Dr. Merseburger presented a case of a 69-year-old gentleman with excellent performance status, Gleason 8 disease, PSA 82 ng/mL, cT3N1 (CT/bone scan) M1 (high volume). There are a number of therapies that would be appropriate for this man – specifically the EAU guidelines recommend androgen withdrawal with a discussion with the patient about docetaxel chemotherapy, if they’re deemed fit enough for chemotherapy . These recommendations are based on three randomized controlled trials, specifically GETUG-15, CHAARTED, and STAMPEDED [2-4]. Since then, the urologic world has once again been turned upside down this past June at ASCO 2017 when both LATITUDE and STAMPEDE [5-6] reported improved OS when treating mHNPC men with abiraterone + ADT compared to ADT alone. Dr. Merseburger notes a quote form STAMPEDE lead-trialist Dr. Nicholas James “This [abiraterone plus androgen-deprivation therapy] is one of the biggest game-changers in prostate cancer.”
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 stratified by the presence of visceral disease (yes/no) and ECOG performance status (0, 1 vs 2) and then 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. The treatment arms were well balanced, with >95% of patients presenting with ≥3 bone metastases at screening in both arms. 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. Median OS was not yet reached in the ADT + AA + prednisone arm compared to 34.7 months in the ADT + placebo arm. OS rates at 3 years for the ADT + AA + prednisone arm was 66%, compared to 49% in the ADT + placebo arm. 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). Third, 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  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. Patients were then randomized 1:1 to standard of care (SOC; ADT for ≥2 years, n=957) vs SOC + AA (1000 mg) + prednisone 5 mg daily (n=960). Treatment with RT was mandated in patients with N0M0 disease, while strongly encouraged for N1M0 patients. 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 were 262 control arm deaths, of which 82% were prostate cancer-related; there were 184 deaths in the SOC + AA + prednisone arm. 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 last week at ESMO 2017 . Stratified randomization allocated patients 2:1:2 to standard of care (ADT), or ADT + docetaxel 75mg/m2 3-weekly x6 + prednisolone 5mg twice daily, or ADT + abiraterone acetate 1000mg + prednisolone 5mg daily. The primary outcome was death from any cause. The authors stated that it is indicative of a likely magnitude of difference if HR < 1 favors ADT + abiraterone, or HR > 1 favors 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, there were 149 deaths: 45 (23.8%) receiving ADT + docetaxel and 111 (29.4%) receiving ADT + abiraterone. The survival HR was 1.16 (95%CI 0.82-1.65), failure free survival HR was 0.51 (95%CI 0.39-0.67), progression free survival HR was 0.65 (95%CI 0.48-0.88), metastases free survival HR was 0.77 (95%CI 0.57-1.03), and skeletal related event 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. The authors concluded that failure free survival and progression free survival favored ADT + abiraterone. Although not statistically significant, ADT + abiraterone also favored metastasis free survival and skeletal related event survival, while overall survival trended toward favoring ADT + docetaxel.
Dr. Merseburger concluded that for mHNPC patients, we must choose wisely between docetaxel and abiraterone; for the foreseeable future, this will likely hinge on drug availability across jurisdictions. ADT remains the backbone of the aforementioned treatment regimens, and the next question to answer according to Dr. Merseburger is what to use after abiraterone/docetaxel.
1. Cornford P, Bellmunt J, Bolla M, et al. EAU-ESTRO-SIOG Guidelines on Prostate Cancer. Part II: Treatment of Relapsing, Metastatic, and Castration-Resistant Prostate Cancer. Eur Urol 2017;71(4):630-642.
2. Gravis G, Boher JM, Joly F, et al. Androgen Deprivation Therapy (ADT) Plus Docetaxel Versus ADT Alone in Metastatic Non castrate Prostate Cancer: Impact of Metastatic Burden and Long-term Survival Analysis of the Randomized Phase 3 GETUG-AFU15 Trial. Eur Urol. 2016;70(2):256-262.
3. Sweeney CJ, Chen YH, Carducci M, et al. Chemohormonal Therapy in Metastatic Hormone Sensitive Prostate Cancer. N Engl J Med. 2015;373(8):737-746.
4. 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.
5. 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.
6. 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.
7. 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.
Speaker: Axel Merseburger, University Hospital Schleswig-Holstein, Lubeck, Germany
Written By: MD, Urologic Oncology Fellow, University of Toronto, Princess Margaret Cancer Centre @zklaassen_md at the EAU - Update on Prostate Cancer – September 15-16, 2017 - Vienna, Austria