No Benefit for Adding Docetaxel to ADT in Localized Prostate Cancer

Within 10 years of primary treatment (radical prostatectomy and/or radiotherapy) for localized prostate cancer, up to 30% of patients develop biochemical relapse with raising prostate-specific antigen (PSA). On average, biochemical relapse precedes the appearance of clinical metastases by about 8 to 10 years. Factors that indicate high risk for early development of metastases include a Gleason score of 8 to 10, biochemical relapse in less than 3 years, and a PSA velocity and PSA doubling time of less than 6 months. There is no defined standard-treatment approach for patients with hormone-sensitive prostate cancer (HSPC) with rising PSA after local therapy. However, patients with high risk features are commonly treated with early ADT administration. Addition of docetaxel to ADT resulted in improved survival in patients with metastatic HSPC in three randomized clinical trials.  A randomized, open-label, multicenter, phase III French trial (N = 254) compared the combination of one year ADT plus six cycles of docetaxel with one year ADT alone in high-risk patients who experienced rising PSA levels after primary local therapy for prostate cancer.

The study failed to meet its primary endpoint of superior PSA progression-free survival (PSA-PFS) in patients receiving docetaxel plus ADT. At a median 30.0-month follow-up, the PSA-PFS was 20.3 months in patients receiving ADT plus docetaxel and 19.3 months in patients receiving ADT alone (HR 0.85, P = .31). The PSA response rate was similar between the two treatment arms, and similar proportions of patients experienced a greater than 50% decrease in PSA levels (93.0% vs 92.8%). The radiologic PFS also did not differ significantly between the treatment arms with 10.5-year follow-up (8.9 years vs 9.0 years; HR 1.03, P = .88). Median survival was not reached in either treatment group. The 12-year survival rates were 60% with ADT plus docetaxel and 55% with ADT alone (HR 0.86, P = .49).

Addition of docetaxel to ADT resulted in an increased rate of grade 3/4 adverse events (AEs) compared to ADT alone, with hematologic AEs as the most common docetaxel-related toxicities. Neutropenia (48.0%), febrile neutropenia (8.0%), and thrombocytopenia (3.0%) were the most common grade 3/4 hematologic AEs in patients receiving docetaxel plus ADT. However, there was no significant effect on quality of life during the first 12 months of treatment.

The investigators concluded that “addition of docetaxel to ADT seems unwarranted in patients with high-risk prostate cancer without metastases in the absence of better predictors of risk for metastatic disease.” In an accompanying commentary, Nicholas Vogelzang, MD (Comprehensive Cancer Centers of Nevada, Las Vegas, Nevada, United States), agreed, highlighting the importance of androgen environment over disease burden in prostate cancer. Based on evidence from this trial and the SWOG S9921 trial, Dr Vogelzang recommends adjuvant ADT for 1 to 2 years in all high-risk patients and indicated that the addition of docetaxel may be effective in selected patients who have a high likelihood of developing androgen receptor independence.

JAMA Oncol. 2019 Jan 31. [Epub ahead of print.]

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