Target trial emulation of early docetaxel and enzalutamide for metastatic hormone-sensitive prostate cancer

Yu Yang Soon^{1

2

3}, Ian C Marschner¹, I Manjula Schou¹, Christopher J Sweeney^{4

5

6}, Ian D Davis^{7

8

6}, Martin R Stockler^{1

9

10

6}, Andrew J Martin^{1

11

6}

Affiliations

¹ National Health and Medical Research Council (NHMRC) Clinical Trials Centre, University of Sydney, Sydney, New South Wales, Australia.
² Department of Radiation Oncology, National University Cancer Institute, Singapore, Singapore.
³ Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
⁴ South Australian Immunogenomics Cancer Institute, Adelaide, South Australia, Australia.
⁵ Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, South Australia, Australia.
⁶ Australian and New Zealand Urogenital and Prostate Cancer Trials Group, Sydney, New South Wales, Australia.
⁷ Eastern Health Clinical School, Monash University, Melbourne, Victoria, Australia.
⁸ Eastern Health, Melbourne, Victoria, Australia.
⁹ Department of Medical Oncology, Concord Repatriation General Hospital, Sydney, New South Wales, Australia.
¹⁰ Department of Medical Oncology, Chris O'Brien Lifehouse, Sydney, New South Wales, Australia.
¹¹ ULTRA, The University of Queensland Clinical Trials Capability, Centre for Clinical Research, Herston, Brisbane, Queensland, Australia.

PMID: 41190384
DOI: 10.1111/bju.70065

Randomized Controlled Trial

Target trial emulation of early docetaxel and enzalutamide for metastatic hormone-sensitive prostate cancer

Yu Yang Soon et al. BJU Int. 2026 Jan.

. 2026 Jan;137(1):173-180.

doi: 10.1111/bju.70065. Epub 2025 Nov 5.

Authors

Yu Yang Soon^{1

2

3}, Ian C Marschner¹, I Manjula Schou¹, Christopher J Sweeney^{4

5

6}, Ian D Davis^{7

8

6}, Martin R Stockler^{1

9

10

6}, Andrew J Martin^{1

11

6}

Affiliations

¹ National Health and Medical Research Council (NHMRC) Clinical Trials Centre, University of Sydney, Sydney, New South Wales, Australia.
² Department of Radiation Oncology, National University Cancer Institute, Singapore, Singapore.
³ Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
⁴ South Australian Immunogenomics Cancer Institute, Adelaide, South Australia, Australia.
⁵ Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, South Australia, Australia.
⁶ Australian and New Zealand Urogenital and Prostate Cancer Trials Group, Sydney, New South Wales, Australia.
⁷ Eastern Health Clinical School, Monash University, Melbourne, Victoria, Australia.
⁸ Eastern Health, Melbourne, Victoria, Australia.
⁹ Department of Medical Oncology, Concord Repatriation General Hospital, Sydney, New South Wales, Australia.
¹⁰ Department of Medical Oncology, Chris O'Brien Lifehouse, Sydney, New South Wales, Australia.
¹¹ ULTRA, The University of Queensland Clinical Trials Capability, Centre for Clinical Research, Herston, Brisbane, Queensland, Australia.

PMID: 41190384
DOI: 10.1111/bju.70065

Abstract

Objective: To apply a trial emulation method using the 'ENZAlutamide in first line androgen deprivation therapy for METastatic prostate cancer' (ENZAMET) trial data to assess the effects of adding early docetaxel to enzalutamide on overall survival (OS) in metastatic hormone-sensitive prostate cancer (mHSPC), as the benefits of adding early docetaxel to novel androgen-receptor pathway inhibitors (ARPIs) are unclear.

Patients and methods: The ENZAMET trial randomised 1125 patients with mHSPC to testosterone suppression plus enzalutamide or standard non-steroidal antiandrogen therapy. Investigators indicated at pre-randomisation if they planned to use early docetaxel. We emulated randomised comparisons of four treatments: (i) docetaxel plus enzalutamide, (ii) no docetaxel plus enzalutamide, (iii) docetaxel plus no enzalutamide, and (iv) no docetaxel plus no enzalutamide. Propensity score matching was applied to mitigate selection bias. OS was evaluated using Cox proportional hazards regression.

Results: Among 987 matched participants (87.7%), baseline characteristics were balanced. OS was similar with or without planned use of early docetaxel (hazard ratio [HR] 1.02, 95% confidence interval [CI] 0.92-1.12; P = 0.72), with effect modification by enzalutamide use (interaction P = 0.02). Among those assigned enzalutamide, OS was similar according to the planned use of early docetaxel or not (HR 1.18, 95% CI 0.94-1.49), regardless of disease volume (interaction P = 0.37). Among those assigned no enzalutamide, OS was longer with the planned use of early docetaxel (HR 0.90, 95% CI 0.82-0.98), especially in high-volume disease (interaction P = 0.006).

Conclusion: Early docetaxel did not appear to improve survival when added to enzalutamide, regardless of disease volume, whereas it did appear to improve survival when enzalutamide was not used, particularly in high-volume disease. While residual confounding could not be excluded, these findings do not support the routine addition of early docetaxel to enzalutamide in mHSPC.

Keywords: docetaxel; enzalutamide; metastatic hormone‐sensitive prostate cancer; propensity score matching; target trial emulation.

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References

1. Sweeney CJ, Chen YH, Carducci M et al. Chemohormonal therapy in metastatic hormone‐sensitive prostate cancer. N Engl J Med 2015; 373: 737–746
1. Kyriakopoulos CE, Chen YH, Carducci MA et al. Chemohormonal therapy in metastatic hormone‐sensitive prostate cancer: long‐term survival analysis of the randomized phase III E3805 CHAARTED trial. J Clin Oncol 2018; 36: 1080–1087
1. James ND, Sydes MR, Clarke NW et al. Addition of docetaxel, zoledronic acid, or both to first‐line long‐term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet 2016; 387: 1163–1177
1. Clarke NW, Ali A, Ingleby FC et al. Addition of docetaxel to hormonal therapy in low‐ and high‐burden metastatic hormone sensitive prostate cancer: long‐term survival results from the STAMPEDE trial. Ann Oncol 2019; 1: 1992–2003
1. Davis ID, Martin AJ, Stockler MR et al. Enzalutamide with standard first‐line therapy in metastatic prostate cancer. N Engl J Med 2019; 381: 121–131

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Target trial emulation of early docetaxel and enzalutamide for metastatic hormone-sensitive prostate cancer

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Target trial emulation of early docetaxel and enzalutamide for metastatic hormone-sensitive prostate cancer

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Medical