Interplay Between Duration of Androgen Deprivation Therapy and External Beam Radiotherapy With or Without a Brachytherapy Boost for Optimal Treatment of High-risk Prostate Cancer: A Patient-Level Data Analysis of 3 Cohorts
Amar U Kishan 1 2 , Alison Steigler 3 , James W Denham 3 , Almudena Zapatero 4 , Araceli Guerrero 5 , David Joseph 6 7 , Xavier Maldonado 8 , Jessica K Wong 9 , Bradley J Stish 10 , Robert T Dess 11 , Avinash Pilar 12 13 , Chandana Reddy 14 , Trude B Wedde 15 , Wolfgang A Lilleby 15 , Ryan Fiano 16 , Gregory S Merrick 16 , Richard G Stock 17 , D Jeffrey Demanes 1 18 , Brian J Moran 19 , Phuoc T Tran 20 , Santiago Martin 21 , Rafael Martinez-Monge 21 , Daniel J Krauss 22 , Eyad I Abu-Isa 11 , Thomas M Pisansky 10 , C Richard Choo 10 , Daniel Y Song 20 , Stephen Greco 20 , Curtiland Deville 20 , Todd McNutt 20 , Theodore L DeWeese 20 , Ashley E Ross 23 , Jay P Ciezki 14 , Derya Tilki 24 25 , R Jeffrey Karnes 26 , Jeffrey J Tosoian 27 , Nicholas G Nickols 1 28 , Prashant Bhat 29 , David Shabsovich 29 , Jesus E Juarez 29 , Tommy Jiang 1 , T Martin Ma 1 , Michael Xiang 1 , Rebecca Philipson 1 , Albert Chang 1 , Patrick A Kupelian 1 , Matthew B Rettig 30 31 , Felix Y Feng 32 , Alejandro Berlin 12 , Jonathan D Tward 33 , Brian J Davis 10 , Robert E Reiter 2 , Michael L Steinberg 1 , David Elashoff 34 , Paul C Boutros 2 35 , Eric M Horwitz 9 , Rahul D Tendulkar 14 , Daniel E Spratt 36 , Tahmineh Romero 34
Importance: Radiotherapy combined with androgen deprivation therapy (ADT) is a standard of care for high-risk prostate cancer. However, the interplay between radiotherapy dose and the required minimum duration of ADT is uncertain.
Objective: To determine the specific ADT duration threshold that provides a distant metastasis-free survival (DMFS) benefit in patients with high-risk prostate cancer receiving external beam radiotherapy (EBRT) or EBRT with a brachytherapy boost (EBRT+BT).
Design, settings, and participants: This was a cohort study of 3 cohorts assembled from a multicenter retrospective study (2000-2013); a post hoc analysis of the Randomized Androgen Deprivation and Radiotherapy 03/04 (RADAR; 2003-2007) randomized clinical trial (RCT); and a cross-trial comparison of the RADAR vs the Deprivación Androgénica y Radio Terapía (Androgen Deprivation and Radiation Therapy; DART) 01/05 RCT (2005-2010). In all, the study analyzed 1827 patients treated with EBRT and 1108 patients treated with EBRT+BT from the retrospective cohort; 181 treated with EBRT and 203 with EBRT+BT from RADAR; and 91 patients treated with EBRT from DART. The study was conducted from October 15, 2020, to July 1, 2021, and the data analyses, from January 5 to June 15, 2021.
Exposures: High-dose EBRT or EBRT+BT for an ADT duration determined by patient-physician choice (retrospective) or by randomization (RCTs).
Main outcomes and measures: The primary outcome was DMFS; secondary outcome was overall survival (OS). Natural cubic spline analysis identified minimum thresholds (months).
Results: This cohort study of 3 studies totaling 3410 men (mean age [SD], 68 [62-74] years; race and ethnicity not collected) with high-risk prostate cancer found a significant interaction between the treatment type (EBRT vs EBRT+BT) and ADT duration (binned to <6, 6 to <18, and ≥18 months). Natural cubic spline analysis identified minimum duration thresholds of 26.3 months (95% CI, 25.4-36.0 months) for EBRT and 12 months (95% CI, 4.9-36.0 months) for EBRT+BT for optimal effect on DMFS. In RADAR, the prolongation of ADT for patients receiving only EBRT was not associated with significant improvements in DMFS (hazard ratio [HR], 1.01; 95% CI, 0.65-1.57); however, for patients receiving EBRT+BT, a longer duration was associated with improved DMFS (DMFS HR, 0.56; 95% CI, 0.36-0.87; P = .01). For patients receiving EBRT alone (DART), 28 months of ADT was associated with improved DMFS compared with 18 months (RADAR HR, 0.37; 95% CI, 0.17-0.80; P = .01).
Conclusions and relevance: These cohort study findings suggest that the optimal minimum ADT duration for treatment with high-dose EBRT alone is more than 18 months; and for EBRT+BT, it is 18 months or possibly less. Additional studies are needed to determine more precise minimum durations.