Optimal Duration of Androgen Deprivation Therapy (ADT) with Definitive Radiotherapy for Prostate Cancer: An Individual Patient Data (IPD) Meta-Analysis from the International MARCAP Consortium

Abstract

<h3>Purpose/Objective(s)</h3> For men with intermediate- and high-risk prostate cancer receiving definitive radiotherapy, the ideal duration of ADT to improve overall survival (OS) is unclear. Additionally, actual treatment duration received, given the low and variable patient compliance with long-term ADT, has not been compared with intention-to-treat (ITT) duration. Recent retrospective data suggest that the optimal ADT duration may exert a continuous non-linear benefit (Kishan et al., JAMA Onc 2022), and herein we aim to assess this in the MARCAP consortium of randomized trials. <h3>Materials/Methods</h3> A meta-analytic framework was generated to determine the optimal duration of ADT. An IPD meta-analysis performed by the MARCAP consortium using 13 randomized trials (EORTC 22863 and 22961, GICOR/DART, ICORG 9701, PCS III and IV, TROG 96.01 and RADAR, and NRG/RTOG 8610, 9202, 9408 and 9910). Both ITT and treatment received ADT durations were analyzed. Inverse probability of treatment weighting (IPTW) was performed to assess the effect of ADT duration with adjustments for age, PSA, Gleason score, cT-stage, radiotherapy dose, pelvic nodal radiotherapy use, and mid-trial enrollment year. Multivariable additive Cox models were then used to model the association between the primary endpoint of OS and ADT duration. Secondary endpoints included prostate cancer-specific survival (PCSM) and other-cause mortality (OCM). A pre-specified sensitivity network meta-analysis (NMA) of EORTC 22961 (6 vs 36 months), PCS IV (18 vs 36 months), and TROG RADAR (6 vs 18 months) was also performed. <h3>Results</h3> There were 10,266 patients included with a median follow-up of 11.3 (IQR: 9.5-14.5) years. On ITT meta-analysis, there were significant improvements in OS from extending ADT from 9 to 18 months (HR 0.77, 95%CI 0.68-0.86, p< 0.0001) and from 18 to 28-36 months (HR 0.78, 95%CI 0.68-0.89, p=0.0002). The optimal duration of ADT for OS on ITT analysis was 28 months, which was not impacted by RT dose (p=1.0). ADT duration based on compliance data demonstrated the optimal ADT duration was actually 21 months for OS. These findings were consistent on the sensitivity NMA. Optimal ADT durations based on PCSM was ≥36 months, while 0 months was optimal for OCM with a 0.5% increase in OCM HR per month (HR 1.005 95%CI 1.002 - 1.008), and HR = 1.19 (95% CI 1.06 - 1.33) for 36 vs 0 months. <h3>Conclusion</h3> For men enrolled in the context of randomized trials, after accounting for much of the non-compliance with durations of ADT beyond 18 months, we demonstrate that 21 months is optimal for OS in men with intermediate- and high-risk prostate cancer. While longer durations of ADT provide incremental benefit on PCSM, this must be balanced against potential worsening of OCM, cost, and quality of life.