Clinical Research

Impact of single-agent daily prednisone on outcomes in men with metastatic castration-resistant prostate cancer

Abstract

Background:

Despite palliative benefits and PSA responses, the objective clinical impact of daily oral prednisone (P) for metastatic castration-resistant prostate cancer (mCRPC) is unknown. We performed a pooled analysis of control arms of randomized trials that either did or did not administer single-agent P to evaluate its impact on overall survival (OS) and toxicities.

Methods:

Individual patient data from control arms of randomized trials of men with mCRPC who received placebo or P+placebo post docetaxel were eligible for analysis. The impact of P on OS and severe toxicities was investigated in Cox regression models adjusted for known prognostic factors. Statistical significance was defined as P<0.05 and all tests were two sided.

Results:

Data from the control arms of two randomized phase III trials were available totaling 794 men: the COU-AA-301 trial (n=394) administered P plus placebo and the CA184-043 trial (n=400) administered placebo alone. P plus placebo was not significantly associated with OS compared with placebo in a multivariable analysis (hazard ratio=0.89 (95% confidence interval 0.72–1.10), P=0.27). Other factors associated with poor OS were Eastern Cooperative Oncology Group (ECOG)-performance status (PS) 1, Gleason score 8, liver metastasis, high PSA, hypoalbuminemia and elevated lactate dehydrogenase (LDH). Grade 3 therapy-related toxicities were significantly increased with P plus placebo compared with placebo (hazard ratio=1.48 (95% confidence interval 1.03–2.13), P=0.034). Other baseline factors significantly associated with a higher risk of grade 3 toxicities were ECOG-PS 1, hypoalbuminemia and elevated LDH. Fatigue, asthenia, anorexia and pain were not different based on P administration.

Conclusions:

P plus placebo was associated with higher grade 3 toxicities but not extension of OS compared with placebo alone in men with mCRPC who received prior docetaxel. Except for the use of P with abiraterone to alleviate toxicities, the use of P should be questioned given its association with toxicities and resistance.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1
Figure 2

References

  1. 1

    Tannock IF, Osoba D, Stockler MR, Ernst DS, Neville AJ, Moore MJ et al. Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer: a Canadian randomized trial with palliative end points. J Clin Oncol 1996; 14: 1756–1764.

    CAS  Article  Google Scholar 

  2. 2

    Kantoff PW, Halabi S, Conaway M, Picus J, Kirshner J, Hars V et al. Hydrocortisone with or without mitoxantrone in men with hormone-refractory prostate cancer: results of the cancer and leukemia group B 9182 study. J Clin Oncol 1999; 17: 2506–2513.

    CAS  Article  Google Scholar 

  3. 3

    Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004; 351: 1502–1512.

    CAS  Article  Google Scholar 

  4. 4

    Kelly WK, Halabi S, Carducci M, George D, Mahoney JF, Stadler WM et al. Randomized, double-blind, placebo-controlled phase III trial comparing docetaxel and prednisone with or without bevacizumab in men with metastatic castration-resistant prostate cancer: CALGB 90401. J Clin Oncol 2012; 30: 1534–1540.

    CAS  Article  Google Scholar 

  5. 5

    de Bono JS, Oudard S, Ozguroglu M, Hansen S, Machiels JP, Kocak I et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet 2010; 376: 1147–1154.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6

    de Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 2011; 364: 1995–2005.

    CAS  Article  Google Scholar 

  7. 7

    Ryan CJ, Smith MR, de Bono JS, Molina A, Logothetis CJ, de Souza P et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med 2013; 368: 138–148.

    CAS  Article  Google Scholar 

  8. 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: 411–422.

    CAS  Article  Google Scholar 

  9. 9

    Isikbay M, Otto K, Kregel S, Kach J, Cai Y, Vander Griend DJ et al. Glucocorticoid receptor activity contributes to resistance to androgen-targeted therapy in prostate cancer. Horm Cancer 2014; 5: 72–89.

    CAS  Article  Google Scholar 

  10. 10

    Small EJ, Lance RS, Gardner TA, Karsh LI, Fong L, McCoy C et al. A randomized phase II trial of sipuleucel-T with concurrent versus sequential abiraterone acetate plus prednisone in metastatic castration-resistant prostate cancer. Clin Cancer Res 2015; 21: 3862–3869.

    CAS  Article  Google Scholar 

  11. 11

    Alves C, Robazzi TC, Mendonca M . Withdrawal from glucocorticosteroid therapy: clinical practice recommendations. J Pediatr 2008; 84: 192–202.

    Article  Google Scholar 

  12. 12

    Morgan CJ, Oh WK, Naik G, Galsky MD, Sonpavde G . Impact of prednisone on toxicities and survival in metastatic castration-resistant prostate cancer: a systematic review and meta-analysis of randomized clinical trials. Crit Rev Oncol Hematol 2014; 90: 253–261.

    Article  Google Scholar 

  13. 13

    Kwon ED, Drake CG, Scher HI, Fizazi K, Bossi A, van den Eertwegh AJ et al. Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol 2014; 15: 700–712.

    CAS  Article  Google Scholar 

  14. 14

    Halabi S, Lin CY, Kelly WK, Fizazi KS, Moul JW, Kaplan EB et al. Updated prognostic model for predicting overall survival in first-line chemotherapy for patients with metastatic castration-resistant prostate cancer. J Clin Oncol 2014; 32: 671–677.

    Article  Google Scholar 

  15. 15

    Halabi S, Lin CY, Small EJ, Armstrong AJ, Kaplan EB, Petrylak D et al. Prognostic model predicting metastatic castration-resistant prostate cancer survival in men treated with second-line chemotherapy. J Natl Cancer Inst 2013; 105: 1729–1737.

    CAS  Article  Google Scholar 

  16. 16

    van Soest RJ, Templeton AJ, Vera-Badillo FE, Mercier F, Sonpavde G, Amir E et al. Neutrophil-to-lymphocyte ratio as a prognostic biomarker for men with metastatic castration-resistant prostate cancer receiving first-line chemotherapy: data from two randomized phase III trial. Ann Oncol 2015; 26: 743–749.

    CAS  Article  Google Scholar 

  17. 17

    Hurria A, Togawa K, Mohile SG, Owusu C, Klepin HD, Gross CP et al. Predicting chemotherapy toxicity in older adults with cancer: a prospective multicenter study. J Clin Oncol 2011; 29: 3457–3465.

    CAS  Article  Google Scholar 

  18. 18

    Venkitaraman R, Lorente D, Murthy V, Thomas K, Parker L, Ahiabor R et al. A randomised phase 2 trial of dexamethasone versus prednisolone in castration-resistant prostate cancer. Eur Urol 2015; 67: 673–679.

    CAS  Article  Google Scholar 

  19. 19

    Nishimura K, Nonomura N, Satoh E, Harada Y, Nakayama M, Tokizane T et al. Potential mechanism for the effects of dexamethasone on growth of androgen-independent prostate cancer. J Natl Cancer Inst 2001; 93: 1739–1746.

    CAS  Article  Google Scholar 

  20. 20

    Tannock I, Gospodarowicz M, Meakin W, Panzarella T, Stewart L, Rider W . Treatment of metastatic prostatic cancer with low-dose prednisone: evaluation of pain and quality of life as pragmatic indices of response. J Clin Oncol 1989; 7: 590–597.

    CAS  Article  Google Scholar 

  21. 21

    Yano A, Fujii Y, Iwai A, Kageyama Y, Kihara K . Glucocorticoids suppress tumor angiogenesis and in vivo growth of prostate cancer cells. Clin Cancer Res 2006; 12: 3003–3009.

    CAS  Article  Google Scholar 

  22. 22

    Yano A, Fujii Y, Iwai A, Kawakami S, Kageyama Y, Kihara K . Glucocorticoids suppress tumor lymphangiogenesis of prostate cancer cells. Clin Cancer Res 2006; 12 (20 Pt 1): 6012–6017.

    CAS  Article  Google Scholar 

  23. 23

    De Wit R, Fizazi K, Jinga V, Efstathiou E, Fong PCC, Wirth M et al. Phase 3, randomized, placebo-controlled trial of orteronel (TAK-700) plus prednisone in patients (pts) with chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC) (ELM-PC 4 trial). J Clin Oncol 2014; 32:5s, (Suppl; abstract 5008).

  24. 24

    Storlie JA, Buckner JC, Wiseman GA, Burch PA, Hartmann LC, Richardson RL . Prostate specific antigen levels and clinical response to low dose dexamethasone for hormone-refractory metastatic prostate carcinoma. Cancer 1995; 76: 96–100.

    CAS  Article  Google Scholar 

  25. 25

    Venkitaraman R, Thomas K, Huddart RA, Horwich A, Dearnaley DP, Parker CC . Efficacy of low-dose dexamethasone in castration-refractory prostate cancer. BJU Int 2008; 101: 440–443.

    CAS  PubMed  Google Scholar 

  26. 26

    Ryan CJ, Smith MR, de Bono JS, Molina A, Logothetis CJ, de Souza P et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med 2013; 368: 138–148.

    CAS  Article  Google Scholar 

  27. 27

    Scher HI, Heller G, Molina A, Kheoh TS, Attard G, Moreira J et al. Evaluation of circulating tumor cell (CTC) enumeration as an efficacy response biomarker of overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC): Planned final analysis (FA) of COU-AA-301, a randomized double-blind, placebo-controlled phase III study of abiraterone acetate (AA) plus low-dose prednisone (P) post docetaxel. J Clin Oncol 2011; 29, (Suppl; abstract LBA4517).

  28. 28

    Teply BA, Luber B, Denmeade SR, Antonarakis ES . The influence of prednisone on the efficacy of docetaxel in men with metastatic castration-resistant prostate cancer. Prostate Cancer Prostatic Dis 2016; 19: 72–78.

    CAS  Article  Google Scholar 

  29. 29

    Scher HI, Fizazi K, Saad F, Chi KN, Taplin M-E, Sternberg CN et al. Association of baseline corticosteroid with outcomes in a multivariate analysis of the phase 3 Affirm study of enzalutamide (ENZA), an androgen receptor signaling inhibitor (ARSI). European Society for Medical Oncology meeting, Vienna, Austria, 28 September–2 October 2 2012.

  30. 30

    Arora VK, Schenkein E, Murali R, Subudhi SK, Wongvipat J, Balbas MD et al. Glucocorticoid receptor confers resistance to antiandrogens by bypassing androgen receptor blockade. Cell 2013; 155: 1309–1322.

    CAS  Article  Google Scholar 

  31. 31

    Chang CY, Walther PJ, McDonnell DP . Glucocorticoids manifest androgenic activity in a cell line derived from a metastatic prostate cancer. Cancer Res 2001; 61: 8712–8717.

    CAS  PubMed  Google Scholar 

  32. 32

    Richards J, Lim AC, Hay CW, Taylor AE, Wingate A, Nowakowska K et al. Interactions of abiraterone, eplerenone, and prednisolone with wild-type and mutant androgen receptor: a rationale for increasing abiraterone exposure or combining with MDV3100. Cancer Res 2012; 72: 2176–2182.

    CAS  Article  Google Scholar 

  33. 33

    Ryan CJ, Molina A, Li J, Kheoh T, Small EJ, Haqq CM et al. Serum androgens as prognostic biomarkers in castration-resistant prostate cancer: results from an analysis of a randomized phase III trial. J Clin Oncol 2013; 31: 2791–2798.

    CAS  Article  Google Scholar 

  34. 34

    Montgomery B, Kheoh T, Molina A, Li J, Bellmunt J, Tran N et al. Impact of baseline corticosteroids on survival and steroid androgens in metastatic castration-resistant prostate cancer: exploratory analysis from COU-AA-301. Eur Urol 2014; 67: 866–873.

    Article  Google Scholar 

  35. 35

    Scher HI, Fizazi K, Saad F, Taplin ME, Sternberg CN, Miller K et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med 2012; 367: 1187–1197.

    CAS  Article  Google Scholar 

  36. 36

    Beer TM, Armstrong AJ, Rathkopf DE, Loriot Y, Sternberg CN, Higano CS et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med 2014; 371: 424–433.

    Article  Google Scholar 

  37. 37

    Parker C, Nilsson S, Heinrich D, Helle SI, O'Sullivan JM, Fossa SD et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med 2013; 369: 213–223.

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We thank Bristol Myers Squibb and Project Data Sphere for providing data.

Author information

Affiliations

Authors

Corresponding author

Correspondence to G Sonpavde.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Sonpavde, G., Pond, G., Templeton, A. et al. Impact of single-agent daily prednisone on outcomes in men with metastatic castration-resistant prostate cancer. Prostate Cancer Prostatic Dis 20, 67–71 (2017). https://doi.org/10.1038/pcan.2016.44

Download citation

Further reading