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Androgen Deprivation Therapy Use and Duration with Definitive Radiotherapy for Localised Prostate Cancer: An Individual Patient Data Meta-Analysis - Beyond the Abstract

In this era of evidence-based medicine, data supporting forms of treatment intensification should be appraised with respect to the hierarchy of levels of evidence.1  The highest level of evidence is a systematic review and meta-analysis of individual patient data from randomized trials, which can circumvent some of the limitations of individual trials, such as lack of generalizability and lack of power to identify significant differences. Examples of these types of meta-analyses have been seen in the oncology literature, including the seminal efforts from the Early Breast Cancer Trialists' Collaborative Group.2 Despite the fact that prostate cancer is an extremely common malignancy worldwide and has been studied in multiple randomized trials, there has never been a comparable international collaborative effort to provide robust treatment effect estimates of the treatment strategies evaluated in localized prostate cancer.


The MARCAP consortium is a large, international effort led by Dr. Kishan and Dr. Spratt with the goal of pooling individual patient data from randomized trials evaluating treatments for prostate cancer. Given the large number of trials investigating treatment intensification strategies with definitive radiotherapy (RT), this was a logical starting point. The first analysis from MARCAP, which is the referenced article, sought to interrogate the metastasis-free survival (MFS) benefit of three common intensification strategies: the use of androgen deprivation therapy (ADT), the extension of neoadjuvant ADT, and the prolongation of adjuvant ADT.3  A systematic review was performed in accordance with PRISMA guidelines, which ultimately identified 12 eligible trials for inclusion. Individual patient data were available for all 12 trials, and a pre-specified analysis plan was in place before any data were analyzed.

Seven randomized comparisons across six trials (n=5136 patients) evaluated ADT use (generally, the addition of 4-6 months of ADT to RT). The addition of ADT to RT significantly improved MFS (HR 0.83, 95% CI 0.77–0.89; p<0·0001). It also improved overall survival and earlier endpoints such as biochemical recurrence. Three randomized trials (n=2213 patients) evaluated neoadjuvant ADT extension (generally, extending total ADT duration from 3-4 months to 6-9 months, with the extension entirely in the neoadjuvant setting). Neoadjuvant extension had no impact on MFS (HR 0.95 [95% CI 0.83–1.09], p=0.50) or any oncologic endpoint. Finally, four randomized trials (n=3774 patients) evaluated adjuvant ADT prolongation (generally, prolonging total ADT duration from 4-6 months to 18-36 months, with the prolongation occurring entirely in the adjuvant setting). This intervention improved MFS (HR 0.84 [95% CI 0.78–0.91], p<0.0001) as well as overall survival and earlier oncologic endpoints.

We further evaluated interaction effects for pre-specified subgroups based on age (≥70 vs <70), National Comprehensive Cancer Network risk group (intermediate vs. high), and RT dose (≥74 Gy vs. <74 Gy). No significant interactions effects for the impact of either ADT use or adjuvant ADT prolongation on MFS were seen. For the addition of ADT to radiotherapy for patients with NCCN intermediate-risk disease, the number-needed-to-treat to avert one distant metastasis event at 10 years was 18.0; for patients with high-risk disease, the number-needed-to-treat was 8.4. The number-needed-to-treat with prolonged adjuvant ADT to avert one distant metastasis event at 10 years was 16.1 for patients with intermediate-risk disease and 10.4 for patients with high-risk disease.

Overall, these results constitute the first individual patient data analysis in localized prostate cancer to rigorously evaluate and quantify the benefits of ADT use, neoadjuvant ADT extension, and adjuvant ADT prolongation for localized prostate cancer patients being treated with definitive radiotherapy. The findings clearly highlight the robust benefit of adding ADT and prolonging adjuvant ADT, while underscoring the lack of data to support routine neoadjuvant ADT extension (which did not impact any outcome). Moreover, the results suggest that these benefits (or lack thereof) are generalizable across relevant patient subgroups based on age, risk group, and RT dose received. On the other hand, the results also highlight that further efforts towards identifying robust predictive markers for the benefit of ADT use and adjuvant ADT prolongation are needed. Work evaluating genomic markers in trials such as GU-009 and GU-010 is particularly exciting in this regard. Finally, the success of the MARCAP consortium highlights that these types of analyses are possible, and multiple other meta-analyses using these data are ongoing. We are actively seeking to expand the MARCAP consortium and encourage investigators to contact us if they wish to participate in future efforts.

Written by: Amar U. Kishan, MD1 & Daniel E. Spratt, MD2

  1. Associate Professor, Vice Chair of Clinical and Translational Research, University of California, Los Angeles, CA
  2. Chair, Department of Radiation Oncology, Vincent K. Smith Professor, Case Western University, Cleveland, OH

References:

  1. Guyatt GH, Sackett DL, Sinclair JC, Hayward R, Cook DJ, Cook RJ. Users' guides to the medical literature. IX. A method for grading health care recommendations. Evidence-Based Medicine Working Group. Jama 1995; 274(22): 1800-4.
  2. Darby S, McGale P, Correa C, et al. Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10,801 women in 17 randomised trials. Lancet 2011; 378(9804): 1707-16.
  3. Kishan AU, Sun Y, Hartman H, et al. Androgen deprivation therapy use and duration with definitive radiotherapy for localised prostate cancer: an individual patient data meta-analysis. Lancet Oncol 2022.

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