Combined Androgen Blockade in Localized Prostate Cancer Treated With Definitive Radiation Therapy

View More View Less
  • a Department of Radiation Medicine and Applied Sciences,
  • b Division of Hematology-Oncology, Department of Internal Medicine, and
  • c Clinical and Translational Research Institute, University of California San Diego, San Diego, California.
Restricted access

Background: The addition of androgen deprivation therapy to radiation therapy (RT) improves survival in patients with intermediate- and high-risk prostate cancer (PCa), but it is not known whether combined androgen blockade (CAB) with a gonadotropin-releasing hormone agonist (GnRH-A) and a nonsteroidal antiandrogen improves survival over GnRH-A monotherapy. Methods: This study evaluated patients with intermediate- and high-risk PCa diagnosed in 2001 through 2015 who underwent RT with either GnRH-A alone or CAB using the Veterans Affairs Informatics and Computing Infrastructure. Associations between CAB and prostate cancer–specific mortality (PCSM) and overall survival (OS) were determined using multivariable regression with Fine-Gray and multivariable Cox proportional hazards models, respectively. For a positive control, the effect of long-term versus short-term GnRH-A therapy was tested. Results: The cohort included 8,423 men (GnRH-A, 4,529; CAB, 3,894) with a median follow-up of 5.9 years. There were 1,861 deaths, including 349 resulting from PCa. The unadjusted cumulative incidences of PCSM at 10 years were 5.9% and 6.9% for those receiving GnRH-A and CAB, respectively (P=.16). Compared with GnRH-A alone, CAB was not associated with a significant difference in covariate-adjusted PCSM (subdistribution hazard ratio [SHR], 1.05; 95% CI, 0.85–1.30) or OS (hazard ratio, 1.02; 95% CI, 0.93–1.12). For high-risk patients, long-term versus short-term GnRH-A therapy was associated with improved PCSM (SHR, 0.74; 95% CI, 0.57–0.95) and OS (SHR, 0.82; 95% CI, 0.73–0.93). Conclusions: In men receiving definitive RT for intermediate- or high-risk PCa, CAB was not associated with improved PCSM or OS compared with GnRH alone.

Submitted April 12, 2019; accepted for publication June 19, 2019.

Author contributions: Study concept: Vitzthum, Straka, McKay, Sandhu, Rose. Data analysis: Vitzthum, Straka, Sarkar, Murphy, Rose. Data curation: Sarkar. Writing of manuscript: Vitzthum, Straka, McKay, Randall, Sandhu, Murphy, Rose. Manuscript editing: Vitzthum, Straka, Randall, Rose.

Disclosures: Dr. McKay has disclosed that he is a scientific advisor for Janssen. The remaining authors have disclosed that they have not received any financial considerations from any person or organization to support the preparation, analysis, results, or discussion of this article.

Funding: This work was supported by NIH grant TL1TR001443 (Sarkar).

Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Correspondence: Brent S. Rose, MD, Department of Radiation Medicine and Applied Sciences, University of California San Diego, Altman Clinical and Translational Research Institute Building, 9452 Medical Center Drive, La Jolla, CA 92037. Email: bsrose@ucsd.edu

Supplementary Materials

    • Supplemental Materials (PDF 509.57 KB)
  • 1.

    Jones CU, Hunt D, McGowan DG, . Radiotherapy and short-term androgen deprivation for localized prostate cancer. N Engl J Med 2011;365:107118.

  • 2.

    D’Amico AV, Chen MH, Renshaw AA, . Androgen suppression and radiation vs radiation alone for prostate cancer: a randomized trial. JAMA 2008;299:289295.

  • 3.

    Bolla M, de Reijke TM, Van Tienhoven G, . Duration of androgen suppression in the treatment of prostate cancer. N Engl J Med 2009;360:25162527.

  • 4.

    Horwitz EM, Bae K, Hanks GE, . Ten-year follow-up of Radiation Therapy Oncology Group protocol 92-02: a phase III trial of the duration of elective androgen deprivation in locally advanced prostate cancer. J Clin Oncol 2008;26:24972504.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5.

    Sharifi N, Gulley JL, Dahut WL. Androgen deprivation therapy for prostate cancer. JAMA 2005;294:238244.

  • 6.

    Mohler JL, Antonarakis ES, Armstrong AJ, . NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer. Version 2.2019. To view the most recent version, visit NCCN.org. Accessed April 15, 2019.

  • 7.

    Lukka H, Waldron T, Klotz L, . Maximal androgen blockade for the treatment of metastatic prostate cancer – a systematic review. Curr Oncol 2006;13:8193.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8.

    Samson DJ, Seidenfeld J, Schmitt B, . Systematic review and meta-analysis of monotherapy compared with combined androgen blockade for patients with advanced prostate carcinoma. Cancer 2002;95:361376.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9.

    Zapatero A, Guerrero A, Maldonado X, . High-dose radiotherapy with short-term or long-term androgen deprivation in localised prostate cancer (DART01/05 GICOR): a randomised, controlled, phase 3 trial. Lancet Oncol 2015;16:320327.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10.

    Hanks GE, Pajak TF, Porter A, . Phase III trial of long-term adjuvant androgen deprivation after neoadjuvant hormonal cytoreduction and radiotherapy in locally advanced carcinoma of the prostate: the Radiation Therapy Oncology Group protocol 92-02. J Clin Oncol 2003;21:39723978.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11.

    Mostaghel EA, Nelson PS, Lange P, . Targeted androgen pathway suppression in localized prostate cancer: a pilot study. J Clin Oncol 2014;32:229237.

  • 12.

    Commission on Cancer. FORDS: Facility Oncology Registry Data Standards: Revised for 2016. Available at: https://www.facs.org/∼/media/files/quality%20programs/cancer/ncdb/fords%202016.as. Accessed October 10, 2019.

  • 13.

    D’Amico AV, Whittington R, Malkowicz SB, . Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. JAMA 1998;280:969974.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14.

    Mohler JL, Antonarakis ES, Armstrong AJ, . NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer. Version 2.2019. J Natl Compr Canc Netw 2019;17:479505.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15.

    Charlson ME, Pompei P, Ales KL, . A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 1987;40:373383.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16.

    Bryant AK, Huynh-Le MP, Simpson DR, . Association of HIV status with outcomes of anal squamous cell carcinoma in the era of highly active antiretroviral therapy. JAMA Oncol 2018;4:120122.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17.

    Bryant AK, McKay RR, Kader AK, . Subcastrate testosterone nadir and clinical outcomes in intermediate- or high-risk localized prostate cancer. Int J Radiat Oncol Biol Phys 2019;103:10681076.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18.

    Buuren S, Groothuis-Oudshoorn K. Multivariate imputation by chained equations in R. J Stat Softw 2011;45:167.

  • 19.

    Fine JP, Gray RJ. A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc 1999;94:496509.

  • 20.

    Nieto FJ, Coresh J. Adjusting survival curves for confounders: a review and a new method. Am J Epidemiol 1996;143:10591068.

  • 21.

    Mostaghel EA, Page ST, Lin DW, . Intraprostatic androgens and androgen-regulated gene expression persist after testosterone suppression: therapeutic implications for castration-resistant prostate cancer. Cancer Res 2007;67:50335041.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22.

    Schmitt B, Bennett C, Seidenfeld J, . Maximal androgen blockade for advanced prostate cancer. Cochrane Database Syst Rev 2000:CD001526.

  • 23.

    Labrie F, Veilleux R, Fournier A. Low androgen levels induce the development of androgen-hypersensitive cell clones in Shionogi mouse mammary carcinoma cells in culture. J Natl Cancer Inst 1988;80:11381147.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24.

    Oefelein MG, Feng A, Scolieri MJ, . Reassessment of the definition of castrate levels of testosterone: implications for clinical decision making. Urology 2000;56:10211024.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25.

    Uemura H. New generation of androgen receptor antagonist in castration resistant prostate cancer [in Japanese]. Nihon Rinsho 2014;72:21642169.

  • 26.

    Siemens DR, Klotz L, Heidenreich A, . Efficacy and safety of enzalutamide vs bicalutamide in younger and older patients with metastatic castration resistant prostate cancer in the TERRAIN trial. J Urol 2018;199:147154.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27.

    Denis L, Murphy GP. Overview of phase III trials on combined androgen treatment in patients with metastatic prostate cancer. Cancer 1993;72(12 Suppl):38883895.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28.

    Klotz L. Maximal androgen blockade for advanced prostate cancer. Best Pract Res Clin Endocrinol Metab 2008;22:331340.

  • 29.

    Laufer M, Denmeade SR, Sinibaldi VJ, . Complete androgen blockade for prostate cancer: what went wrong? J Urol 2000;164:39.

  • 30.

    Loblaw DA, Virgo KS, Nam R, . Initial hormonal management of androgen-sensitive metastatic, recurrent, or progressive prostate cancer: 2006 update of an American Society of Clinical Oncology practice guideline. J Clin Oncol 2007;25:15961605.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 31.

    Zapatero A, Guerrero A, Maldonado X, . High-dose radiotherapy with short-term or long-term androgen deprivation in localised prostate cancer (DART01/05 GICOR): a randomised, controlled, phase 3 trial. Lancet Oncol 2015;16:320327.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32.

    Nanda A, Chen MH, Moran BJ, . Total androgen blockade versus a luteinizing hormone-releasing hormone agonist alone in men with high-risk prostate cancer treated with radiotherapy. Int J Radiat Oncol Biol Phys 2010;76:14391444.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33.

    D’Amico AV, Chen MH, Renshaw AA, . Risk of prostate cancer recurrence in men treated with radiation alone or in conjunction with combined or less than combined androgen suppression therapy. J Clin Oncol 2008;26:29792983.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 34.

    Feng FY, Blas K, Olson K, . Retrospective evaluation reveals that long-term androgen deprivation therapy improves cause-specific and overall survival in the setting of dose-escalated radiation for high-risk prostate cancer. Int J Radiat Oncol Biol Phys 2013;86:6471.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 35.

    Beer TM, Armstrong AJ, Rathkopf DE, . Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med 2014;371:424433.

  • 36.

    Scher HI, Fizazi K, Saad F, . Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med 2012;367:11871197.

  • 37.

    de Bono JS, Logothetis CJ, Molina A, . Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 2011;364:19952005.

  • 38.

    Fizazi K, Tran N, Fein L, . Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer. N Engl J Med 2017;377:352360.

  • 39.

    Ryan CJ, Smith MR, de Bono JS, . Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med 2013;368:138148.

  • 40.

    James ND, de Bono JS, Spears MR, . Abiraterone for prostate cancer not previously treated with hormone therapy. N Engl J Med 2017;377:338351.

All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 1467 1467 55
PDF Downloads 386 386 19
EPUB Downloads 0 0 0