christopher J. Sweeney, MBBS

Concomitant therapy with docetaxel and androgen deprivation therapy (ADT) initiated at the start of treatment for men with metastatic prostate cancer resulted in an increased survival of 13.6 months compared with men who received ADT alone, according to results of the E3805 trial that were published in The New England Journal of Medicine.¹

The median overall survival (OS) with the combination was 57.6 versus 44.0 months with ADT alone (HR, 0.61; 95% CI, 0.47—0.80; P < 0.001). The clinical benefit seen in this trial is significant, given that patients who develop hormone-sensitive metastatic prostate cancer make up approximately 20% to 40% of the roughly 30,000 men who die annually from prostate cancer. Initial results of this study were first presented at the ASCO Annual Meeting in 2014, and resulted in a variable uptake among clinicians worldwide.

Lead author of the study, Christopher J. Sweeney, MBBS, associate professor of medicine at the Dana-Farber Cancer Institute’s Lark Center for Genitourinary Oncology, explained that the trial was the “first to identify a strategy that prolongs survival in men newly diagnosed with metastatic, hormone-sensitive prostate cancer.”

Given the magnitude of the results, Sweeney expects “treatment guidelines to be updated around the globe.”

In the trial, also known as CHAARTED, a total of 790 patients underwent randomization from July 2006 to November 2012 in the multicenter phase III trial. Patients received either ADT plus docetaxel every three weeks for six cycles or ADT alone. Stratification was performed prospectively according to high or low burden of metastatic disease. Median age for the combination group was 64 years and 63 years in the other group. Additionally, about 65% of patients had high-volume disease, approximately 60% had a Gleason score of 8 or higher, and 73% of patients had received no prior local therapy for prostate cancer.

The median time to progression was 20.2 months in the combination group, compared with 11.7 months in the ADT-only group (HR, 0.61; 95% CI, 0.51—0.72; P < 0.001). Approximately 27% of patients who received the combination treatment demonstrated a decline in prostate-specific antigen (PSA) levels to less than 0.2 ng/mL at 12 months compared with 16.8% for those taking the single therapy (P < 0.001), according to study findings. The trial was designed in 2005 by the Eastern Cooperative Oncology Group (ECOG), which is now part of ECOG-ACRIN.

In patients with high-volume disease, the median OS was 49.2 months with the combination versus 32.2 months with ADT alone (HR, 0.60; 95% CI, 0.45-0.81; P <.001). In patients with low-volume disease, the median OS had not yet been reached after a median follow-up of 27.6 months (HR, 0.60; 95% CI, 0.32-1.13; P = .11).

In the combination arm, grade 3 adverse events (AEs) occurred in 16.7% of patients and grade 4 events were seen in 12.6%. The most frequently observed grade 4 AE was neutropenia (9%). The most common grade 3 AEs included fatigue (4.1%), febrile neutropenia (3.8%), and neutropenia (3.1%).

Other studies, such as the GETUG-AFU 15 and STAMPEDE trials, have assessed ADT plus chemotherapy. Results from GETUG-AFU 15 did not demonstrate a benefit in OS with combination therapy.² However, this study was analyzed in 2011, before there was widespread access to newer therapies that have been shown to prolong OS among patients with castration-resistant prostate cancer.

Confirmatory results were presented from the STAMPEDE trial at the 2015 ASCO Annual Meeting,³ demonstrating a similar improvement in OS with the addition of chemotherapy. In the phase III STAMPEDE trial, the addition of docetaxel to standard hormonal therapy significantly improved OS among men with newly diagnosed, hormone-naïve advanced prostate cancer. OS was 77 months and 67 months for those receiving docetaxel with ADT versus ADT alone, respectively (HR, 0.76; P = .003).

Given the findings of both the STAMPEDE and CHAARTED findings, it is expected that the combination therapy will become the new standard of care for patients with metastatic hormone-sensitive prostate cancer.

References

1. Sweeney CJ, Chen YH, Carducci M, et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer [published online August 5, 2015]. N Engl J Med. doi: 10.1056/NEJMoa1503747.
2. Gravis G, Fizazi K, Joly F, et al. Androgen-deprivation therapy alone or with docetaxel in non-castrate metastatic prostate cancer (GETUG-AFU 15): a randomized, open-label, phase lll trial. Lancet Oncol. 2013;14:149-158.
3. James ND, Sydes, MR, Mason, MD, et al. Docetaxel and/or zoledronic acid for hormone-naïve prostate cancer: First overall survival results from STAMPEDE. J Clin Oncol. 2015;(suppl; abstr 5001).