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
Year: 2021
Type: review
Abstract: Background Men with high-risk non-metastatic prostate cancer are treated with androgen-deprivation therapy (ADT) for 3 years, often combined with radiotherapy. We analysed new data from two randomised controlled phase 3 trials done in a multiarm, multistage platform protocol to assess the efficacy of adding abiraterone and prednisolone alone or with enzalutamide to ADT in this patient population. Methods These open-label, phase 3 trials were done at 113 sites in the UK and Switzerland. Eligible patients (no age restrictions) had high-risk (defined as node positive or, if node negative, having at least two of the following: tumour stage T3 or T4, Gleason sum score of 8–10, and prostate-specific antigen [PSA] concentration ≥40 ng/mL) or relapsing with high-risk features (≤12 months of total ADT with an interval of ≥12 months without treatment and PSA concentration ≥4 ng/mL with a doubling time of <6 months, or a PSA concentration ≥20 ng/mL, or nodal relapse) non-metastatic prostate cancer, and a WHO performance status of 0–2. Local radiotherapy (as per local guidelines, 74 Gy in 37 fractions to the prostate and seminal vesicles or the equivalent using hypofractionated schedules) was mandated for node negative and encouraged for node positive disease. In both trials, patients were randomly assigned (1:1), by use of a computerised algorithm, to ADT alone (control group), which could include surgery and luteinising-hormone-releasing hormone agonists and antagonists, or with oral abiraterone acetate (1000 mg daily) and oral prednisolone (5 mg daily; combination-therapy group). In the second trial with no overlapping controls, the combination-therapy group also received enzalutamide (160 mg daily orally). ADT was given for 3 years and combination therapy for 2 years, except if local radiotherapy was omitted when treatment could be delivered until progression. In this primary analysis, we used meta-analysis methods to pool events from both trials. The primary endpoint of this meta-analysis was metastasis-free survival. Secondary endpoints were overall survival, prostate cancer-specific survival, biochemical failure-free survival, progression-free survival, and toxicity and adverse events. For 90% power and a one-sided type 1 error rate set to 1·25% to detect a target hazard ratio for improvement in metastasis-free survival of 0·75, approximately 315 metastasis-free survival events in the control groups was required. Efficacy was assessed in the intention-to-treat population and safety according to the treatment started within randomised allocation. STAMPEDE is registered with ClinicalTrials.gov, NCT00268476, and with the ISRCTN registry, ISRCTN78818544. Findings Between Nov 15, 2011, and March 31, 2016, 1974 patients were randomly assigned to treatment. The first trial allocated 455 to the control group and 459 to combination therapy, and the second trial, which included enzalutamide, allocated 533 to the control group and 527 to combination therapy. Median age across all groups was 68 years (IQR 63–73) and median PSA 34 ng/ml (14·7–47); 774 (39%) of 1974 patients were node positive, and 1684 (85%) were planned to receive radiotherapy. With median follow-up of 72 months (60–84), there were 180 metastasis-free survival events in the combination-therapy groups and 306 in the control groups. Metastasis-free survival was significantly longer in the combination-therapy groups (median not reached, IQR not evaluable [NE]–NE) than in the control groups (not reached, 97–NE; hazard ratio [HR] 0·53, 95% CI 0·44–0·64, p<0·0001). 6-year metastasis-free survival was 82% (95% CI 79–85) in the combination-therapy group and 69% (66–72) in the control group. There was no evidence of a difference in metatasis-free survival when enzalutamide and abiraterone acetate were administered concurrently compared with abiraterone acetate alone (interaction HR 1·02, 0·70–1·50, p=0·91) and no evidence of between-trial heterogeneity ( I 2 p=0·90). Overall survival (median not reached [IQR NE–NE] in the combination-therapy groups vs not reached [103–NE] in the control groups; HR 0·60, 95% CI 0·48–0·73, p<0·0001), prostate cancer-specific survival (not reached [NE–NE] vs not reached [NE–NE]; 0·49, 0·37–0·65, p<0·0001), biochemical failure-free-survival (not reached [NE–NE] vs 86 months [83–NE]; 0·39, 0·33–0·47, p<0·0001), and progression-free-survival (not reached [NE–NE] vs not reached [103–NE]; 0·44, 0·36–0·54, p<0·0001) were also significantly longer in the combination-therapy groups than in the control groups. Adverse events grade 3 or higher during the first 24 months were, respectively, reported in 169 (37%) of 451 patients and 130 (29%) of 455 patients in the combination-therapy and control groups of the abiraterone trial, respectively, and 298 (58%) of 513 patients and 172 (32%) of 533 patients of the combination-therapy and control groups of the abiraterone and enzalutamide trial, respectively. The two most common events more frequent in the combination-therapy groups were hypertension (abiraterone trial: 23 (5%) in the combination-therapy group and six (1%) in control group; abiraterone and enzalutamide trial: 73 (14%) and eight (2%), respectively) and alanine transaminitis (abiraterone trial: 25 (6%) in the combination-therapy group and one (<1%) in control group; abiraterone and enzalutamide trial: 69 (13%) and four (1%), respectively). Seven grade 5 adverse events were reported: none in the control groups, three in the abiraterone acetate and prednisolone group (one event each of rectal adenocarcinoma, pulmonary haemorrhage, and a respiratory disorder), and four in the abiraterone acetate and prednisolone with enzalutamide group (two events each of septic shock and sudden death). Interpretation Among men with high-risk non-metastatic prostate cancer, combination therapy is associated with significantly higher rates of metastasis-free survival compared with ADT alone. Abiraterone acetate with prednisolone should be considered a new standard treatment for this population. Funding Cancer Research UK, UK Medical Research Council, Swiss Group for Clinical Cancer Research, Janssen, and Astellas.
Source: The Lancet
Authors: Gerhardt Attard, Laura Murphy, Noel W Clarke, William Cross, Robert J Jones, Christopher C Parker, Silke Gillessen, Adrian Cook, Chris Brawley, Claire L Amos, Nafisah Atako, Cheryl Pugh, Michelle Buckner, Simon Chowdhury, Zafar Malik, J Martin Russell, Clare Gilson, Hannah Rush, Jo Bowen, Anna Lydon, Ian Pedley, Joe M O'Sullivan, Alison Birtle, Joanna Gale, Narayanan Srihari, Carys Thomas, Jacob Tanguay, John Wagstaff, Prantik Das, Emma Gray, Mymoona Alzoueb, Omi Parikh, Angus Robinson, Isabel Syndikus, James Wylie, Anjali Zarkar, George Thalmann, Johann S de Bono, 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, Elin Jones, Katherine Hyde, Hilary Glen, Sarah Needleman, Ursula McGovern, Denise Sheehan, Sangeeta Paisey, Richard Shaffer, Mark Beresford, Zafar Malik, Anjali Zarkar, Emilio Porfiri, David Fackrell, Ling Lee, Thiagarajan Sreenivasan, Sue Brock, Simon Brown, Amit Bahl, Mike Smith-Howell, Cathryn Woodward, Mau-Don Phan, Danish Mazhar, Krishna Narahari, Jacob Tanguay, Fiona Douglas, Anil Kumar, Abdel Hamid, Azman Ibrahim, Dakshinamoorthy Muthukumar, Matthew Simms, Jane Worlding, Anna Tran, Mohammed Kagzi, Prantik Das, Carmel Pezaro, Virgil Sivoglo, Benjamin Masters, Pek Keng-Koh, Caroline Manetta, Duncan McLaren, Nishi Gupta, Denise Sheehan, Stergios Boussios, Henry Taylor, John Graham, Carla Perna, Lucinda Melcher, Warren Grant, Katherine Hyde, Ami Sabharwal, Uschi Hofmann, Robert Dealey, Neil McPhail, Robert Brierly, Simon Brown, Lisa Capaldi, Norma Sidek, Peter Whelan, Thiagarajan Sreenivasan, Peter Robson, Alison Falconer, Sarah Rudman, Sindu Vivekanandan, Vinod Mullessey, Sarah Needleman, Maria Vilarino-Varela, Vincent Khoo, Karen Tipples, Mehran Afshar, Alison Falconer, Patryk Brulinski, Vijay Sangar, Clive Peedell, Ashraf Azzabi, Peter Hoskin, Viwod Mullassery, Santhanam Sundar, Yakhub Khan, Ruth Conroy, Andrew Protheroe, Judith Carser, Paul Rogers, Lisa Capaldi, Kathryn Tarver, Stephanie Gibbs, Mohammad Muneeb Khan, Mohan Hingorani, Ashraf Azzabi, Simon Crabb, Manal Alameddine, Neeraj Bhalla, Caroline Manetta, Robert Hughes, John Logue, Darren Leaning, Salil Vengalil, Ashraf Azzabi, Daniel Ford, Georgina Walker, Ahmed Shaheen, Omar Khan, Andrew Chan, Imtiaz Ahmed, Serena Hilman, Fiona Douglas, Anil Kumar, Anna Tran, Sangeeta Paisey, Ian Sayers, Lisa Capaldi, Ashok Nikapota, David Bloomfield, Tim Porter, Joji Joseph, Cyrill Rentsch, Ricardo Pereira Mestre, Enrico Roggero, Jörg Beyer, Markus Borner, Raeto Strebel, Dominik Berthold, Daniel Engeler, Hubert John, Razvan Popescu, Donat Durr
Institutions: University College London Hospitals NHS Foundation Trust, University College London, MRC Clinical Trials Unit at UCL, Salford Royal NHS Foundation Trust, The Christie NHS Foundation Trust, St James's University Hospital, Beatson West of Scotland Cancer Centre, Royal Marsden NHS Foundation Trust, Institute of Cancer Research, Istituto Oncologico della Svizzera Italiana, Università della Svizzera italiana, Guy's and St Thomas' NHS Foundation Trust, Clatterbridge Cancer Centre NHS Foundation Trust, University of Glasgow, Cheltenham General Hospital, Torbay and South Devon NHS Foundation Trust, Queen's University Belfast, Royal Preston Hospital, Queen Alexandra Hospital, Shrewsbury and Telford Hospital NHS Trust, Maidstone Hospital, Velindre Cancer Centre, Singleton Hospital, Royal Derby Hospital, Yeovil District Hospital NHS Foundation Trust, Musgrove Park Hospital, Weston Park Cancer Centre, Lancashire Teaching Hospitals NHS Foundation Trust, Royal Sussex County Hospital, University Hospitals Sussex NHS Foundation Trust, University Hospitals Birmingham NHS Foundation Trust, University Hospital of Bern, Cardiff University, University of Wolverhampton
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $5,000
Funders: Pfizer, Astellas Pharma US, Novartis, Sanofi, Royal Marsden NHS Foundation Trust, Clovis Oncology, Cancer Research UK, National Institute for Health and Care Research, Institute of Cancer Research, University College London, Astellas Pharma, Schweizerische Arbeitsgemeinschaft für Klinische Krebsforschung, Manchester Biomedical Research Centre, Medical Research Council, Janssen Pharmaceuticals
Awards: G1289590720, G170213847, G2978326887, G3114799256, G3302706239, G3747035981, G3882831376, G4258354855, NIHR Senior Investigator Award, G493837290, G5124205782, G5281518545, G5283155218, G6352384130, G7772859830, G8363072258, NIHR Senior Investigator Award, Evaluating new healthcare technologies in cancer
OpenAlex ID: W4200383319