ZYTIGA - STAMPEDE Trial

CLINICAL DATA

The ongoing STAMPEDE trial includes patients initiating long-term ADT (orchiectomy or gonadotropin-releasing hormone [GnRH] agonists or antagonists) for the first time for locally advanced or metastatic prostate cancer. This study uses a multigroup, multistage (also called multi-arm, multistage [MAMS]) platform design to evaluate whether the addition of further treatments to ADT improves OS if used in this setting.¹

ZYTIGA plus Prednisolone with ADT vs ADT Alone

James et al (2017)¹ evaluated the efficacy of ZYTIGA in combination with prednisolone in patients with locally advanced or metastatic prostate cancer who had not previously received hormone therapy and were initiating long-term ADT (N=1917).

Study Design/Methods

• Randomized, controlled, MAMS, multicenter trial
  • Patients from 111 sites in the United Kingdom and 5 sites in Switzerland were included.
• Patients were randomized 1:1 to receive ZYTIGA 1000 mg daily plus prednisolone 5 mg daily with ADT (combination group) or ADT alone.
• Local radiotherapy (RT) was mandatory for patients with node-negative, nonmetastatic
• disease and optional for those patients with node-positive nonmetastatic disease.
• For patients with nonmetastatic disease with no RT planned and for patients with metastatic disease, treatment continued until PSA, radiologic, or clinical progression or until another treatment was started.
• For patients with nonmetastatic disease with RT planned, treatment was to continue for 2 years or until any type of progression, whichever came first.
• Patients included had prostate cancer that was:
  • Newly diagnosed and metastatic, node-positive, or high-risk locally advanced (defined as having ≥2 of the following disease characteristics: a tumor stage of T3 or T4, a Gleason score of 8 to 10, and a PSA level ≥40 ng/mL) OR
  • Disease that was previously treated with radical surgery or RT and was now relapsing with high-risk features (defined as a PSA level >4 ng/mL with a doubling time of <6 months, a PSA level >20 ng/mL, nodal or metastatic relapse, or <12 months of total ADT with an interval of >12 months without treatment)
• Key exclusion criteria: clinically significant cardiovascular disease (severe angina, recent myocardial infarction, or a history of cardiac failure)
• Primary endpoint: OS
• Intermediate primary outcome: FFS, defined as the time to the first of the following forms of treatment failure: biochemical PSA failure; progression of local, lymph-node, or distant metastases; or death from prostate cancer
• Secondary endpoints: AEs, symptomatic skeletal events, progression-free survival (PFS; ie, FFS biochemical failure), prostate cancer-specific survival, and QOL.

Results

Patient Characteristics

• Median age was 67 years and median PSA level was 53 ng/mL.
• Patient baseline characteristics are described in Table: Patient Baseline Characteristics.

Efficacy

• The median follow-up was 40 months.
• The median duration of treatment with ZYTIGA was 23.7 months in the patients whose therapy was capped at 2 years and 33.2 months in the patients who could continue through progression.
  • 51% discontinued due to progression, and 20% discontinued for toxicity.
• The reported rate of use of RT was 39% in the combination group and 40% in the ADT alone group.
• There were 184 deaths in the combination group as compared with 262 in the ADT alone group. A survival advantage was observed in the combination group, with a 3-year survival of 83% compared with 76% in the ADT alone group (HR, 0.63; 95% CI, 0.52-0.76; P<0.001).
  • The HR in patients with nonmetastatic disease was 0.75 and 0.61 in patients with metastatic disease.
• Based on central review, 140 of the 184 deaths in the combination group (76%) and 216 of the 262 deaths in the ADT alone group (82%) were attributed to prostate cancer. The competing-risks subhazard ratio for death from prostate cancer was 0.58 (95% CI, 0.47-0.72).
• Additional results are summarized in Table: Efficacy Outcome Measures.

• Exploratory analyses of PFS and prostate cancer-specific survival within subgroups of age at randomization suggested a favorable treatment effect regardless of age, with proportionally fewer events noted in patients ≥70 years of age compared to patients <70 years of age.
• Treatment options for patients are summarized in Table: Treatment After Progression.

Additional Analyses

• In a 5-year follow-up analysis, after a median follow-up of 6.1 years, 244 and 329 deaths occurred in the ZYTIGA plus prednisolone with SOC (SOC was ADT) and SOC alone groups, respectively (adjusted HR, 0.60; 95% CI, 0.50-0.71; P<0.0001). Median survival in the ZYTIGA plus prednisolone with SOC and SOC alone groups was 79 and 46 months, respectively. The 5-year survival was 60% in the ZYTIGA plus prednisolone with SOC group and 41% in the SOC alone group. The relative effect of ZYTIGA was similar among patients with low- and high-risk disease (low-risk HR, 0.54; 95% CI, 0.40-0.74 and high-risk HR, 0.54; 95% CI, 0.43-0.69, respectively).⁴
  • Additional results are summarized in Table: Additional Efficacy Outcome Measures at 5-Year Follow-up.

• A subgroup analysis of randomized patients with high-risk M0 disease (n=915; median follow-up of 38 months) showed FFS was improved with ZYTIGA plus prednisolone with SOC in patients with N0M0 disease (HR, 0.14; 95% CI, 0.07-0.30) with 3 year FFS of 98% compared to 80% with SOC. In N+M0 disease, FFS was improved with ZYTIGA plus prednisolone with SOC (HR, 0.26; 95% CI, 0.17-0.40), and MFS was also favorable for both subgroups: N0M0 (HR, 0.62; 95% CI, 0.33-1.14) and N+M0 (HR, 0.47; 95% CI, 0.29-0.78).²
• Another subgroup analysis of evaluable randomized patients classified as having low- (n=428) or high-risk (n=473) M1 disease demonstrated that those receiving ZYTIGA plus prednisolone with SOC had OS improvements (the study primary endpoint) in both the high-risk (HR, 0.54; 95% CI, 0.41-0.70) and low-risk (HR, 0.66; 95% CI, 0.44-0.98) groups. A total of 191 and 354 FFS events occurred in the ZYTIGA plus prednisolone with SOC and ADT alone groups, respectively. There was an absolute improvement of 44% in the 3-year FFS in patients with low-risk disease among patients treated with ZYTIGA plus prednisolone with SOC compared to ADT alone (76% vs 32%; HR, 0.25; 95% CI, 0.17-0.33). There was an absolute improvement of 33% in the 3-year FFS in patients with high-risk disease among patients treated with ZYTIGA plus prednisolone with SOC compared to ADT alone (45% vs 12%; HR, 0.31; 95% CI, 0.25-0.39). No evidence of heterogeneity between risk groups was found in OS or FFS (P-interaction=0.39 and 0.29, respectively). An exploratory analysis among patients with low-volume disease showed improvement in OS among patients treated with ZYTIGA plus prednisolone with SOC compared to patients treated with ADT alone (83% vs 77%; HR, 0.64; 95% CI, 0.42-0.97). The 3-year FFS among patients with low-volume disease in the ZYTIGA plus prednisolone with SOC group was 74% compared to 32% in the ADT alone group (HR, 0.26; 95% CI, 0.19-0.36). No evidence of heterogeneity of effect by the ZYTIGA plus prednisolone with SOC group among patients with high- or low-volume disease was observed for OS or FFS (P-interaction=0.77 and 0.47, respectively).³

Safety

• Grade 3-5 AEs reported in the safety population are summarized in Table: Grade 3-5 Adverse Events.
• There were 12 grade 5 AEs reported overall.
  • Combination group (n=9): 2 events of pneumonia (1 including sepsis), 2 events of stroke, and 1 event each of dyspnea, lower respiratory tract infection, liver failure, pulmonary hemorrhage, and chest infection.
  • ADT alone group (n=3): 2 events of myocardial infarction and 1 event of bronchopneumonia.

ZYTIGA plus Prednisolone with ADT vs Docetaxel plus Prednisolone with ADT

Sydes et al (2018)⁵evaluated survival in a STAMPEDE subset directly comparing ZYTIGA plus prednisolone/prednisone with SOC to docetaxel plus prednisolone/prednisone with SOC (N=566).

Study Design/Methods

• Patients were contemporaneously randomized 2:1:2 to receive:
  • SOC: long-term ADT or 2+ years ADT (plus RT for some nonmetastatic disease).
  • Docetaxel 75 mg/m² every 3 weeks for 6 cycles plus prednisolone/prednisone 10 mg daily with SOC (n=189) OR
  • ZYTIGA 1000 mg plus prednisolone/prednisone 5 mg orally daily with SOC (n=377)
• Duration of treatment with ZYTIGA plus prednisolone/prednisone was capped after 2 years in M0 patients having radical RT.
• Primary endpoint: death from any cause.

Results

Patient Characteristics

• Treatment groups were well balanced.
  • M1: n=342 (60%)
  • Gleason 8-10: n=429 (76%)
  • World Health Organization (WHO) performance status 0: n=449 (79%)
• Median age was 66 years, and median PSA level was 56 ng/mL.

Efficacy

• The median follow-up was 48 months.
• There were 105 deaths in the ZYTIGA plus prednisolone/prednisone group with SOC and 44 in the docetaxel plus prednisolone/prednisone with SOC group.
• No heterogeneity was observed by baseline metastasis status (M0/M1; P=0.69).
• With HR<1 favoring the ZYTIGA plus prednisolone/prednisone with SOC group, OS HR was 1.16 (95% CI, 0.82-1.65; P=0.40), and event-free survival was:
  • FFS: HR, 0.51; 95% CI, 0.39-0.67; P<0.001
  • PFS: HR, 0.65; 95% CI, 0.48-0.88; P=0.005
  • Metastatic PFS: HR, 0.77; 95% CI, 0.57-1.03; P=0.079
  • Symptomatic skeletal events: HR, 0.83; 95% CI, 0.55-1.25; P=0.375

Safety

• A total of 48% and 50% of patients in the ZYTIGA plus prednisolone/prednisone with SOC and docetaxel plus prednisolone/prednisone with SOC groups experienced a grade 3-5 AE. Grade 3-5 AEs included: endocrine disorder, febrile neutropenia, neutropenia, general disorder (fatigue or edema), musculoskeletal disorder, cardiovascular disorder (hypertension, myocardial infarction, and cardiac dysrhythmia), gastrointestinal disorder, hepatic disorder (increased aspartate aminotransferase [AST]/alanine aminotransferase [ALT]), respiratory disorder (dyspnea), renal disorder, and lab abnormalities (hypokalemia).

Meta-Analysis of ZYTIGA plus Prednisolone with ADT vs ADT and ZYTIGA plus Prednisolone with Enzalutamide vs ADT

Attard et al (2022)⁷ conducted a meta-analysis to evaluate the results of 2 trials of the STAMPEDE platform protocol involving ZYTIGA and prednisolone with or without enzalutamide for patients with high-risk nonmetastatic prostate cancer.

Study Design/Methods

• Patients were randomized 1:1 to receive SOC alone or with combination therapy:
  • SOC: 3 years ADT, which could include luteinizing-hormone-releasing hormone agonists and antagonists and surgery (plus RT [required for node-negative disease and encouraged for node-positive disease]) OR
  • SOC plus ZYTIGA 1000 mg plus prednisolone/prednisone 5 mg orally daily alone (ZYTIGA trial) or with enzalutamide 160 mg orally once daily (ZYTIGA and enzalutamide trial).
    • ZYTIGA and enzalutamide therapy was continued for 2 years or until progression, whichever occurred first.
• Primary endpoint: MFS
• Secondary endpoints: OS, prostate cancer-specific survival, FFS, PFS, and toxicity/AEs.
• Stratifications: randomization center, age (<70 vs ≥70), planned use of prostate RT, nodal involvement, WHO performance status, type of ADT, and regular, long-term use of aspirin or non-steroidal anti-inflammatory drugs.

Results

Patient Characteristics

• A total of 1974 nonmetastatic patients were assigned in both trials.
• Baseline characteristics of patients were well balanced between treatment groups.
• Median age was 68 years, and median PSA level was 34 ng/mL.
• Patient baseline characteristics are described in Table: Select Patient Baseline Characteristics.

Efficacy

• The median follow-up was 72 months (85 months in the ZYTIGA trial and 60 months in the ZYTIGA and enzalutamide trial).
• A total of 451/459 patients randomly assigned to ZYTIGA and prednisolone started treatment; 512/527 patients randomly assigned to ZYTIGA, prednisolone, and enzalutamide started both treatments, and 1 patient started only ZYTIGA and prednisolone.
• Eighty-four of the 964 patients (9%) continued treatment beyond 24 months.
• The planned rate of use of local RT was 1684/1974 patients (85%), namely for newly diagnosed patients, 99% and 71% for node-negative and node-positive patients, respectively, and 7% for previously treated patients.
• Efficacy results are summarized in Table: Efficacy Outcome Measures.
• A preplanned subgroup analysis evaluated 294 MFS events in the ZYTIGA trial and 192 MFS events in the ZYTIGA and enzalutamide trial.
  • Strong effects were observed in each trial (ZYTIGA trial: HR, 0.54; 95% CI, 0.43-0.68; P<0.0001; ZYTIGA and enzalutamide trial: HR, 0.53; 95% CI, 0.39-0.71; P<0.0001), with no difference in treatment effect (interaction HR, 1.02; 95% CI, 0.70-1.50; P=0.91) and no between-trial heterogeneity (I² P=0.90).
  • Analysis of treatment effect on MFS for baseline randomization stratification factors in the control groups and combination groups found statistically significant heterogeneity for WHO performance status 1-2 (I² P=0.00656) or use of non-steroidal anti-inflammatory drugs or aspirin (I² P=0.0052).
• A preplanned subgroup analysis evaluated 237 deaths in the ZYTIGA trial and 146 deaths in the ZYTIGA and enzalutamide trial.
  • Strong effects were observed in both trials (ZYTIGA trial: HR, 0.63; 95% CI, 0.48-0.82; P<0.0005; ZYTIGA and enzalutamide trial: HR, 0.54; 95% CI, 0.39-0.76; P<0.0004), with no between-trial heterogeneity (I² P=0.51).

• In an analysis of OS, the ADT plus ZYTIGA plus prednisolone plus enzalutamide trial (N=916) had an HR of 0.65 (95% CI, 0.55-0.77; P=1.4×10^-6), with 9% of patients receiving docetaxel plus ADT. In the ADT plus ZYTIGA plus prednisolone trial (N=1003), HR for OS was 0.62 (95% CI, 0.53-0.73; P=1.4×10^-9). The interaction HR was 1.05 (95% CI, 0.83-1.32; P=0.71) with no evidence of between-trial heterogeneity (I² P=0.70).⁸
• In the ADT plus ZYTIGA plus prednisolone trial, at a median follow-up of 95.8 months, 30% and 48% of patients, respectively, in the ADT alone and ADT plus ZYTIGA plus prednisolone groups of the ADT plus ZYTIGA plus prednisolone trial were alive at 7 years. The restricted mean survival time was 50.4 months in the ADT alone and 60.6 months in the ADT plus ZYTIGA plus prednisolone groups (P=6.6x10^-9).⁸

Safety

• Grade 3-5 AEs reported in the safety population are summarized in Table: Grade 3-5 Adverse Events.
• There were 7 grade 5 AEs reported overall.
  • None in the control groups.
  • Three in the combination group of the ZYTIGA trial (rectal adenocarcinoma, pulmonary hemorrhage, and respiratory disorder, n=1 each).
  • Four in the combination group of the ZYTIGA and enzalutamide trial (septic shock, n=2; sudden death, n=2).

• In an analysis of OS, the percentage of patients reporting grade 3-5 toxicity in the first 5 years was 38.5% in the ADT alone and 54.5% in the ADT plus ZYTIGA plus prednisolone groups of the ADT plus ZYTIGA plus prednisolone trial and 45.2% in the ADT alone and 67.9% in the ADT plus ZYTIGA plus prednisolone plus enzalutamide groups of the ADT plus ZYTIGA plus prednisolone plus enzalutamide trial. Liver derangement and hypertension were the most frequent; however, no specific incidence was reported.⁸

Information from Additional Relevant Literature

Gray et al (2025)⁹ conducted a subanalysis of the STAMPEDE trial to assess whether the addition of ARPIs to ADT was associated with BMD loss on longitudinal scans among patients randomized to receive ADT alone, ADT plus ZYTIGA and prednisolone, or ADT plus ZYTIGA and prednisolone plus enzalutamide.

Study Design/Methods

• Staging CT scans from patients enrolled in the STAMPEDE trial were centrally retrieved and pseudo-anonymized. Patients with nonmetastatic disease who had adequate baseline and follow-up CT scans obtained 6 to 120 months after randomization were included.

Results

Patient Characteristics

• Overall, 113 patients met the inclusion criteria, contributing 226 scans and 1130 bone segmentations; 14 bone segments were excluded because of implants.
• The median age was 66 years, with no statistically significant age (P=0.582) or time between scans across treatment groups (mean, 38.4 months; P=0.972).
• Baseline characteristics were balanced across the treatment groups.

Efficacy

• Total bone density decreased across all treatment groups.
• A significant decline in vertebral BMD was observed with ADT plus ZYTIGA and prednisolone compared with ADT alone (MD, -2.07 mgHA/cc/month; P=0.031).
• Longitudinal BMD changes were comparable between ADT alone vs ADT plus ZYTIGA and prednisolone plus enzalutamide (total MD, -1.79; P=0.385) and between ADT plus ZYTIGA and prednisolone vs ADT plus ZYTIGA and prednisolone plus enzalutamide (total MD, 1.06; P=0.728).
• A multivariate analysis identified significant reductions in total BMD with ADT plus ZYTIGA and prednisolone (P=0.0156) and with increasing baseline BMD (P=0.009) and age (P=0.008).
• The T10 vertebra showed the highest rate of BMD loss across the treatment groups, corresponding to a clinically significant mean bone loss of 10% after 13 months.

Jones et al (2024)¹⁰ conducted a secondary analysis of the STAMPEDE trial to evaluate the long-term effects of ARSIs and prostate RT plus ADT on bone health and fracture risks.

Study Design/Methods

• Health systems data from Hospital Episode Statistics (HES) up to March 2021 were linked to patients from the STAMPEDE trial in England who were randomized to ZYTIGA and prednisolone, ZYTIGA and prednisolone plus enzalutamide, and RT trials.
• Patients were stratified by M1 or M0 disease status.

Results

Patient Characteristics

• Between January 2013 and September 2016, patients were randomized to ZYTIGA and prednisolone, ZYTIGA and prednisolone plus enzalutamide, and RT trials.
• Linked data were available for 1453 of 1774 eligible patients in the ZYTIGA and prednisolone trial, 1649 of 1843 patients in the ZYTIGA and prednisolone plus enzalutamide trial, and 1724 of 2024 patients in the M1-RT trial.

Efficacy

• The 5-year model-based cumulative incidence of FRH was high in both the M0 and M1 patients randomized to ADT alone, at 15% (95% CI, 12%-18%) in the M0 population and 30% (95% CI, 25%-34%) in the M1 population (ZYTIGA and prednisolone trial).
• In M1 patients, SDHR for FRH was significantly reduced with ZYTIGA and prednisolone (0.77; 95% CI, 0.59-0.99; P=0.044) and ZYTIGA and prednisolone plus enzalutamide (0.69; 95% CI, 0.54-0.88; P=0.002).
• In M0 patients, the corresponding SDHRs were 0.98 (P=0.897) for ZYTIGA and prednisolone and 0.76 (P=0.104) for ZYTIGA and prednisolone plus enzalutamide.
• For M1 patients allocated to RT, SDHR was 0.92 (P=0.299).

Literature Search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 18 August 2026.