Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Clinical Research
  • Published:

Surrogate endpoints for overall survival for patients with metastatic hormone-sensitive prostate cancer in the CHAARTED trial

Prostate Cancer and Prostatic Diseases volume 23, pages 638–645 (2020)Cite this article

Subjects

Abstract

Background

Metastasis-free survival has been shown to be a robust surrogate for overall survival (OS) in men with nonmetastatic prostate cancer (PC). However, this surrogate only holds true for a select subset of patients, and leaves those trials analyzing metastatic disease at a disadvantage. We aimed to identify the best surrogate for predicting OS in patients with metastatic hormone-sensitive PC.

Methods

We analyzed data from the Chemohormonal Therapy versus Androgen Ablation Randomized Trial for Extensive Disease trial in which patients were randomly assigned to receive either androgen deprivation therapy (ADT) or ADT plus docetaxel. PSA response, progression and development of castration-resistant PC (CRPC) within 6 and 12 months were investigated as potential OS surrogates, in accordance with the Prentice Criteria. The proportion the of treatment effect (PTE) was calculated for each surrogate and used to identify the best one.

Results

Data from 790 patients were considered: 393 (49.7%) men received ADT alone, while 397 (50.3%) received combination therapy. Four intermediate clinical endpoints met the criteria for surrogacy: progression within 6 months (HR: 5.70; 95%CI: 4.26, 7.64; p < 0.001) and 12 months (HR: 7.09; 95%CI: 5.16, 9.76; p < 0.001) as well as development of CRPC within 6 (HR: 5.11; 95%CI: 3.81, 6.85; p < 0.001) and 12 months (HR: 6.24; 95%CI: 4.58, 8.51; p < 0.001). The PTE for the four surrogates were 88%, 52%, 80%, and 46%, respectively. The 2-year OS rates for patients who progressed within 6 months of randomization were 42 versus 89% for the patient population that did not progress that quickly.

Conclusions

Progression within 6 months following combination therapy emerged as the best surrogate for OS.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Kaplan–Meier survivor functions stratified according to each intermediate clinical endpoint demonstrating overall survival.
Fig. 2

Similar content being viewed by others

References

  1. Miller KD, Nogueira L, Mariotto AB, Rowland JH, Yabroff KR, Alfano CM, et al. Cancer treatment and survivorship statistics. CA Cancer J Clin. 2019;69:363–85.

    Article  Google Scholar 

  2. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69:7–34.

    Article  Google Scholar 

  3. Dalela D, Sun M, Diaz M, Karabon P, Seisen T, Trinh QD, et al. Contemporary trends in the incidence of metastatic prostate cancer among US men: results from Nationwide Analyses. Eur Urol Focus. 2019;5:77–80.

    Article  Google Scholar 

  4. Davis ID, Martin AJ, Stockler MR, Begbie S, Chi KN, Chowdhury S, et al. Enzalutamide with standard first-line therapy in metastatic prostate cancer. N Engl J Med. 2019;381:121–31.

    Article  CAS  Google Scholar 

  5. Fizazi K, Shore N, Tammela TL, Ulys A, Vjaters E, Polyakov S, et al. Darolutamide in nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2019;380:1235–46.

    Article  CAS  Google Scholar 

  6. Fizazi K, Tran N, Fein L, Matsubara N, Rodriguez-Antolin A, Alekseev BY, et al. Abiraterone plus Prednisone in metastatic, castration-sensitive prostate cancer. N Engl J Med. 2017;377:352–60.

    Article  CAS  Google Scholar 

  7. Hussain M, Fizazi K, Saad F, Rathenborg P, Shore N, Ferreira U, et al. Enzalutamide in men with nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2018;378:2465–74.

    Article  CAS  Google Scholar 

  8. Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363:411–22.

    Article  CAS  Google Scholar 

  9. Smith MR, Saad F, Chowdhury S, Oudard S, Hadaschik BA, Graff JN, et al. Apalutamide treatment and metastasis-free survival in prostate cancer. N Engl J Med. 2018;378:1408–18.

    Article  CAS  Google Scholar 

  10. Sweeney CJ, Chen YH, Carducci M, Liu G, Jarrard DF, Eisenberger M, et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med. 2015;373:737–46.

    Article  CAS  Google Scholar 

  11. Armstrong AJ, Szmulewitz RZ, Petrylak DP, Holzbeierlein J, Villers A, Azad A, et al. ARCHES: a randomized, phase III study of androgen deprivation therapy with enzalutamide or placebo in men with metastatic hormone-sensitive prostate cancer. J Clin Oncol. 2019;37:2974–86.

    Article  CAS  Google Scholar 

  12. Chi KN, Agarwal N, Bjartell A, Chung BH, Pereira de Santana Gomes AJ, Given R, et al. Apalutamide for metastatic, castration-sensitive prostate cancer. N Engl J Med. 2019;381:13–24.

    Article  CAS  Google Scholar 

  13. Group ICW, Sweeney C, Nakabayashi M, Regan M, Xie W, Hayes J, et al. The development of intermediate clinical endpoints in cancer of the prostate (ICECaP). J Natl Cancer Inst. 2015;107:djv261.

    Google Scholar 

  14. Jackson WC, Suresh K, Tumati V, Allen SG, Dess RT, Salami SS, et al. Intermediate endpoints after postprostatectomy radiotherapy: 5-year distant metastasis to predict overall survival. Eur Urol. 2018;74:413–9.

    Article  Google Scholar 

  15. Martini A, Gandaglia G, Karnes RJ, Zaffuto E, Bianchi M, Gontero P, et al. Defining the most informative intermediate clinical endpoints for predicting overall survival in patients treated with radical prostatectomy for high-risk prostate cancer. Eur Urol Oncol. 2019;2:456–63.

    Article  Google Scholar 

  16. Xie W, Regan MM, Buyse M, Halabi S, Kantoff PW, Sartor O, et al. Metastasis-free survival is a strong surrogate of overall survival in localized prostate cancer. J Clin Oncol. 2017;35:3097–104.

    Article  CAS  Google Scholar 

  17. Chen EY, Joshi SK, Tran A, Prasad V. Estimation of study time reduction using surrogate end points rather than overall survival in oncology clinical trials. JAMA Intern Med. 2019;179:642–7.

    Article  Google Scholar 

  18. Royce TJ, Chen MH, Wu J, Loffredo M, Renshaw AA, Kantoff PW, et al. Surrogate end points for all-cause mortality in men with localized unfavorable-risk prostate cancer treated with radiation therapy vs radiation therapy plus androgen deprivation therapy: a secondary analysis of a randomized clinical trial. JAMA Oncol. 2017;3:652–8.

    Article  Google Scholar 

  19. Prentice RL. Surrogate endpoints in clinical trials: definition and operational criteria. Stat Med. 1989;8:431–40.

    Article  CAS  Google Scholar 

  20. Parast L, McDermott MM, Tian L. Robust estimation of the proportion of treatment effect explained by surrogate marker information. Stat Med. 2016;35:1637–53.

    Article  Google Scholar 

  21. Wang Y, Taylor JM. A measure of the proportion of treatment effect explained by a surrogate marker. Biometrics. 2002;58:803–12.

    Article  Google Scholar 

  22. Lin DY, Fleming TR, De Gruttola V. Estimating the proportion of treatment effect explained by a surrogate marker. Stat Med. 1997;16:1515–27.

    Article  CAS  Google Scholar 

  23. Harshman LC, Chen YH, Liu G, Carducci MA, Jarrard D, Dreicer R, et al. Seven-month prostate-specific antigen is prognostic in metastatic hormone-sensitive prostate cancer treated with androgen deprivation with or without docetaxel. J Clin Oncol. 2018;36:376–82.

    Article  CAS  Google Scholar 

  24. Hussain M, Tangen CM, Higano C, Schelhammer PF, Faulkner J, Crawford ED, et al. Absolute prostate-specific antigen value after androgen deprivation is a strong independent predictor of survival in new metastatic prostate cancer: data from Southwest Oncology Group Trial 9346 (INT-0162). J Clin Oncol. 2006;24:3984–90.

    Article  Google Scholar 

  25. Matsubara N, Chi KN, Ozguroglu M, Rodriguez Antolin A, Feyerabend S, Fein L, et al. LATITUDE study: PSA response characteristics and correlation with overall survival (OS) and radiological progression-free survival (rPFS) in patients with metastatic hormone-sensitive prostate cancer (mHSPC) receiving ADT+abiraterone acetate and prednisone (AAP) or placebo (PBO). Ann Oncol. 2018;29:viii273–4.

    Article  Google Scholar 

Download references

Acknowledgements

This paper was prepared using data from Datasets NCT00309985-D3 from the National Clinical Trials Network (NCTN) Data Archive of the National Cancer Institute’s (NCI’s) NCTN. Data were originally collected from clinical trial NCT number NCT00309985, Chemohormonal Therapy versus Androgen Ablation Randomized Trial for Extensive Disease (CHAARTED). All analyses and conclusions in this paper are the sole responsibility of the authors and do not necessarily reflect the opinions or views of the clinical trial investigators, the NCTN, or the NCI. Data were accessed through http://www.projectdatasphere.org/, which is maintained by Project Data Sphere, LLC (PDS). Neither PDS nor the owner(s) of any information from the Web site have contributed to, approved, or are in any way responsible for the contents of this publication.

Author information

Authors and Affiliations

  1. Department of Urology, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Alberto Martini & John Pfail

  2. Department of Urology, Vita-Salute San Raffaele University, Milan, Italy

    Alberto Martini & Francesco Montorsi

  3. Department of Medicine, Division of Hematology and Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Matthew D. Galsky & William K. Oh

Authors
  1. Alberto Martini
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. John Pfail
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Francesco Montorsi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Matthew D. Galsky
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. William K. Oh
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Alberto Martini.

Ethics declarations

Conflict of interest

MDG has served as consultant for BioMotiv, Janssen, Merk, Dendreon, GlaxoSmithKline, Lilly, Astellas, Genetech, BMS, Novartis, Pfizer, EMD Serono, AZ, Seattle Genetics, Incyte, Aileron Therapeutics, Dracen, Inovio Pharmaceuticals, NuMab, has received research funding from Janssen, Merk, Dendreon, Novartis, BMS, AZ, Genentech/Roche, and owns stock of Rapt Therapeutics, outside the submitted work. WKO has served as consultant for Sema4, Sanofi, Astellas, Bayer, Janssen, outside the submitted work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Martini, A., Pfail, J., Montorsi, F. et al. Surrogate endpoints for overall survival for patients with metastatic hormone-sensitive prostate cancer in the CHAARTED trial. Prostate Cancer Prostatic Dis 23, 638–645 (2020). https://doi.org/10.1038/s41391-020-0231-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41391-020-0231-5

This article is cited by

Search

Advanced search

Quick links