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 - 28/03/23

Doi : 10.1016/S1470-2045(23)00063-3

Christopher J Sweeney, ProfMBBS ^a,⁎ , Andrew J Martin, ProfPhD ^c, Martin R Stockler, ProfMBBS MSc ^c,^d,^e, Stephen Begbie, MBBS FRACP ^f,^g, Leanna Cheung, PhD ^c, Kim N Chi, ProfMD ^h,ⁱ, Simon Chowdhury, MBBS PhD ^j,^k, Mark Frydenberg, ProfMBBS FRACS ^l,^m, Lisa G Horvath, ProfMBBS PhD ^e,^n,^o, Anthony M Joshua, MBBS PhD ^p,^q, Nicola J Lawrence, MBChB PhD ^r,^s, Gavin Marx, ProfMBBS FRACP ^t,^u, John McCaffrey, ProfMBBCh FRCPI ^v,^w, Ray McDermott, ProfMD PhD ^v,^x,^y, Margaret McJannett, RN ^z, Scott A North, ProfMD FRCPC ^aa,^ab, Francis Parnis, MBBS FRACP ^b,^ac, Wendy Parulekar, ProfMD ^ad, David W Pook, MBBS MD ^l,^ae, Martin Neil Reaume, MD MSc ^af,^ag, Shahneen K Sandhu, MBBS FRACP ^ah,^ai, Alvin Tan, MBChB FRACP ^aj, Thean Hsiang Tan, MBBS FRACP ^ak, Alastair Thomson, BM MRCP ^al, Francisco Vera-Badillo, MD MSc ^ad,^am, Scott G Williams, ProfMBBS MD ^ah,^ai, Diana Winter, BMedSci ^c, Sonia Yip, BSc PhD ^c, Alison Y Zhang, MBBS MMed ^c,^e,^an, Robert R Zielinski, MBBS FRACP ^ao,^ap, Ian D Davis, ProfMBBS PhD ^l,^aq
for the
ENZAMET trial investigators and Australian and New Zealand Urogenital and Prostate Cancer Trials Group^*
Members listed in the Supplementary Material

Ehtesham Abdi, Suzanne Allan, Patricia Bastick, Stephen Begbie, Robert Blum, Karen Briscoe, Daniel Brungs, Sean Bydder, Bala Renuka Chittajallu, Michelle Cronk, Katharine Cuff, Ian D Davis, Anthony Dowling, Mark Frydenberg, Matthew George, Lisa Horvath, Elizabeth Hovey, Anthony Joshua, Narayan Karanth, Ganessan Kichenadasse, Laurence Krieger, Gavin Marx, Maitham Mathlum, Louise Nott, Zulfiquer Otty, Francis Parnis, David Pook, Shahneen Sandhu, Sanjeev Sewak, Amanda Stevanovic, Martin Stockler, Aneta Suder, Hsiang Tan, Javier Torres, Simon Troon, Craig Underhill, Andrew Weickhardt, Robert Zielinski, Tahir Abbas, Ghadeer Anan, Chris Booth, Holly Campbell, Kim Chi, Joseph Chin, Edmond Chouinard, Bryan Donnelly, Darrel Drachenberg, Amir Faghih, Antonio Finelli, Sebastien Hotte, Krista Noonan, Scott North, Mohammad Rassouli, Neil Reaume, Ricardo Rendon, Fred Saad, Evgeny Sadikov, Eric Vigneault, Pawel Zalewski, John McCaffrey, Ray McDermott, Patrick Morris, Miriam O’Connor, Paul Donnellan, Dearbhaile O’Donnell, Jim Edwards, Peter Fong, Alvin Tan, Simon Chowdhury, Simon Crabb, Omar Khan, Vincent Khoo, Graham Macdonald, Heather Payne, Angus Robinson, Jonathon Shamash, John Staffurth, Carys Thomas, Alastair Thomson, Christopher J Sweeney

^a South Australian Immunogenomics Cancer Institute, University of Adelaide, Adelaide, SA, Australia

^b Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA, Australia

^c NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia

^d Concord Cancer Centre, Concord Repatriation General Hospital, Concord, NSW, Australia

^e Chris O’Brien Lifehouse, Sydney, NSW Australia

^f Port Macquarie Base Hospital, Port Macquarie, NSW, Australia

^g Mid North Coast Cancer Institute, Port Macquarie, NSW, Australia

^h BC Cancer, Vancouver, BC, Canada

ⁱ University of British Columbia, Vancouver, BC, Canada

^j Guys and St Thomas’ NHS Foundation Trust, Biomedical Research Centre, Cancer Research UK, King’s College London, UK

^k Sarah Cannon Research Institute, London, UK

^l Monash University, Melbourne, VIC, Australia

^m Australian Urology Associates, Melbourne, VIC, Australia

ⁿ University of Sydney, Sydney, NSW, Australia

^o Royal Prince Alfred Hospital, Sydney, NSW, Australia

^p Kinghorn Cancer Centre, St Vincent’s Hospital, Sydney, NSW, Australia

^q Garvan Institute of Medical Research, Sydney, NSW, Australia

^r Te Whatu Ora, Te Toka Tumai Auckland, Auckland, New Zealand

^s Department of Oncology, The University of Auckland, New Zealand

^t Sydney Adventist Hospital, Sydney, NSW, Australia

^u Australian National University, Canberra, ACT, Australia

^v Cancer Trials Ireland, Dublin, Ireland

^w Mater Misericordiae University Hospital, Dublin, Ireland

^x St Vincent’s University Hospital, Dublin, Ireland

^y University College Dublin, Dublin, Ireland

^z Australian and New Zealand Urogenital and Prostate Cancer Trials Cancer Trials Group, Camperdown, NSW, Australia

^aa Cross Cancer Institute, Edmonton, AB, Canada

^ab University of Alberta, Edmonton, AB, Canada

^ac Icon Cancer Centre, Adelaide, SA, Australia

^ad Canadian Cancer Trials Group, Queen’s University, Kingston, ON, Canada

^ae Monash Health, Melbourne, VIC, Australia

^af University of Ottawa, Ottawa, ON, Canada

^ag Ottawa Hospital Research Institute, Ottawa, ON, Canada

^ah Peter MacCallum Cancer Centre, Melbourne, VIC, Australia

^ai University of Melbourne, Melbourne, VIC, Australia

^aj Te Whatu Ora Waikato, Hamilton, New Zealand

^ak Royal Adelaide Hospital, Adelaide, SA, Australia

^al Royal Cornwall Hospital, Truro, UK

^am Kingston Health Sciences Center, Kingston, ON, Canada

^an Macquarie University, Sydney, NSW, Australia

^ao Orange Health Service, Central West Cancer Care Centre, Orange, NSW, Australia

^ap Western Sydney University, Sydney, NSW, Australia

^aq Eastern Health, Melbourne, VIC, Australia

^* Correspondence to: Prof Christopher J Sweeney, South Australian Immunogenomics Cancer Institute, University of Adelaide, Adelaide, SA 5005, Australia South Australian Immunogenomics Cancer Institute University of Adelaide Adelaide SA 5005 Australia

Summary

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 ^{99^m}Tc 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.

Funding

Astellas Pharma.

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Randomisation and masking

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Vol 24 - N° 4

P. 323-334 - avril 2023 Retour au numéro

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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 - 28/03/23

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