Prognostic and predictive value of plasma testosterone levels in patients receiving first-line chemotherapy for metastatic castrate-resistant prostate cancer

A G de Liaño, O Reig, B Mellado, C Martin, E U Rull, J P Maroto, A G de Liaño, O Reig, B Mellado, C Martin, E U Rull, J P Maroto

Abstract

Background: Biomarkers for metastatic castration-resistant prostatic cancer (mCRPC) are an unmet medical need.

Methods: The prognostic and predictive value for survival and response to salvage hormonal therapy (SHT) of baseline testosterone level (TL) was analysed in a cohort of 101 mCRPC patients participating in 9 non-hormonal first-line chemotherapy phase II-III trials. Inclusion criteria in all trials required a TL of <50 ng dl(-1).

Results: Median age: 70 years; visceral metastases: 19.8%; median prostate-specific antigen (PSA): 50.7 ng ml(-1); median TL: 11.5 ng dl(-1). Median overall survival (OS; 24.5 months) was significantly longer if baseline TL was above (High TL; n=52) than under (Low TL; n=49) the TL median value (32.7 vs 22.4 months, respectively; P=0.0162, hazard ratio (HR)=0.6). The presence of anaemia was an unfavourable prognostic factor (median OS: 20.6 vs 28.4 months; P=0.0025, HR=1.88 (CI95%: 1.01-3.48)). Patients presenting both anaemia and low testosterone had a worse outcome compared to those with one or none of them (median OS: 17.9 vs 22.4 vs 38.1 months; P=0.0024). High vs Low TL was associated with PSA response rate (55.6% vs 21.7%) in 41 patients receiving SHT.

Conclusion: Testosterone level under castration range was a prognostic factor for survival mCRPC patients. The PSA response to SHT differed depending on TLs. Testosterone levels might help in treatment decision.

Trial registration: ClinicalTrials.gov NCT00278993 NCT00321620 NCT00411528 NCT00519285 NCT00642018 NCT00744497 NCT01057810 NCT01188187 NCT01308567.

Figures

Figure 1
Figure 1
Distribution of serum androgen levels at baseline.
Figure 2
Figure 2
Disease-free survival (A) and overall survival (B) according to testosterone baseline levels.
Figure 3
Figure 3
Overall survival according to the presence of anaemia (A) or age (B) at baseline.
Figure 4
Figure 4
Overall survival according to prognostic groups.
Figure 5
Figure 5
Time from progression to first-line therapy to death.

References

    1. Armstrong AJ, Garrett-Mayer ES, Yang YO, de Witt R, Tannock IF, Eisenberger M. A contemporary prognostic nomogram for men with hormone-refractory metastatic prostate cancer: a TAX327 study analysis. Clin Cancer Res. 2007;13:6396–6403.
    1. Attard G, Reid AH, Yap TA, Raynaud F, Dowsett M, Settatree S, Barrett M, Parker C, Martins V, Folkerd E, Clark J, Cooper CS, Kaye SB, Dearnaley D, Lee G, de Bono JS. Phase I clinical trial of a selective inhibitor of CYP17, abiraterone acetate, confirms that castration-resistant prostate cancer commonly remains hormone driven. J Clin Oncol. 2008;26:4563–4571.
    1. Darshan MS, Loftus MS, Thadani-Mulero M, Levy BP, Escuin D, Zhou XK, Gjyrezi A, Chanel-Vos C, Shen R, Tagawa ST, Bander NH, Nanus DM, Giannakakou P. Taxane-induced blockade to nuclear accumulation of the androgen receptor predicts clinical responses in metastatic prostate cancer. Cancer Res. 2011;71 (18:6019–6029.
    1. de Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L, Chi KN, Jones RJ, Goodman OB, Jr, Saad F, Staffurth JN, Mainwaring P, Harland S, Flaig TW, Hutson TE, Cheng T, Patterson H, Hainsworth JD, Ryan CJ, Sternberg CN, Ellard SL, Flechon A, Saleh M, Scholz M, Efstathiou E, Zivi A, Bianchini D, Loriot Y, Chieffo N, Kheoh T, Haqq CM, Scher HI. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364:1995–2005.
    1. de Bono JS, Oudard S, Ozguroglu M, Hansen S, Machiels JP, Kocak I, Gravis G, Bodrogi I, Mackenzie MJ, Shen L, Roessner M, Gupta S, Sartor AO. 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.
    1. Efstathiou E, Titus M, Tsavachidou D, Tzelepi V, Wen S, Hoang A, Molina A, Chieffo N, Smith LA, Karlou M, Troncoso P, Logothetis CJ. Effects of abiraterone acetate on androgen signaling in castrate-resistant prostate cancer in bone. J Clin Oncol. 2012;30:637–643.
    1. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1) Eur J Cancer. 2009;45:228–247.
    1. Hashimoto K, Masumori N, Hashimoto J, Takayanagi A, Fukuta F, Tsukamoto T. Serum testosterone level to predict the efficacy of sequential use of antiandrogens as second-line treatment following androgen deprivation monotherapy in patients with castration-resistant prostate cancer. Jpn J Clin Oncol. 2011;41:405–410.
    1. Locke JA, Guns ES, Lubik AA, Adomat HH, Hendy SC, Wood CA, Ettinger SL, Gleave ME, Nelson CC. Androgen levels increase by intratumoral de novo steroidogenesis during progression of castration-resistant prostate cancer. Cancer Res. 2008;68:6407–6415.
    1. Loriot Y, Bianchini D, Ileana E, Sandhu S, Patrikidou A, Pezaro C, Albiges L, Attard G, Fizazi K, De Bono JS, Massard C. Antitumour activity of abiraterone acetate against metastatic castration-resistant prostate cancer progressing after docetaxel and enzalutamide (MDV3100) Ann Oncol. 2013;24 (7:1807–1812.
    1. McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM. Reporting recommendations for tumor marker prognostic studies (REMARK) J Natl Cancer Inst. 2005;97 (16:1180–1184.
    1. Mezynski J, Pezaro C, Bianchini D, Zivi A, Sandhu S, Thompson E, Hunt J, Sheridan E, Baikady B, Sarvadikar A, Maier G, Reid AH, Mulick CA, Olmos D, Attard G, de BJ. Antitumour activity of docetaxel following treatment with the CYP17A1 inhibitor abiraterone: clinical evidence for cross-resistance. Ann Oncol. 2012;23:2943–2947.
    1. Montgomery RB, Mostaghel EA, Vessella R, Hess DL, Kalhorn TF, Higano CS, True LD, Nelson PS. Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res. 2008;68:4447–4454.
    1. Morote J, Orsola A, Planas J, Trilla E, Raventos CX, Cecchini L, Catalan R. Redefining clinically significant castration levels in patients with prostate cancer receiving continuous androgen deprivation therapy. J Urol. 2007;178:1290–1295.
    1. Noonan KL, North S, Bitting RL, Armstrong AJ, Ellard SL, Chi KN. Clinical activity of abiraterone acetate in patients with metastatic castration-resistant prostate cancer progressing after enzalutamide. Ann Oncol. 2013;24:1802–1807.
    1. Perachino M, Cavalli V, Bravi F. Testosterone levels in patients with metastatic prostate cancer treated with luteinizing hormone-releasing hormone therapy: prognostic significance. BJU Int. 2010;105:648–651.
    1. Prevail Trial 2013. Medivation Press Release (Last accessed on 13 December 2013).
    1. Ryan CJ, Smith MR, de Bono JS, Molina A, Logothetis CJ, de SP, Fizazi K, Mainwaring P, Piulats JM, Ng S, Carles J, Mulders PF, Basch E, Small EJ, Saad F, Schrijvers D, Van PH, Mukherjee SD, Suttmann H, Gerritsen WR, Flaig TW, George DJ, Yu EY, Efstathiou E, Pantuck A, Winquist E, Higano CS, Taplin ME, Park Y, Kheoh T, Griffin T, Scher HI, Rathkopf DE. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med. 2013;368:138–148.
    1. Ryan CJ, Molina A, Li J, Kheoh T, Small EJ, Haqq CM, Grant RP, de Bono JS, Scher HI. 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.
    1. Scher HI, Halabi S, Tannock I, Morris M, Sternberg CN, Carducci MA, Eisenberger MA, Higano C, Bubley GJ, Dreicer R, Petrylak D, Kantoff P, Basch E, Kelly WK, Figg WD, Small EJ, Beer TM, Wilding G, Martin A, Hussain M. Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group. J Clin Oncol. 2008;26:1148–1159.
    1. Scher HI, Fizazi K, Saad F, Taplin ME, Sternberg CN, Miller K, de WR, Mulders P, Chi KN, Shore ND, Armstrong AJ, Flaig TW, Flechon A, Mainwaring P, Fleming M, Hainsworth JD, Hirmand M, Selby B, Seely L, de Bono JS. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367:1187–1197.
    1. Small EJ, Halabi S, Dawson NA, Stadler WM, Rini BI, Picus J, Gable P, Torti FM, Kaplan E, Vogelzang NJ. Antiandrogen withdrawal alone or in combination with ketoconazole in androgen-independent prostate cancer patients: a phase III trial (CALGB 9583) J Clin Oncol. 2004;22:1025–1033.

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