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.

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/m ² 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.
Competing Interests: Declaration of interests CJS received institutional research grants from Bayer, Sanofi, Astellas Pharma (Pfizer), Dendreon, and Janssen and personal consulting fees from Bayer, Astellas Pharma, Janssen, CellCentric, Point Biopharma, Pfizer, Novartis, Genentech (Roche), Bristol Myers Squibb, Lilly, Hengrui Europe Biosciences, and AstraZeneca. MRS received institutional research grants from Astellas Pharma, Amgen, AstraZeneca, Bionomics, Bristol Myers Squibb, Celgene, Medivation, MSD, Pfizer, Roche, Sanofi, and Tilray. KNC received institutional research grants from AstraZeneca, Bayer, Novartis, Pfizer, Point Biopharma, Roche, and Janssen; personal consulting fees from AstraZeneca, Bayer, Novartis, Pfizer, Point Biopharma, and Roche; institutional consulting fees from Janssen; and honoraria from Janssen and AstraZeneca. SC had stock or ownership interests in Clovis Oncology; received honoraria from Novartis and Clovis Oncology; had a consulting or advisory role for Astellas Pharma, Bayer, Pfizer, Janssen-Cilag, BeiGene, and Novartis; and received payment for speakers’ bureaus from Janssen-Cilag and Sanofi (Aventis). MF had a leadership or fiduciary role as a board director for the Royal Australasian College of Surgeons. LGH received institutional research grants, honoraria, and Support for meetings or travel from Astellas Pharma. NJL was on the data safety monitoring board or advisory board for Thoracic Oncology Group of Australia; had a leadership or fiduciary role as a deputy director for Cancer Trials New Zealand; and was a member of the executive committee for New Zealand Society for Oncology. JM had a leadership or fiduciary role as a treasurer for the Irish Society of Medical Oncology; and was a chairman for National Annual Conferences. RM had stock or ownership interests in Bayer; received honoraria from Sanofi, Janssen, Astellas Pharma, Bristol Myers Squibb, MSD, Pfizer, Novartis, and Clovis Oncology; had a consulting or advisory role for MSD Oncology; received research funding from Janssen, Bayer, and Astellas Pharma; provided expert testimony for Pfizer; and received support for meetings or travel from Janssen-Cilag, Roche, and Ipsen. SAN received honoraria from Janssen, Bayer, MSD, AstraZeneca, and Advanced Accelerator Application. FP received honoraria from Bayer and AstraZeneca. DWP received institutional research funding from Medivation, Bristol Myers Squibb, Roche, Exelixis, MSD, Pfizer, Astellas Pharma, Bayer, Symvivo, and Amgen; personal consulting fees from Bristol Myers Squibb, Pfizer, MSD, Cipla, Astellas Pharma, and MSD (Pfizer); institutional consulting fees from Pfizer and MSD; honoraria from Bayer and MSD (Pfizer); and support for meetings or travel from Bristol Myers Squibb, Astellas Pharma, Pfizer, Amgen, MSD (Pfizer), and Janssen. MNR was on the data safety monitoring board or advisory board for Pfizer, Ipsen, EMD, Serono, MSD, and Bayer. SKS received research grants from Novartis/AAA, Genentech, AstraZeneca, Pfizer, and MSD; honoraria from AstraZeneca, Bristol Myer Squibb, MSD, and Janssen; and was on the data safety monitoring board or advisory board as the chair for the data safety monitoring committee at Novartis. AlvT had a leadership or fiduciary role as the head of department for the Te Whatu Ora hospital. THT received honoraria from AstraZeneca. AlvT received honoraria from Novartis and Gilead; support for meetings or travel from MSD, Lilly, Astellas Pharma, and Ipsen; and was on the data safety monitoring board or advisory board for Amgen, Novartis, and MSD. FV-B received institutional research grants from Janssen, MSD, and Seagen and consulting fees from Janssen, MSD, AstraZeneca, and Bayer. AYZ received institutional research grants from Astellas Pharma, Amgen, AstraZeneca, Bionomics, Bristol Myers Squibb, Celgene, Medivation, MSD, Pfizer, Roche, Sanofi, and Tilray; personal consulting fees from MSD; honoraria from MSD, Astellas Pharma, Bayer, Pfizer, Mundipharma, Janssen, and AstraZeneca; and was on the data safety monitoring board or advisory board for MSD, Astellas Pharma, and Bayer. RRZ received honoraria from AstraZeneca and Pfizer. IDD is the director and chair of the Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP); and a member or chair of advisory boards for Astellas Pharma, AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, Ipsen, Janssen, MSD (Pfizer), MSD, Pio Therapeutics, Roche, and Xennials Therapeutics (all honoraria are paid directly to ANZUP). All other authors declare no competing interests.
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