Editing Metastatic Hormone-Sensitive Prostate Cancer (section)

==== Landmark Trials ====
*'''<span style="color:#ff00ff">CHAARTED (Sweeney et al. NEJM 2015)</span>'''
** Population: 790 men with metastatic, hormone-sensitive prostate cancer
** '''Randomized to ADT +/- docetaxel'''
** '''<span style="color:#ff0000">Stratified analysis by disease burden: high vs. low volume</span>'''
*** '''<span style="color:#ff0000">High-volume:</span>'''
**** '''<span style="color:#ff0000">Visceral mets or</span>'''
**** '''<span style="color:#ff0000">≥4 bone lesions with ≥ 1 beyond the vertebral bodies and pelvis</span>'''
*** '''<span style="color:#ff0000">Low-volume: all others</span>'''
** Results:
*** Median follow-up: 28.9 months
*** '''OS improved by 13.6 months in ADT + docetaxel arm''' (median OS 57.6 ADT + docetaxel vs. 44.0 months ADT, HR 0.61) '''in non-stratified analysis'''
**** '''<span style="color:#ff0000">In stratified analysis by high vs. low volume disease, benefit only significant on high-volume disease</span>'''
** [https://pubmed.ncbi.nlm.nih.gov/26244877/ Sweeney, Christopher J., et al.] "Chemohormonal therapy in metastatic hormone-sensitive prostate cancer." ''New England Journal of Medicine'' 373.8 (2015): 737-746.
** '''2019 NCCN guidelines recommend ADT and docetaxel for patients with M1, castration-naïve disease; ADT as monotherapy recommended for asymptomatic patients with metastatic disease and life expectancy ≤ 5 years'''
* '''<span style="color:#ff00ff">STAMPEDE (James et al. Lancet 2016)</span>'''
** Multi-arm, multi-stage design
** Population: 2692 men with newly diagnosed as metastatic, node positive, or high-risk locally advanced prostate cancer (with ≥2 of T3/4, Gleason score of 8–10, and PSA ≥40 ng/mL); or previously treated with radical surgery, radiotherapy, or both and relapsing with high-risk features and were starting first-line long-term hormone therapy
*** Of all patients, majority (≈60%) were newly diagnosed with metastasis at the time of diagnosis , some were newly diagnosed with M0 disease, and few patients previously treated.
*** '''(In contrast to CHAARTED, this trial included patients with non-metastatic disease. Similar to CHAARTED, this trial was in hormone-sensitive patients)'''
** '''Randomized to standard of care (ADT x 2 years), SOC + zoledronic acid, SOC + docetaxel, and SOC + ZA + docetaxel.'''
*** Radiotherapy, at 6–9 months after randomisation, was encouraged for patients with N0M0 disease, until November, 2011, then mandated; radiotherapy was optional for patients with N+M0 disease; staging
*** '''Docetaxel (75 mg/m²) was given for six 3-weekly cycles''' with prednisolone (10 mg) daily,
** The definitive and intermediate primary outcome measures were overall survival and failure-free survival, respectively.
*** Failure-free survival, which is commonly used to drive decisions in the clinic, was selected because it is on the causal pathway to death from prostate cancer and was not required to be a surrogate for overall survival. It was defined as time from randomisation to first evidence of at least one of: biochemical failure; progression either locally, in lymph nodes, or in distant metastases; or death from prostate cancer.
** Results:
*** Median follow-up: 43 months
*** Majority (71-76%) of patients assigned to docetaxel completed the 6 cycles
*** SOC + '''docetaxel improved OS by 10 months''' (median OS in SOC + doce 81 months vs. SOC 71 months, HR 0.78). SOC + ZA + doce has improved survival compared to SOC but no difference with SOC + doce. SOC + ZA did not improve survival compared to OS, suggesting that ZA as an agent did not improve survival beyond that attributed to doce.
*** Failure-free survival, skeletal-related events, and cancer-specific survival also improved in patients receiving docetaxel.
*** Febrile neutropenia and neutropenia were the most common adverse events in the docetaxel arm
*** [https://pubmed.ncbi.nlm.nih.gov/26719232/ James, Nicholas D., 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." The Lancet 387.10024 (2016): 1163-1177.