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
Authors: Amar U. Kishan, Alison Steigler, James W. Denham, Almudena Zapatero, Araceli Guerrero, David Joseph, Xavier Maldonado, Jessica K. Wong, Bradley J. Stish, Robert T. Dess, Avinash Pilar, Chandana Reddy, Trude B. Wedde, Wolfgang A. Lilleby, Ryan Fiano, Gregory S. Merrick, Richard G. Stock, D. Jeffrey Demanes, Brian J. Moran, Phuoc T. Tran, Santiago Martin, Rafael Martinez-Monge, Daniel J. Krauss, Eyad I. Abu-Isa, Thomas M. Pisansky, C. Richard Choo, Daniel Y. Song, Stephen Greco, Curtiland Deville, Todd McNutt, Theodore L. DeWeese, Ashley E. Ross, Jay P. Ciezki, Derya Tilki, R. Jeffrey Karnes, Jeffrey J. Tosoian, Nicholas G. Nickols, Prashant Bhat, David Shabsovich, Jesus E. Juarez, Tommy Jiang, T. Martin Ma, Michael Xiang, Rebecca Philipson, Albert Chang, Patrick A. Kupelian, Matthew B. Rettig, Felix Y. Feng, Alejandro Berlin, Jonathan D. Tward, Brian J. Davis, Robert E. Reiter, Michael L. Steinberg, David Elashoff, Paul C. Boutros, Eric M. Horwitz, Rahul D. Tendulkar, Daniel E. Spratt, Tahmineh Romero
Journal: JAMA Oncology (2022)

<h3>Importance</h3> 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. <h3>Objective</h3> 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). <h3>Design, Settings, and Participants</h3> 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<i>Deprivación Androgénica y Radio Terapía</i>(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. <h3>Exposures</h3> High-dose EBRT or EBRT+BT for an ADT duration determined by patient-physician choice (retrospective) or by randomization (RCTs). <h3>Main Outcomes and Measures</h3> The primary outcome was DMFS; secondary outcome was overall survival (OS). Natural cubic spline analysis identified minimum thresholds (months). <h3>Results</h3> 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 &lt;6, 6 to &lt;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;<i>P</i> = .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;<i>P</i> = .01). <h3>Conclusions and Relevance</h3> 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.