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Randomized Controlled Trial
. 2022 Mar 1;8(3):e216871.
doi: 10.1001/jamaoncol.2021.6871. Epub 2022 Mar 17.

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
Affiliations
Randomized Controlled Trial

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 et al. JAMA Oncol. .

Abstract

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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Kishan reported consulting fees and speaking honoraria from Varian Medical Systems, ViewRay, and Intelligent Automation; equity in ViewRay; and serving on the Janssen advisory board, all outside the submitted work. Dr Zapatero reported consulting and/or speaking fees from Astellas Pharma, Bayer, and Janssen; serving on the Bayer advisory board; and grants from SEOR/GICOR, all outside the submitted work. Dr Joseph reported grants from NHMRC (Australia) during the conduct of the study. Dr Tran reported grants from Astellas and Bayer and personal fees from RefleXion, Johnson & Johnson, and Myovant during the conduct of the study; and holding a patent for Compounds and Methods of Use in Ablative Radiotherapy (No. 9114158) with royalties paid from Natsar Pharm. Dr Song reported grants from BioProtect, Candel Therapeutics, Bayer, Celgene, and the US National Cancer Institute, all outside the submitted work. Dr Ross reported personal fees from Bayer, Astellas, Blue Earth, Myovant, GenomeDx Biosciences, and Janssen outside the submitted work. Dr Tilki reported personal fees from Ipsen, Exact Sciences, miR Scientific, AstraZeneca, Apogepha, Roche, Takeda, and AAA (Novartis) outside the submitted work. Dr Tosoian reported equity in LynxDx outside the submitted work. Dr Nickols reported grants from Lantheus, Janssen, and Bayer, and personal fees from OncoLinea, all outside the submitted work. Dr Rettig reported consulting fees from Ambrx, Amgen, Roivant Sciences, Clovis, Bayer, and Janssen; nonfinancial support from Merck; and grants from Novartis, all outside the submitted work; and holding a pending patent for Inhibitors of the N-terminus of the Androgen Receptor. Dr Feng reported consulting fees from Janssen, Blue Earth Diagnostics, Astellas, Myovant, Roivant Sciences, Bayer, Bristol Myers Squibb; stock options in Serimmune and BlueStar Genomics; serving on the advisory boards of Serimmune and BlueStar Genomics; consulting fees from Exact Sciences and Varian; and equity in Artera, all outside the submitted work. Dr Tward reported grants from Bayer and serving on the advisory boards of Myriad, Blue Earth, Boston Scientific, and Merck, all outside the submitted work. Dr Steinberg reported honoraria from ViewRay. Dr Boutros reported holding patents on biomarkers for localized prostate cancer and serving on the advisory boards to Sage BioNetworks, BioSymetrics, and Intersect Diagnostics. Dr Spratt reported grants from Janssen and personal fees from AstraZeneca, Varian, and Boston Scientific, outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Associations of Androgen Deprivation Therapy Duration With Distant Metastasis-Free Survival and Overall Survival in Men Receiving External Beam Radiotherapy With or Without Brachytherapy Boost
A and B, Forest plot comparison ADT duration of 6 to less than 18 months ADT vs less than 6 months. C and D, Comparison of ADT duration of 18 months or more vs 6 to less than 18 months; natural cubic splines evaluating nonlinear associations between ADT duration and DMFS for patients receiving EBRT or EBRT+BT. An arrow on each spline indicates the ADT duration threshold (lowest in [HR]); higher numerical values on the y-axis indicate a less favorable DMFS, and lower values, a more favorable DMFS. Abbreviations: ADT, androgen deprivation therapy; DMFS, distant metastasis-free survival; EBRT, external beam radiotherapy; EBRT+BT, external beam radiotherapy plus brachytherapy boost; HR, hazard ratio; OS, overall survival.
Figure 2.
Figure 2.. Associations of Longer Duration of Androgen Deprivation Therapy With Distant Metastasis-Free Survival and Overall Survival
A and B, Kaplan-Meier curves for DMFS and OS for patients receiving EBRT+BT and 6 or 18 months of ADT on the RADAR trial. Because the RADAR comparison for patients receiving EBRT+BT is the direct randomization from that trial, unadjusted curves are presented. C and D, Adjusted survival curves for DMFS and OS for the cross-trial comparison between patients receiving ADT for 6 and 18 months (RADAR) vs 28 months (DART). Survival curves were adjusted using an inverse probability treatment weighting approach wherein propensity scores included the following independent variables: treatment type (if relevant), ln(iPSA), clinical T category, Gleason grade group, and age (y) at treatment. Abbreviations: ADT, androgen deprivation therapy; DART, Deprivación Androgénica y Radio Terapía (Androgen Deprivation and Radiation Therapy) 01/05 trial; DMFS, distant metastasis-free survival; EBRT, external beam radiotherapy; EBRT+BT, external beam radiotherapy plus brachytherapy boost; OS, overall survival; RADAR, the Randomized Androgen Deprivation and Radiotherapy 03/04 trial.
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Comment in

  • Urological Oncology: Prostate Cancer.
    Taneja SS. Taneja SS. J Urol. 2023 Mar;209(3):635-637. doi: 10.1097/JU.0000000000003088. Epub 2022 Dec 1. J Urol. 2023. PMID: 36453267 No abstract available.

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