Testosterone suppression plus enzalutamide versus testosterone suppression plus standard antiandrogen therapy for metastatic hormone-sensitive prostate cancer (ENZAMET): an international, open-label, randomised, phase 3 trial

Author(s): Prof Christopher J Sweeney, MBBS1;Prof Andrew J Martin, PhD2;Prof Martin R Stockler, MBBS MSc2,3;Stephen Begbie, MBBS FRACP4,5;Leanna Cheung, PhD2;Prof Kim N Chi, MD6,7;Simon Chowdhury, MBBS PhD8,9;Prof Mark Frydenberg, MBBS FRACS10,11;Prof Lisa G Horvath, MBBS PhD12,13,14;Anthony M Joshua, MBBS PhD15,16;Nicola J Lawrence, MBChB PhD17,18;Prof Gavin Marx, MBBS FRACP19,20;Prof John McCaffrey, MBBCh FRCPI21,22;Prof Ray McDermott, MD PhD21,23,24;Margaret McJannett, RN25;Prof Scott A North, MD FRCPC26,27;Francis Parnis, MBBS FRACP28,29;Prof Wendy Parulekar, MD30;David W Pook, MBBS MD31,32;Martin Neil Reaume, MD MSc33,34;Shahneen K Sandhu, MBBS FRACP35,36;Alvin Tan, MBChB FRACP37;Thean Hsiang Tan, MBBS FRACP38;Alastair Thomson, BM MRCP39;Francisco Vera-Badillo, MD MSc40,41;Prof Scott G Williams, MBBS MD35,36;Diana Winter, BMedSci42;Sonia Yip, BSc PhD42;Alison Y Zhang, MBBS MMed42,43,44;Robert R Zielinski, MBBS FRACP45,46;Prof Ian D Davis, MBBS PhD36,47;for theENZAMET trial investigators and Australian and New Zealand Urogenital and Prostate Cancer Trials Group
Source: https://doi.org/10.1016/S1470-2045(23)00063-3
Maem Hussein MD

Dr. Maen Hussein's Thoughts

Confirms what we already know. No real surprises.


The interim analysis of the ENZAMET trial of testosterone suppression plus either enzalutamide or standard nonsteroidal antiandrogen therapy showed an early overall survival benefit with enzalutamide. Here, we report the planned primary overall survival analysis, with the aim of defining the benefit of enzalutamide treatment in different prognostic subgroups (synchronous and metachronous high-volume or low-volume disease) and in those who received concurrent docetaxel.


ENZAMET is an international, open-label, randomised, phase 3 trial conducted at 83 sites (including clinics, hospitals, and university centres) in Australia, Canada, Ireland, New Zealand, the UK, and the USA. Eligible participants were males aged 18 years or older with metastatic, hormone-sensitive prostate adenocarcinoma evident on CT or bone scanning with 99mTc and an Eastern Cooperative Oncology Group performance status score of 0–2. Participants were randomly assigned (1:1), using a centralised web-based system and stratified by volume of disease, planned use of concurrent docetaxel and bone antiresorptive therapy, comorbidities, and study site, to receive testosterone suppression plus oral enzalutamide (160 mg once per day) or a weaker standard oral non-steroidal antiandrogen (bicalutamide, nilutamide, or flutamide; control group) until clinical disease progression or prohibitive toxicity. Testosterone suppression was allowed up to 12 weeks before randomisation and for up to 24 months as adjuvant therapy. Concurrent docetaxel (75 mg/m2 intravenously) was allowed for up to six cycles once every 3 weeks, at the discretion of participants and physicians. The primary endpoint was overall survival in the intention-to-treat population. This planned analysis was triggered by reaching 470 deaths. This study is registered with ClinicalTrials.gov, NCT02446405, ANZCTR, ACTRN12614000110684, and EudraCT, 2014-003190-42.


Between March 31, 2014, and March 24, 2017, 1125 participants were randomly assigned to receive non-steroidal antiandrogen (n=562; control group) or enzalutamide (n=563). The median age was 69 years (IQR 63–74). This analysis was triggered on Jan 19, 2022, and an updated survival status identified a total of 476 (42%) deaths. After a median follow-up of 68 months (IQR 67–69), the median overall survival was not reached (hazard ratio 0·70 [95% CI 0·58–0·84]; p<0·0001), with 5-year overall survival of 57% (0·53–0·61) in the control group and 67% (0·63–0·70) in the enzalutamide group. Overall survival benefits with enzalutamide were consistent across predefined prognostic subgroups and planned use of concurrent docetaxel. The most common grade 3–4 adverse events were febrile neutropenia associated with docetaxel use (33 [6%] of 558 in the control group vs 37 [6%] of 563 in the enzalutamide group), fatigue (four [1%] vs 33 [6%]), and hypertension (31 [6%] vs 59 [10%]). The incidence of grade 1–3 memory impairment was 25 (4%) versus 75 (13%). No deaths were attributed to study treatment.


The addition of enzalutamide to standard of care showed sustained improvement in overall survival for patients with metastatic hormone-sensitive prostate cancer and should be considered as a treatment option for eligible patients.

Author Affiliations

1South Australian Immunogenomics Cancer Institute, University of Adelaide, Adelaide, SA, Australia2NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia3Concord Cancer Centre, Concord Repatriation General Hospital, Concord, NSW, Australia4Port Macquarie Base Hospital, Port Macquarie, NSW, Australia5Mid North Coast Cancer Institute, Port Macquarie, NSW, Australia6BC Cancer, Vancouver, BC, Canada7University of British Columbia, Vancouver, BC, Canada8Guys and St Thomas’ NHS Foundation Trust, Biomedical Research Centre, Cancer Research UK, King’s College London, UK9Sarah Cannon Research Institute, London, UK10Monash University, Melbourne, VIC, Australia11Australian Urology Associates, Melbourne, VIC, Australia12Chris O’Brien Lifehouse, Sydney, NSW Australia13University of Sydney, Sydney, NSW, Australia14Royal Prince Alfred Hospital, Sydney, NSW, Australia15Kinghorn Cancer Centre, St Vincent’s Hospital, Sydney, NSW, Australia16Garvan Institute of Medical Research, Sydney, NSW, Australia17Te Whatu Ora, Te Toka Tumai Auckland, Auckland, New Zealand18Department of Oncology, The University of Auckland, New Zealand19Sydney Adventist Hospital, Sydney, NSW, Australia20Australian National University, Canberra, ACT, Australia21Cancer Trials Ireland, Dublin, Ireland22Mater Misericordiae University Hospital, Dublin, Ireland23St Vincent’s University Hospital, Dublin, Ireland24University College Dublin, Dublin, Ireland25Australian and New Zealand Urogenital and Prostate Cancer Trials Cancer Trials Group, Camperdown, NSW, Australia26Cross Cancer Institute, Edmonton, AB, Canada27University of Alberta, Edmonton, AB, Canada28Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA, Australia29Icon Cancer Centre, Adelaide, SA, Australia30Canadian Cancer Trials Group, Queen’s University, Kingston, ON, Canada31Monash University, Melbourne, VIC, Australia32Monash Health, Melbourne, VIC, Australia33University of Ottawa, Ottawa, ON, Canada34Ottawa Hospital Research Institute, Ottawa, ON, Canada35Peter MacCallum Cancer Centre, Melbourne, VIC, Australia36University of Melbourne, Melbourne, VIC, Australia37Te Whatu Ora Waikato, Hamilton, New Zealand38Royal Adelaide Hospital, Adelaide, SA, Australia39Royal Cornwall Hospital, Truro, UK40Canadian Cancer Trials Group, Queen’s University, Kingston, ON, Canada41Kingston Health Sciences Center, Kingston, ON, Canada42NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia43Chris O’Brien Lifehouse, Sydney, NSW Australia44Macquarie University, Sydney, NSW, Australia45Orange Health Service, Central West Cancer Care Centre, Orange, NSW, Australia46Western Sydney University, Sydney, NSW, Australia47Eastern Health, Melbourne, VIC, Australia

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