The CHAARTED trial randomized 790 men with metastatic hormone naïve prostate cancer to receive either ADT + docetaxel (75 mg/m2 every 3 weeks for six cycles) or ADT alone, with OS as an endpoint1. After a median follow-up of 28.9 months, the median overall survival was 13.6 months longer with ADT + docetaxel than with ADT alone (57.6 months vs. 44.0 months; HR 0.61; 95%CI 0.47-0.80). Furthermore, the median time to biochemical, symptomatic, or radiographic progression was 20.2 months in the ADT + docetaxel group, as compared with 11.7 months in the ADT-alone group (HR 0.61, 95%CI 0.51-0.72).
The UK STAMPEDE trial also assessed outcomes of OS comparing ADT + docetaxel vs ADT alone2. Patients were randomized 2:1:1:1 to standard of care (SOC; ADT alone), SOC + zoledronic acid (SOC + ZA), SOC + docetaxel, or SOC with both zoledronic acid and docetaxel (SOC + ZA + Doc). There were 2,962 men randomized between 2005 and 2013, including 1,817 (61%) men with M+ disease, 448 (15%) with N+/X M0, and 697 (24%) men who were N0M0. Over a median follow-up of 43 months (IQR 30–60), there were 415 deaths in the control group, with a median OS of 71 months (IQR 32-not reached (NR)) for SOC, NR (IQR 32-NR) for SOC + ZA (HR 0.94, 95%CI 0.79–1.11), 81 months (41-NR) for ADT + docetaxel (HR 0.78, 95%CI 0.66–0.93), and 76 months (IQR 39-NR) for SOC + ZA + Doc (HR 0.82, 95%CI 0.69–0.97).
Recently, the CHAARTED trial published an updated survival analysis: at a median follow-up 53.7 months, the HR for OS was 0.72 (95%CI 0.59-0.89) favoring docetaxel over ADT standard of care, a 28% risk reduction of death compared to 39% in the first analysis3. In subset analyses, the benefit was observed across all subgroups with two notable exceptions. Specifically, patients with low burden of disease (HR 1.04, 95%CI 0.7-1.55) or those who had prior local therapy (HR 0.97, 95%CI 0.58-1.56) did not seem to experience a benefit through the addition of docetaxel to standard ADT.
LATITUDE was an international trial evaluating ADT + abiraterone/prednisone compared to ADT alone among men with high-risk mHSPC4. High-risk was defined as meeting at least two of three criteria: (i) Gleason score ≥8, (ii) presence of ≥3 lesions on bone scan, or (iii) presence of measurable visceral lesions. Patients were randomized 1:1 to either ADT + abiraterone/prednisone (1000 mg abiraterone acetate + 5mg prednisone daily) (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 + abiraterone/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 + abiraterone/prednisone arm, compared to 34.7 months in the ADT + placebo arm. There was also a 53% risk of reduction of radiographic progression or death for patients treated with ADT + abiraterone/prednisone compared to ADT alone (HR 0.47, 95%CI 0.39-0.55). Additionally, there was statistically significant improvement across all secondary endpoints for ADT + abiraterone/prednisone.
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STAMPEDE also had an abiraterone acetate arm and reported findings in 20175. Patients were then randomized 1:1 to SOC (ADT for ≥2 years, n=957) vs ADT + abiraterone/prednisone (1000 mg abiraterone acetate + 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, where failure was defined as PSA failure, local failure, lymph node failure, distant metastases or prostate cancer death. Over a median follow-up of 40 months, there was a 37% relative improvement in OS (HR 0.63, 95%CI 0.52-0.76) favoring ADT + abiraterone/prednisone. Furthermore, ADT + abiraterone/prednisone demonstrated a 71% improvement in FFS (HR 0.29, 95%CI 0.25-0.34) as well as significantly decreasing SREs among the entire cohort (HR 0.46, 95%CI 0.37-0.58) and specifically in the M1 cohort (HR 0.45, 95%CI 0.37-0.58).
Based on these studies, ASCO updated their clinical practice guideline for metastatic hormone naïve prostate cancer:
- ADT + docetaxel or abiraterone in newly diagnosed metastatic noncastrate prostate cancer offers a survival benefit compared to ADT alone
- The strongest evidence of benefit with docetaxel is in men with de novo high-volume (CHAARTED criteria) metastatic disease
- Similar survival benefits are seen using abiraterone acetate in high-risk patients (LATITUDE criteria) and in the metastatic population of STAMPEDE
- ADT plus abiraterone and ADT plus docetaxel have not been compared and it is not known if some men benefit from one regimen as opposed to the other
- Fitness for chemotherapy, patient comorbidities, toxicity profiles, quality of life, drug availability, and cost should be considered in this decision
The phase III ARCHES trial presented initial results at GU ASCO 20197. This study randomized patients 1:1 to receive enzalutamide (160 mg/day) + ADT or placebo + ADT, stratified by disease volume (CHAARTED criteria) and prior to docetaxel therapy. The primary endpoint was radiographic PFS. There were 1,150 men randomized to enzalutamide (n=574) or placebo (n=576). Overall, 67% had distant metastasis at initial diagnosis; 63% had high volume disease, and 18% had prior docetaxel. Over a median follow-up of 14.4 months, enzalutamide + ADT significantly improved rPFS HR 0.39 (95%CI 0.30-0.50) and similar significant improvements in rPFS were reported in prespecified subgroups of disease volume, pattern of spread, region and prior docetaxel. Grade 3–4 adverse events were reported in 23.6% of enzalutamide patients vs 24.7% of placebo patients with no unexpected adverse events. Other ongoing trials are the ARASENS trial assessing ADT + darolutamide + docetaxel, and the TITAN trial assessing ADT + apalutamide.
Dr. Oh concluded with several take home messages:
- Newly diagnosed patients with metastatic hormone naïve prostate cancer can be considered for six cycles of docetaxel or abiraterone/prednisone for 2+ years
- Low volume patients may not benefit from docetaxel
- Ongoing studies are evaluating other agents and combinations in the setting: enzalutamide, apalutamide, darolutamide/docetaxel, and abiraterone/cabazitaxel
Written By: Zachary Klaassen, MD, MSc – Assistant Professor of Urology, Georgia Cancer Center, Augusta University - Medical College of Georgia @zklaassen_md at the American Urological Association's 2019 Annual Meeting (AUA 2019), May 3 – 6, 2019 in Chicago, Illinois
References:
- 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.
- 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.
- Kyriakopoulos CE, Chen YH, Carducci MA, et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer: Long-term survival analysis of the randomized phase III E3805 CHAARTED trial. J Clin Oncol 2018 Apr 10;36(11):1080-1087.
- 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.
- 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.
- Sydes MR, Spears MR, Mason MD, Clarke NW, Dearnaley DP, de Bono JS, et al. Adding abiraterone or docetaxel to long-term hormone therapy for prostate cancer: directly randomised data from the STAMPEDE multi-arm, multi-stage platform protocol. Ann Oncol. 2018;29:1235-48.
- Armstrong AJ, Szmulewitz RZ, Petrylak DP, et al. Phase 3 study of androgen deprivation therapy (ADT) with enzalutamide (ENZA) or placebo (PBO) in metastatic hormone-sensitive prostate cancer (mHSPC): The ARCHES trial. J Clin Oncol 37, 2019 (suppl 7S; abstr 687).