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

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 (I2 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.

Conflict of interest statement

Declaration of interests GA reports personal fees, grants, and travel support from Janssen and Astellas Pharma during the conduct of the study; personal fees or travel support from Pfizer, Ipsen, Novartis/AAA, Abbott Laboratories, Ferring, ESSA Pharmaceuticals, Bayer Healthcare Pharmaceuticals, Beigene, Takeda, AstraZeneca, and Sanofi-Aventis; and grant support from AstraZeneca, Innocrin Pharma, and Arno Therapeutics, outside the submitted work; in addition, GA's former employer, The Institute of Cancer Research, receives royalty income from abiraterone and GA receives a share of this income through the Institute's Rewards to Discoverers Scheme. NWC reports personal fees from Janssen Pharmaceuticals and Astellas Pharma, during the conduct of the study; and personal fees from Bayer outside the submitted work. WC reports personal fees from Janssen and Bayer, outside the submitted work. RJJ reports grants from Sanofi, and grants and non-financial support from Novartis, during the conduct of the study; grants, personal fees, and non-financial support from Sanofi and Novartis, and grants and personal fees from Janssen, Astellas, and Bayer, outside the submitted work. CCP reports personal fees from AAA and Janssen, and research funding and speaker's honoraria from Bayer, outside the submitted work. SG reports personal fees from Bayer, Janssen Cilag, Dendreon Corporation, Millennium Pharmaceuticals, Orion, Sanofi, and MaxiVax; and speaker's fees and travel support from Bayer, CureVac, Janssen Cilag, Astellas, AAA Advanced Accelerator Applications International, Bristol-Myers Squibb (BMS), Ferring, Roche, Orion, lnnocrin Pharmaceuticals, Sanofi, Novartis, Nektar Therapeutics, and ProteoMedix, outside the submitted work. SC reports grants and personal fees from Sanofi-Aventis and personal fees from Janssen Pharmaceutical, outside the submitted work. ZM reports consultancy and advisory board membership for Janssen Consultancy, advisory board membership for Sanofi and Astellas, and sponsorship to attend medical conferences from Astellas, Bayer, and Janssen. JMR reports personal fees from Janssen (lecture fee), outside the submitted work. JB reports payments from Janssen for webinar presentations. AL reports payment or honoraria for lectures, presentation, or events from BMS, and support for attending meetings or travel from Astellas, Bayer, BMS, and Merck Sharpe and Dohme. IP reports sponsorship from Bayer for attending the European Society for Medical Oncology congress virtually in 2021. JMO reports participating on a data safety monitoring board or advisory board for AA, Astellas, Bayer, Janssen, Novartis, and Sanofi. AB reports speaker's fees and travel support from Astellas, and personal fees, speaker's fees, and travel support from Sanofi and Janssen, during the conduct of the study; speaker's fees and travel support from Bayer and AstraZeneca, outside the submitted work; and speaker fee payment from Janssen. NS reports support for attending meetings or travel from Jansen, Astellas, and Eusa Pharma UK. JT reports support for travel and speaker fees from Jansen, Roche, and Bayer, and participating on a data safety monitoring board or advisory board for AstraZeneca, Astellas, and Bayer. JWa reports a paid consultancy for BMS, Eisai, Novartis, and MSD, oustide the submitted work. OP reports participating on a data safety monitoring board and advisory board for Janssen in October, 2021. IS reports support for attending meetings or travel for the 2020 American Society of Clinical Oncology Genitourinary Cancers symposium from Bayer. AZ reports payment or honoraria for lectures, presentations, speaking, bureaus, manuscript writing, or educational events from Pfizer, Janssen, Astellas, and Sanofi, and received support for attending meetings or travel from Bayer and Merck Sharpe and Dohme. JSdB reports employment by the Institute of Cancer Research that has a commercial interest in abiraterone acetate and personal fees from Janssen, during the conduct of the study; and personal fees, speaker's fees, and travel support from AstraZeneca, Pfizer, GlaxoSmithKline, Taiho, Daiichi, Novartis, Genmab, Merck Serono, Merck, and Genentech/Roche, outside the submitted work. DPD reports personal fees and speaker's fees and travel support from Takeda, Amgen, Astellas, Sandoz, and Cadence Research; personal fees and non-financial support from Janssen; travel support from Clovis; and personal fees and non-financial support from International Society for the Study and Exchange of evidence from Clinical research And Medical experience, outside the submitted work; in addition, DPD has a patent (GB9305269–17-substituted steroids useful in cancer treatment) with royalties paid to Janssen Pharmaceutical. MDM reports personal fees from Sanofi, Bayer, Dendreon, BMS, and Janssen, outside the submitted work. REL reports support for the present manuscript with funding from the UK Medical Research Council, part of the UK Research and Innovation. DM reports grants or contracts from Health Education England made to their institution, University of Wolverhampton, payments from Routledge for royalties on a book, payments from Authors' licensing and collecting society for royalties on photocopies of the book and chapters, and unpaid role as chair of a patient advocacy group, Prostate Cancer Research. MRS reports grants and non-financial support from Sanofi-Aventis, Novartis, Pfizer, Janssen, and Astellas, during the conduct of the study; and personal fees from Eli-Lilly, outside the submitted work. MKBP reports grants and non-financial support from Janssen, during the conduct of the study; and grants and non-financial support from Astellas, Clovis Oncology, Novartis, Pfizer, and Sanofi, outside the submitted work. NDJ reports grants and personal fees from Sanofi and Novartis, during the conduct of the study; and grants and personal fees from Janssen, Astellas, and Bayer, outside the submitted work. All other authors declare no competing interests.

Copyright © 2022 Elsevier Ltd. All rights reserved.

Figures

Figure 1

Study profile ITT=intention-to-treat. *Withdrawn patients include both patients with no further data collection allowed and those withdrawn from follow-up but some data collection allowed; the number shown is those who have withdrawn and do not have any data in the past 2 years.

Figure 2

Metastasis-free survival (A) Kaplan-Meier estimates of all patients in individual patient data meta-analysis; shaded regions represent 95% CIs. (B) Prespecified subgroup analysis by trial. HR=hazard ratio. SOC=standard of care.

Figure 3

Forest plots of treatment effect on metastasis-free survival for baseline randomisation stratification factors (except recruiting centre and type of androgen-deprivation therapy) Weighting is by sample size. Three patients were excluded from the nodal status subgroup analysis as Nx. HR=hazard ratio. NSAID=non-steroidal anti-inflammatory drug. SOC=standard of care.

Figure 4

Overall survival (A) Kaplan-Meier estimates of all patients in individual patient data meta-analysis; shaded regions represent 95% CIs. (B) Prespecified subgroup analysis by trial. HR=hazard ratio. SOC=standard of care.

Figure 5

Kaplan-Meier estimates of prostate cancer-specific survival (A) and progression-free survival (B) Kaplan-Meier estimates of all patients in individual patient data meta-analysis; shaded regions represent 95% CIs. SOC=standard of care.