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 MSc^2,3;Stephen Begbie, MBBS FRACP^4,5;Leanna Cheung, PhD2;Prof Kim N Chi, MD^6,7;Simon Chowdhury, MBBS PhD^8,9;Prof Mark Frydenberg, MBBS FRACS^10,11;Prof Lisa G Horvath, MBBS PhD^12,13,14;Anthony M Joshua, MBBS PhD^15,16;Nicola J Lawrence, MBChB PhD^17,18;Prof Gavin Marx, MBBS FRACP^19,20;Prof John McCaffrey, MBBCh FRCPI^21,22;Prof Ray McDermott, MD PhD^21,23,24;Margaret McJannett, RN²⁵;Prof Scott A North, MD FRCPC^26,27;Francis Parnis, MBBS FRACP^28,29;Prof Wendy Parulekar, MD³⁰;David W Pook, MBBS MD^31,32;Martin Neil Reaume, MD MSc^33,34;Shahneen K Sandhu, MBBS FRACP^35,36;Alvin Tan, MBChB FRACP³⁷;Thean Hsiang Tan, MBBS FRACP³⁸;Alastair Thomson, BM MRCP³⁹;Francisco Vera-Badillo, MD MSc^40,41;Prof Scott G Williams, MBBS MD^35,36;Diana Winter, BMedSci⁴²;Sonia Yip, BSc PhD⁴²;Alison Y Zhang, MBBS MMed^42,43,44;Robert R Zielinski, MBBS FRACP^45,46;Prof Ian D Davis, MBBS PhD^36,47;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

Dr. Maen Hussein's Thoughts

Confirms what we already know. No real surprises.

BACKGROUND

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.

METHODS

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.

FINDINGS

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.

INTERPRETATION

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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