All patients received 3 years of ADT. This trial started in 2002. High-risk disease was defined as patients with one of the following characteristics: stage T3–T4 disease, Gleason score of ≥8, prostate-specific antigen concentration >20 ng/mL, or pathological node-positive. Docetaxel was given at 70 mg/m2 every 3 weeks for a total of four cycles and estramustine was given orally for 5 days, every three weeks, at a dose of 10 mg/kg. A total of 413 patients were randomized to either ADT + Docetaxel + Estramustine or ADT only. For men with the pathologically node-negative disease, they went on to receive conformal radiotherapy or radical prostatectomy. For patients with node-positive disease, they could receive radiotherapy or no definitive local treatment.
At the time of an earlier data cutoff (median 8.8 years), 43% (88/207) of patients in the Docetaxel arm had an event (relapse or death) compared to 54% (111/206) of the patients in the ADT only group and the hazard ratio for relapsed free survival was 0.71, (95% CI 0.54–0.94, p=0.017). Most patients (87% (358/413)) received radiotherapy. A planned analysis of response, toxicity, and quality of life demonstrated that there were no toxicity-related deaths, no secondary leukemias, and no excess second cancers, and while chemotherapy had a negative impact on quality of life during the first three months, this effect disappeared at 1 year3. Only 2% of men had a neutropenic fever with no deaths from toxicity. This session provided updated 12-year data.
413 patients were enrolled in the study from 2002-2006. The median age was 77 years old in both arms. About 67% of patients were T3 and T4. In this analysis, they revised the statistical methods to report on three variables in a pre-specified order. First, they wanted to test if there was a difference in relapse-free survival (RFS), which includes PSA relapse, local relapse, metastases, death by prostate cancer, and other reason for death. If there was a significant difference in RFS, then the investigators would look to see if there was a difference in clinical relapse-free survival (cRFS), which includes all of the same variables mentioned before with the exception of PSA relapse. If that difference was significant, they would test metastases-free survival (MFS), which includes all of the features except for local relapse.
The authors found that there was a significant difference for relapse-free survival, 11.6 months vs 8.1 months (HR 0.71, 96%CI 0.55 0.55-0.93). For relapse-free survival, those patients who benefited the most were those with high-risk features as expected (node positive, PSA>20). One unexpected finding was that those with a Gleason 7 also had improved RFS. In terms of cRFS, there was also a benefit to upfront docetaxel, with a median cRFS of 13.9 months vs 12.5 months (HR 0.75, 95%CI 0.56-0.99, p=0.049). The improvements were seen in local relapse (6.9% vs 10.6%) as well as metastatic relapse. Thus, the authors went on to perform a MFS analysis. Here, there was no significant difference between the experimental and control arm (HR 0.81, 95%CI 0.6-1.09, p=0.16). At this time, only 50 prostate cancer-specific deaths have occurred at 12 years, and 134 deaths total.
Four cycles of docetaxel-based chemotherapy can reduce the risk of clinical relapse-free survival. However, it does not affect metastases-free survival. Based on the results of this study, the author and discussant concluded that there is insufficient evidence at this time to recommend docetaxel for high risk localized prostate cancer outside of a clinical trial. Several factors may have impacted the final outcome including:
- Only 42% of patients in the experimental arm and 43% of patients in the control arm had Gleason 8 or higher – thus, the majority of patients actually had Gleason 7 disease.
- Only 29% of all patients were node positive.
- Only 4 cycles of docetaxel were given. Many oncologists are comfortable giving 6 cycles of chemotherapy for prostate cancer.
Presented by: Karim Fizazi, MD, Ph.D., Medical Oncologist, Head of the Department of Cancer Medicine at the Institut Gustave Roussy, Villejuif, France and Professor in Oncology at the University of Paris
Discussant: Eleni Efstathiou, MD, Ph.D., Associate Professor, Department of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Houston, US
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2. Fizazi K, Faivre L, Lesaunier F, et al. Androgen deprivation therapy plus docetaxel and estramustine versus androgen deprivation therapy alone for high-risk localised prostate cancer (GETUG 12): a phase 3 randomised controlled trial. The Lancet Oncology 2015;16:787-94.
3. Fizazi K, Lesaunier F, Delva R, et al. A phase III trial of docetaxel–estramustine in high-risk localised prostate cancer: A planned analysis of response, toxicity and quality of life in the GETUG 12 trial. European Journal of Cancer 2012;48:209-17.
4. Sandler HM, McKenzie MR, Tombal BF, et al. ATLAS: A randomized, double-blind, placebo-controlled, phase 3 trial of apalutamide (ARN-509) in patients with high-risk localized or locally advanced prostate cancer receiving primary radiation therapy. American Society of Clinical Oncology; 2016.
5. Williams S, Davis ID, Sweeney C, et al. Randomised phase III trial of enzalutamide in androgen deprivation therapy (ADT) with radiation therapy for clinically localised, high risk, or node-positive prostate cancer: ENZARAD (ANZUP 1303). American Society of Clinical Oncology; 2017.
Written by: Jason Zhu, MD. Fellow, Division of Hematology and Oncology, Duke University, Twitter: @TheRealJasonZhu at the 2018 European Society for Medical Oncology Congress (#ESMO18), October 19-23, 2018, Munich Germany