Meta-analysisPhase 3Prostate cancer

Abiraterone acetate and prednisolone with or without enzalutamide for high-risk non-metastatic prostate cancer: a meta-analysis of primary results from two randomised controlled phase 3 trials of the STAMPEDE platform protocol

Lancet · 20221974 patients

Attard G, Murphy L, Clarke NW, Cross W, Jones RJ, Parker CC, et al. Lancet. 2022. 399:447-460

Study type: Meta-analysis
Study name: STAMPEDE
Phase: Phase 3
Design: Meta-analysis of two open-label randomised phase 3 trials in the multi-arm STAMPEDE platform (113 centres in the UK and Switzerland)
Sample size: 1974 patients
Source: Lancet · 2022
Trial registration: NCT00268476

In plain words

In men with high-risk prostate cancer that had not yet spread to distant organs, adding two years of abiraterone tablets with prednisolone to hormone therapy (usually with radiotherapy) raised the chance of being alive and free of metastases after 6 years from 69% to 82% and lowered the risk of death. Adding enzalutamide gave no extra benefit.

Key results

82% vs 69%

6-year metastasis-free survival

HR 0.53 (0.44 to 0.64); p<0.0001

HR 0.60

Overall survival

0.48 to 0.73; p<0.0001

No additional benefit

Adding enzalutamide to abiraterone

Interaction HR 1.02 (0.70 to 1.50)

37% vs 29%

Grade 3 or higher adverse events in the first 24 months (abiraterone trial)

Drugs in this study:Abiraterone (Zytiga)Enzalutamide (Xtandi)

Dose and schedule cards

Radiotherapy + ADT + 2 years of abiraterone (STAMPEDE)

High-risk non-metastatic prostate cancer: nodal involvement, or at least two of T3/T4, Gleason 8 to 10, PSA ≥40 ng/mL (or relapse with high-risk features); WHO performance status 0 to 2Cycle length: ContinuousOn the page “Prostate cancer” · Backbone hormone therapy, high-risk localized disease and biochemical recurrence

High-risk non-metastatic prostate cancer: nodal involvement, or at least two of T3/T4, Gleason 8 to 10, PSA ≥40 ng/mL (or relapse with high-risk features); WHO performance status 0 to 2

Drug	Dose	Route	Schedule
ADT	Per formulation	—	Continuous for 3 years
Abiraterone acetate	1000 mg once daily	Oral, on an empty stomach	Daily for 2 years
Prednisolone	5 mg once daily	Oral	Daily with abiraterone
Radiotherapy to the prostate and seminal vesicles	74 Gy in 37 fractions or a hypofractionated equivalent	External-beam radiotherapy	Mandatory for N0 and recommended for N+

Cycle length: Continuous
Duration: Abiraterone for 2 years or until progression; ADT for 3 years (until progression if radiotherapy is not given)

STAMPEDE trial regimen; adding enzalutamide concurrently gave no benefit and only increased toxicity. In this regimen, prednisolone 5 mg is given once daily.

On the page “Prostate cancer” · Backbone hormone therapy, high-risk localized disease and biochemical recurrence

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1ADT + abiraterone + prednisolone (± enzalutamide)

ADT for 3 years (surgical or LHRH agonist/antagonist, started no more than 12 weeks before randomisation) with abiraterone acetate 1000 mg and prednisolone 5 mg (prednisone at Swiss centres) orally once daily for 2 years or until progression; in the second trial enzalutamide 160 mg once daily was also added. Local radiotherapy (74 Gy in 37 fractions to the prostate and seminal vesicles, or a hypofractionated equivalent) was mandatory for node-negative patients and recommended for node-positive disease; if radiotherapy was omitted, treatment continued until progression.

2ADT alone

ADT for 3 years (surgical or LHRH agonist/antagonist) with the same local radiotherapy policy.

Source of the regimen details: Full text of the paper (PMC8811484)

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

High-risk non-metastatic prostate cancer (node involvement, or if node-negative at least two of: stage T3 or T4, Gleason score 8 to 10, PSA 40 or higher) or relapse with high-risk features; WHO performance status 0 to 2. Local radiotherapy was mandatory for node-negative patients and encouraged for node-positive patients.

Endpoints

Primary outcome: metastasis-free survival; secondary outcomes: overall survival, prostate cancer-specific survival, biochemical failure-free survival, progression-free survival and toxicity.

Safety and side effects

Grade 3 or higher adverse events in the first 24 months were 37% versus 29% in the abiraterone trial and 58% versus 32% in the abiraterone + enzalutamide trial; hypertension and raised liver enzymes were more common in the combination groups. Seven grade 5 events (three with abiraterone and four with abiraterone + enzalutamide) and none in the control groups were reported.

Clinical significance and place in guidelines

The authors considered abiraterone and prednisolone a new standard of care in high-risk non-metastatic prostate cancer; European guidelines recommend adding 2 years of abiraterone to ADT and radiotherapy in selected high-risk patients.

Limitations

The trials were open-label and staging imaging used conventional methods (not PSMA PET); the two trials with separate control groups were combined by meta-analysis.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.