CHAARTED  randomized 790 castrate sensitive men with metastatic prostate cancer to receive either ADT + 6 cycles of docetaxel vs ADT alone; one of the stratification variables was low vs high volume metastatic burden (visceral metastasis and/or ≥4 bone metastatic lesions with at least one lesion beyond the pelvis and spine). The HR for death in patients with high volume metastatic disease significantly favored ADT + docetaxel (HR 0.60, 95%CI 0.45-0.81), whereas with low-volume disease there was no significant benefit (HR 0.60, 95%CI 0.32-1.13). An update of survival outcomes presented at ESMO 2016 demonstrated a continued survival advantage for docetaxel + ADT for high-volume patients and once again showed no benefit for low-volume patients (HR 1.04, 95%CI 0.70-1.55).
STAMPEDE  also evaluated the impact of adding docetaxel to ADT in men with metastatic and high prostate cancer, albeit with a more heterogeneous inclusion criteria compared to patients included in CHAARTED. Inclusion criteria included men with locally advanced or metastatic prostate cancer, including newly diagnosed with N1 or M1 disease, or any two of the following: stage T3/4, PSA ≥ 40 ng/mL, or Gleason score 8-10. Patients undergoing prior radical prostatectomy or RT were eligible if they had more than one of the following: PSA ≥ 4 ng/mL and PSADT < 6 months, PSA ≥ 20 ng/mL, N1, or M1 disease. Similar to CHAARTED, there was an OS advantage for patients receiving docetaxel + ADT (HR 0.78, 95%CI 0.66-0.93) compared to those receiving ADT alone. Specifically, in M1 patients, the effect of docetaxel was even greater (HR 0.73, 95%CI 0.59-0.89). These two trials demonstrated that ADT + docetaxel improves OS and quality of life in M1 castrate sensitive prostate cancer patients, with a clear effect for patients with high-volume disease and a less certain benefit in low-volume patients.
LATITUDE  set to evaluate the addition of AA + prednisone to ADT on clinical benefit in men with newly diagnosed, high-risk, metastatic hormone-naïve prostate cancer. High-risk was defined as meeting at least two of three criteria: (i) Gleason score ≥8, (ii) presence of ≥3 lesions on bone scan, (iii) presence of measurable visceral lesions. Patients were randomized 1:1 to either ADT + AA (1000 mg daily) + prednisone (5 mg) (n=597) or ADT + placebo (n=602). The co-primary endpoints were OS and radiographic progression-free survival (rPFS). Secondary endpoints included time to: pain progression, PSA progression, next symptomatic skeletal event, chemotherapy, and subsequent prostate cancer therapy. Over a median follow-up of 30.4 months, patients treated with ADT + AA + prednisone had a 38% risk reduction of death (HR 0.62, 95%CI 0.51-0.76) compared to ADT + placebo. There was also 53% risk of reduction of radiographic progression or death for patients treated with ADT + AA + prednisone (median 33.0 months; HR 0.47, 95%CI 0.39-0.55) compared to ADT + placebo (14.8 months). There was statistically significant improvement across all secondary endpoints for ADT + AA + prednisone: (i) time to PSA progression (HR 0.30, 95%CI 0.26-0.35), (ii) time to pain progression (HR 0.70, 95%CI 0.58-0.83), (iii) time to next symptomatic skeletal event (HR 0.70, 95%CI 0.54-0.92), (iv) time to chemotherapy (HR 0.44, 95%CI 0.35-0.56), and (v) and time to subsequent prostate cancer therapy (HR 0.42, 95%CI 0.35-0.50).
STAMPEDE  randomized patients 1:1 to standard of care (SOC; ADT for ≥2 years, n=957) vs SOC + AA (1000 mg) + prednisone 5 mg daily (n=960). Primary outcomes were OS and failure-free survival (FFS), where failure was defined as PSA failure, local failure, lymph node failure, distant metastases or prostate cancer death. Secondary outcomes included toxicity and skeletal-related events (SREs). Both groups were balanced and patients were predominantly metastatic (52% M1, 20% N+M0, 28% N0M0). Over a median follow-up of 40 months, there was a 37% relative improvement in overall survival (HR 0.63, 95%CI 0.52-0.76) favoring SOC + AA + prednisone. Second, SOC+AA + prednisone demonstrated a 71% improvement in FFS (HR 0.29, 95%CI 0.25-0.34). SOC + AA + prednisone also significantly decreased SREs among the entire cohort (HR 0.46, 95%CI 0.37-0.58), as well as specifically in the M1 cohort (HR 0.45, 95%CI 0.37-0.58).
Given the STAMPEDE design, recruitment of patients for the comparison of docetaxel + prednisone plus ADT versus ADT overlapped for 16 months with recruiting patients for abiraterone acetate + prednisone + ADT versus ADT. This allowed a comparison of randomized patients receiving docetaxel + ADT to those receiving abiraterone + ADT, which was presented at ESMO 2017 . The primary outcome was death from any cause. A magnitude difference of HR < 1 favored ADT + abiraterone, whereas HR > 1 favored ADT + docetaxel. There were 566 patients randomized to ADT + docetaxel (n=189; the last of 592 ADT + docetaxel patients) and ADT + abiraterone (n=377; the first of 960 ADT + abiraterone patients). At a median follow up 4 years, the OS HR was 1.16 (95%CI 0.82-1.65), FFS HR was 0.51 (95%CI 0.39-0.67), PFS HR was 0.65 (95%CI 0.48-0.88), metastases free survival HR was 0.77 (95%CI 0.57-1.03), and SRE survival HR was 0.83 (95%CI 0.55-1.25). Grade 3, 4, 5, toxicity was 36%, 13%, 1% for ADT + docetaxel, respectively, and 40%, 7%, 1% for ADT + abiraterone, respectively.
Moving forward, Dr. Chi notes there are currently six clinical trials ongoing with various combinations of docetaxel, abiraterone, enzalutamide, apalutamide, and darolutamide to further improve on OS outcomes in this patient population. As of now, we have level 1 evidence demonstrating improved OS for ADT + docetaxel or ADT + abiraterone, although we need additional predictors to assess who will benefit from each therapy. We look forward to the outcomes of these trials addressing the efficacy of ADT + AR targeted therapies with docetaxel combinations.
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2. James ND, Sydes MR, Clarke NW, et al. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet. 2016;387(10024):1163-1177.
3. Fizazi K, Tran N, Fein L, et al. Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer. N Engl J Med. 2017;377(4):352-360.
4. James ND, de Bono JS, Spears MR, et al. Abiraterone for Prostate Cancer Not Previously Treated with Hormone Therapy. N Engl J Med. 2017;377(4):338-351.
5. Sydes MR, Mason MD, Spears MR, et al. Adding abiraterone acetate plus prednisolone or docetaxel for patients with high-risk prostate cancer starting long-term androgen deprivation therapy: directly randomized data from STAMPEDE. ESMO 2017 abstr LBA31.
Presented by: Kim N. Chi, MD, Vancouver Prostate Centre, Vancouver, BC, Canada
Written by: Zachary Klaassen, MD, Society of Urologic Oncology Fellow, University of Toronto, Princess Margaret Cancer Centre @zklaassen_md at the 18th Annual Meeting of the Society of Urologic Oncology, November 20-December 1, 2017 – Washington, DC