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      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

      research-article
      , Prof, PhD a , b , * , , PhD c , , Prof, ChM d , , FRCS e , , Prof, PhD f , , Prof, MD g , , Prof, MD h , i , , MSc c , , MSc c , , PhD c , , MSc c , , MSc c , , MSc c , , PhD j , , FRCR k , , FRCR l , , MD c , , MRCP c , , FRCR m , , FRCR n , , FRCR o , , Prof, PhD p , , Prof, FRCR q , , FRCR r , , FRCR s , , MA t , , FRCR u , , ChB v , , FRCR w , , FRCR x , y , , FRCR z , , FRCR aa , , FRCR ab , , FRCR k , , FRCR d , , FRCR ac , , Prof, MD ad , , Prof, PhD g , , Prof, FRCR g , * , , FRCR ae , * , , PhD c , , Prof, MRCP c , c , , PhD af , , Prof, MSc c , , , Prof, PhD c , , , Prof, DPhil c , , , Prof, PhD g , , Systemic Therapy in Advancing or Metastatic Prostate cancer: Evaluation of Drug Efficacy (STAMPEDE) investigators
      Lancet (London, England)
      Elsevier

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          Summary

          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.

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          Most cited references32

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          Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer.

          Androgen-deprivation therapy (ADT) has been the backbone of treatment for metastatic prostate cancer since the 1940s. We assessed whether concomitant treatment with ADT plus docetaxel would result in longer overall survival than that with ADT alone.
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            Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer.

            Background Abiraterone acetate, a drug that blocks endogenous androgen synthesis, plus prednisone is indicated for metastatic castration-resistant prostate cancer. We evaluated the clinical benefit of abiraterone acetate plus prednisone with androgen-deprivation therapy in patients with newly diagnosed, metastatic, castration-sensitive prostate cancer. Methods In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned 1199 patients to receive either androgen-deprivation therapy plus abiraterone acetate (1000 mg daily, given once daily as four 250-mg tablets) plus prednisone (5 mg daily) (the abiraterone group) or androgen-deprivation therapy plus dual placebos (the placebo group). The two primary end points were overall survival and radiographic progression-free survival. Results After a median follow-up of 30.4 months at a planned interim analysis (after 406 patients had died), the median overall survival was significantly longer in the abiraterone group than in the placebo group (not reached vs. 34.7 months) (hazard ratio for death, 0.62; 95% confidence interval [CI], 0.51 to 0.76; P<0.001). The median length of radiographic progression-free survival was 33.0 months in the abiraterone group and 14.8 months in the placebo group (hazard ratio for disease progression or death, 0.47; 95% CI, 0.39 to 0.55; P<0.001). Significantly better outcomes in all secondary end points were observed in the abiraterone group, including the time until pain progression, next subsequent therapy for prostate cancer, initiation of chemotherapy, and prostate-specific antigen progression (P<0.001 for all comparisons), along with next symptomatic skeletal events (P=0.009). These findings led to the unanimous recommendation by the independent data and safety monitoring committee that the trial be unblinded and crossover be allowed for patients in the placebo group to receive abiraterone. Rates of grade 3 hypertension and hypokalemia were higher in the abiraterone group. Conclusions The addition of abiraterone acetate and prednisone to androgen-deprivation therapy significantly increased overall survival and radiographic progression-free survival in men with newly diagnosed, metastatic, castration-sensitive prostate cancer. (Funded by Janssen Research and Development; LATITUDE ClinicalTrials.gov number, NCT01715285 .).
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              Enzalutamide with Standard First-Line Therapy in Metastatic Prostate Cancer

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                Author and article information

                Contributors
                Journal
                Lancet
                Lancet
                Lancet (London, England)
                Elsevier
                0140-6736
                1474-547X
                29 January 2022
                29 January 2022
                : 399
                : 10323
                : 447-460
                Affiliations
                [a ]Cancer Institute, University College London, London, UK
                [b ]University College London Hospitals, London, UK
                [c ]MRC Clinical Trials Unit at University College London, London, UK
                [d ]The Christie and Salford Royal NHS Foundation Trusts, Manchester, UK
                [e ]St James's University Hospital, Leeds, UK
                [f ]Beatson West of Scotland Cancer Centre, Glasgow, UK
                [g ]Royal Marsden NHS Foundation Trust and Institute of Cancer Research, London, UK
                [h ]Oncology Institute of Southern Switzerland, Bellinzona, Switzerland
                [i ]Universita della Svizzera Italiana, Lugano, Switzerland
                [j ]Guy's and St Thomas' NHS Foundation Trust, London, UK
                [k ]Clatterbridge Cancer Centre NHS Foundation Trust, Wirral, UK
                [l ]University of Glasgow Institute of Cancer Sciences, Glasgow, UK
                [m ]Cheltenham General Hospital, Cheltenham, UK
                [n ]Torbay and South Devon NHS Foundation Trust, Torbay, UK
                [o ]Northern Centre for Cancer Care, Newcastle upon Tyne, UK
                [p ]Queen's University Belfast, Belfast, UK
                [q ]Royal Preston Hospital, Preston, UK
                [r ]Queen Alexandra Hospital, Portsmouth, UK
                [s ]Shrewsbury and Telford Hospital NHS Trust, Shrewsbury, UK
                [t ]Kent Oncology Centre, Maidstone, UK
                [u ]Velindre Hospital, Cardiff, UK
                [v ]Singleton Hospital, Swansea, UK
                [w ]Royal Derby Hospital, Derby, UK
                [x ]Yeovil District Hospital NHS Foundation Trust, Yeovil, UK
                [y ]Musgrove Park Hospital, Taunton, UK
                [z ]Weston Park Hospital, Sheffield, UK
                [aa ]Lancashire Teaching Hospitals NHS Foundation Trust, Preston, UK
                [ab ]Royal Sussex County Hospital, Brighton, UK
                [ac ]University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
                [ad ]Inselspital Universitatsspital Bern, Bern, Switzerland
                [ae ]Cardiff University, Cardiff, UK
                [af ]Faculty of Education Health and Wellbeing, University of Wolverhampton, Walsall, UK
                Author notes
                [* ]Correspondence to: Prof Gerhardt Attard, Cancer Institute, University College London, London WC1E 6DD, UK g.attard@ 123456ucl.ac.uk
                [*]

                Retired

                [†]

                Contributed equally

                [‡]

                A complete list of STAMPEDE investigators and collaborators is provided in the appendix (p 230)

                Article
                S0140-6736(21)02437-5
                10.1016/S0140-6736(21)02437-5
                8811484
                34953525
                775b5e8b-6f4e-44d1-99d5-242f43a79327
                © 2022 The Authors. Published by Elsevier Ltd.

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

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