Abiraterone acetate plus prednisolone (herein referred to as abiraterone) or enzalutamide added at the start of androgen deprivation therapy improves outcomes for patients with metastatic prostate cancer. Here, we aimed to evaluate long-term outcomes and test whether combining enzalutamide with abiraterone and androgen deprivation therapy improves survival.
We analysed two open-label, randomised, controlled, phase 3 trials of the STAMPEDE platform protocol, with no overlapping controls, conducted at 117 sites in the UK and Switzerland. Eligible patients (no age restriction) had metastatic, histologically-confirmed prostate adenocarcinoma; a WHO performance status of 0-2; and adequate haematological, renal, and liver function. Patients were randomly assigned (1:1) using a computerised algorithm and a minimisation technique to either standard of care (androgen deprivation therapy; docetaxel 75 mg/m2 intravenously for six cycles with prednisolone 10 mg orally once per day allowed from Dec 17, 2015) or standard of care plus abiraterone acetate 1000 mg and prednisolone 5 mg (in the abiraterone trial) orally or abiraterone acetate and prednisolone plus enzalutamide 160 mg orally once a day (in the abiraterone and enzalutamide trial). Patients were stratified by centre, age, WHO performance status, type of androgen deprivation therapy, use of aspirin or non-steroidal anti-inflammatory drugs, pelvic nodal status, planned radiotherapy, and planned docetaxel use. The primary outcome was overall survival assessed in the intention-to-treat population. Safety was assessed in all patients who started treatment. A fixed-effects meta-analysis of individual patient data was used to compare differences in survival between the two trials. STAMPEDE is registered with ClinicalTrials.gov (NCT00268476) and ISRCTN (ISRCTN78818544).
Between Nov 15, 2011, and Jan 17, 2014, 1003 patients were randomly assigned to standard of care (n=502) or standard of care plus abiraterone (n=501) in the abiraterone trial. Between July 29, 2014, and March 31, 2016, 916 patients were randomly assigned to standard of care (n=454) or standard of care plus abiraterone and enzalutamide (n=462) in the abiraterone and enzalutamide trial. Median follow-up was 96 months (IQR 86-107) in the abiraterone trial and 72 months (61-74) in the abiraterone and enzalutamide trial. In the abiraterone trial, median overall survival was 76·6 months (95% CI 67·8-86·9) in the abiraterone group versus 45·7 months (41·6-52·0) in the standard of care group (hazard ratio [HR] 0·62 [95% CI 0·53-0·73]; p<0·0001). In the abiraterone and enzalutamide trial, median overall survival was 73·1 months (61·9-81·3) in the abiraterone and enzalutamide group versus 51·8 months (45·3-59·0) in the standard of care group (HR 0·65 [0·55-0·77]; p<0·0001). We found no difference in the treatment effect between these two trials (interaction HR 1·05 [0·83-1·32]; pinteraction=0·71) or between-trial heterogeneity (I2 p=0·70). In the first 5 years of treatment, grade 3-5 toxic effects were higher when abiraterone was added to standard of care (271 [54%] of 498 vs 192 [38%] of 502 with standard of care) and the highest toxic effects were seen when abiraterone and enzalutamide were added to standard of care (302 [68%] of 445 vs 204 [45%] of 454 with standard of care). Cardiac causes were the most common cause of death due to adverse events (five [1%] with standard of care plus abiraterone and enzalutamide [two attributed to treatment] and one (<1%) with standard of care in the abiraterone trial).
Enzalutamide and abiraterone should not be combined for patients with prostate cancer starting long-term androgen deprivation therapy. Clinically important improvements in survival from addition of abiraterone to androgen deprivation therapy are maintained for longer than 7 years.
Cancer Research UK, UK Medical Research Council, Swiss Group for Clinical Cancer Research, Janssen, and Astellas.
The Lancet. Oncology. 2023 May [Epub]
Gerhardt Attard, Laura Murphy, Noel W Clarke, Ashwin Sachdeva, Craig Jones, Alex Hoyle, William Cross, Robert J Jones, Christopher C Parker, Silke Gillessen, Adrian Cook, Chris Brawley, Clare Gilson, Hannah Rush, Hoda Abdel-Aty, Claire L Amos, Claire Murphy, Simon Chowdhury, Zafar Malik, J Martin Russell, Nazia Parkar, Cheryl Pugh, Carlos Diaz-Montana, Carmel Pezaro, Warren Grant, Helen Saxby, Ian Pedley, Joe M O'Sullivan, Alison Birtle, Joanna Gale, Narayanan Srihari, Carys Thomas, Jacob Tanguay, John Wagstaff, Prantik Das, Emma Gray, Mymoona Alzouebi, Omi Parikh, Angus Robinson, Amir H Montazeri, James Wylie, Anjali Zarkar, Richard Cathomas, Michael D Brown, Yatin Jain, David P Dearnaley, Malcolm D Mason, Duncan Gilbert, Ruth E Langley, Robin Millman, David Matheson, Matthew R Sydes, Louise C Brown, Mahesh K B Parmar, Nicholas D James, STAMPEDE investigators
Cancer Institute, University College London, London, UK; University College London Hospitals, London, UK. Electronic address: ., Medical Research Council Clinical Trials Unit, University College London, London, UK., Christie and Salford Royal NHS Foundation Trusts, Manchester, UK., St James's University Hospital, Leeds, UK., Beatson West of Scotland Cancer Centre, University of Glasgow, Glasgow, UK., Royal Marsden NHS Foundation Trust and Institute of Cancer Research, London, UK., Oncology Institute of Southern Switzerland, Bellinzona, Switzerland; CH and Universita della Svizzera Italiana, Lugano, Switzerland., Medical Research Council Clinical Trials Unit, University College London, London, UK; Guy's and St Thomas' NHS Foundation Trust, London, UK., Guy's and St Thomas' NHS Foundation Trust, London, UK., Clatterbridge Cancer Centre NHS Foundation Trust, Wirral, UK., Institute of Cancer Sciences, University of Glasgow, Glasgow, UK., Singleton Hospital, Swansea, UK., Gloucestershire Oncology Centre, Cheltenham, UK., Torbay and South Devon NHS Foundation Trust, Torbay, UK., Northern Centre for Cancer Care, Newcastle upon Tyne, UK., Queen's University Belfast, Belfast, UK., Rosemere Cancer Centre, Royal Preston Hospital, Preston, UK., Queen Alexandra Hospital, Portsmouth, UK., Shrewsbury and Telford Hospital NHS Trust, Shrewsbury, UK., Kent Oncology Centre, Maidstone, UK., Velindre Cancer Centre, Cardiff, UK., Royal Derby Hospital, Derby, UK., Yeovil District Hospital NHS Foundation Trust, Yeovil, UK., Weston Park Hospital, Sheffield, UK., East Lancashire Hospitals NHS Trust, Preston, UK., Royal Sussex County Hospital, Brighton, UK., University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK., Division of Oncology and Hematology, Cantonal Hospital Graubünden, Chur, Switzerland; Swiss Group for Clinical Cancer Research, Bern, Switzerland., Cardiff University, Cardiff, UK., Faculty of Education Health and Wellbeing, University of Wolverhampton, Walsall, UK.