3248 - Survival Outcomes and Toxicity with Reduced-Dose ARPI Therapy: Rationale for the ENHANCE Phase III Trial
Presenter(s)
A. Choudhury1,2, E. J. Saad3, V. Cope4, A. Ahmad3, F. Aquillina5, E. Edoh5, N. Nityey5, N. Potts6, G. Smallwood7, M. Varughese8, K. Reeves1, T. Adedoyin9, A. Bundred9, H. Bromley3, D. Powe10, P. Hoskin3, and A. Hackshaw11; 1Division of Cancer Sciences, University of Manchester, Manchester, England, United Kingdom, 2Department of Clinical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom, 3The Christie NHS Foundation Trust, Manchester, United Kingdom, 4South Devon Healthcare NHS Foundation Trust, Torbay, United Kingdom, 5Royal Devon University Healthcare NHS Foundation Trust, Devon, United Kingdom, 6Torbay and South Devon NHS Foundation Trust, Torbay, United Kingdom, 7University Hospitals Plymouth NHS Trust, Plymouth, United Kingdom, 8Royal Devon & Exeter NHS Foundation Trust, Department of Oncology, Exeter, United Kingdom, 9Cancer Research UK & UCL Cancer Trials Centre, London, United Kingdom, 10Friends & Bredrins Prostate Cancer Support Group, Nottingham, United Kingdom, 11University College London, London, United Kingdom
Purpose/Objective(s):
Androgen receptor pathway inhibitors (ARPIs), including enzalutamide, apalutamide, darolutamide, and abiraterone, are standard systemic therapies for metastatic hormone-sensitive (mHSPC) and metastatic castration-resistant prostate cancer (mCRPC). However, pivotal trials report substantial rates of grade 3–4 adverse events, frequently resulting in dose modification or discontinuation. Real-world evidence suggests that reduced-dose ARPI may maintain efficacy while improving tolerability. We evaluated outcomes associated with ARPI dose reduction and present the design of the ENHANCE phase III trial.Materials/Methods:
A retrospective multi-centre analysis of 639 patients treated with enzalutamide or abiraterone for metastatic castrate-resistant prostate cancer between 2016 and 2018 was performed to evaluate the impact of ARPI dose reduction on overall survival (OS). Kaplan–Meier and multivariable Cox regression analyses were conducted.Results:
Among 639 patients, 3.9% initiated therapy at reduced dose and 11.3% underwent dose reduction during treatment. Fatigue and cardiovascular comorbidity were the most common reasons for dose modification. Median OS was 30 months (95%CI: 24-36m) in the reduced-dose group versus 21 months (95% CI: 19-23m) in the full-dose group. On multivariable analysis, dose reduction was independently associated with improved OS, adjusting for age, disease volume, and PSA nadir with a hazard ratio 0.71 (95%CI: 0.56-0.91, p=0.007).Conclusion:
In this real-world cohort, ARPI dose reduction was independently associated with superior OS. This data supports the ENHANCE trial. ENHANCE is a UK multi-centre, open-label, phase III randomised non-inferiority trial comparing reduced-dose ARPI (50% standard dose) versus standard-dose ARPI (100%) in patients with mHSPC or mCRPC. Patients are randomised 1:1. A total of 1500 patients will be recruited across 25 sites, with recruitment planned to take place over a 3 year period, followed by a 2 year follow up phase. Co-primary endpoints are OS (with a non-inferiority margin of 4 percentage points) and superiority in patient-reported fatigue and avoidance of permanent treatment discontinuation.