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Clinical Research

Androgen decline and survival during docetaxel therapy in metastatic castration resistant prostate cancer (mCRPC)

Prostate Cancer and Prostatic Diseases volume 23, pages 66–73 (2020)Cite this article

Subjects

Abstract

Background

Multiple androgens drive prostate cancer progression and higher pre-treatment levels of androgens, even within the castrate range, have been previously shown to be associated with an improved overall survival (OS) in mCRPC. Docetaxel impairs microtubules, has androgen receptor (AR) inhibitory effects and is used in both the castration resistant and sensitive settings, where androgen dynamics may impact outcome. The present analysis evaluates the association of decline in serum androgen levels (Testosterone (T), Androstenedione (A) and DHEA in docetaxel-treated mCRPC patients with OS.

Methods

Data from 1050 men treated on CALGB 90401 with docetaxel, prednisone and either bevacizumab or placebo were evaluated. Eligibility required progressive mCRPC and no prior chemotherapy. Pre-treatment, 6 week and progression serum assays for T, A and DHEA were performed via tandem Liquid Chromatography-Mass Spectrometry (LC-MS/MS). Changes in T, A and DHEA levels from baseline to 6 weeks were calculated as the ratio of 6-week over baseline. The proportional hazards model was used to assess the prognostic significance of changes in T, A, and DHEA from baseline to 6 weeks in predicting OS adjusting for known prognostic factors.

Results

Median baseline values for T, A, and, DHEA were 1.0, 13.5, and 8.1 ng/dL respectively while 6 week levels were 0.64, 7.0, and 6.8 ng/dL respectively. Median OS for low testosterone decline is 20.9 months vs 26.3 months for high testosterone decline. In multivariable analysis including known prognostic variables, change in testosterone levels was independently associated with greater OS; the hazard ratio for death with each unit increase in the 6-week/baseline ratio is 1.02 (95% CI = 1.01–1.03, p = 0.001). Decline in A and DHEA were not significant predictors of OS. In multivariable analysis change in the serum changes did not predict PFS however the ratio of T at 6-weeks over baseline was prognostic of ≥50% decline in PSA with an odds ratio of 0.93 (95% CI = 0.85–0.98, p-value = 0.039).

Conclusions

Declines in testosterone during docetaxel treatment is associated with a longer survival, consistent with a favorable prognostic significance of higher serum androgens in the CRPC.

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References

  1. Montgomery RB, Mostaghel EA, Vessella R, Hess DL, Kalhorn TF, Higano CS, et al. Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res. 2008;68:4447–54.

    Article  CAS  Google Scholar 

  2. Locke JA, Guns ES, Lubik AA, Adomat HH, Hendy SC, Wood CA, et al. Androgen levels increase by intratumoral de novo steroidogenesis during progression of castration-resistant prostate cancer. Cancer Res. 2008;68:6407–15.

    Article  CAS  Google Scholar 

  3. Ryan CJ, Halabi S, Ou SS, Vogelzang NJ, Kantoff P, Small EJ, et al. Adrenal androgen levels as predictors of outcome in prostate cancer patients treated with ketoconazole plus antiandrogen withdrawal: results from a cancer and leukemia group B study. Clin Cancer Res. 2007;13:2030–7.

    Article  CAS  Google Scholar 

  4. 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;31:2791–8.

    Article  CAS  Google Scholar 

  5. Ryan CJ, Dutta S, Kelly KK, Russell C, Small EJ, Morris MJ, et al. Androgens and overall survival in metastatic castration-resistant prostate cancer patients treated with docetaxel (Submitted)

  6. Palarea-Albaladejo J, Martín-Fernández JA. ZCompositions—R package for multivariate imputation of left-censored data under a compositional approach. Chemom Intell Lab Syst. 2015;143:85–960.

    Article  CAS  Google Scholar 

  7. 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;371:424–33.

    Article  Google Scholar 

  8. Rathkopf DE, Smith MR, de Bono JS, Logothetis CJ, Shore ND, de Souza P, et al. Updated interim efficacy analysis and long-term safety of abiraterone acetate in metastatic castration-resistant prostate cancer patients without prior chemotherapy (COU-AA-302). Eur Urol. 2014;66:815–25.

    Article  CAS  Google Scholar 

  9. Ryan CJ, Peng W, Kheoh T, Welkowsky E, Haqq CM, Chandler DW, et al. Androgen dynamics and serum PSA in patients treated with abiraterone acetate. Prostate Cancer Prostatic Dis. 2014;17:192–8. https://doi.org/10.1038/pcan.2014.8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Hearn JWD, AbuAli G, Reichard CA, Reddy CA, Magi-Galluzzi C, Chang KH, et al. HSD3B1 and resistance to androgen-deprivation therapy in prostate cancer: a retrospective, multicohort study. Lancet Oncol. 2016;17:1435–44.

    Article  CAS  Google Scholar 

  11. Small EJ, Halabi S, Dawson NA, Stadler WM, Rini BI, Picus J, et al. Antiandrogen withdrawal alone or in combination with ketoconazole in androgen-independent prostate cancer patients: a phase III trial (CALGB 9583). J Clin Oncol. 2004;22:1025–33.

    Article  CAS  Google Scholar 

  12. Small EJ, Baron AD, Fippin L, Apodaca D. Ketoconazole retains activity in advanced prostate cancer patients with progression despite flutamide withdrawal. J Urol. 1997;157:1204–7.

    Article  CAS  Google Scholar 

  13. 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;32:671–7.

    Article  Google Scholar 

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Acknowledgements

Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Numbers U10CA180821, U10CA180882, U24CA196171 (to the Alliance for Clinical Trials in Oncology), W81XWH-15-1-0467, P30 CA 008748 and R21 CA195424-01, and also in part by Genentech. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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Authors and Affiliations

  1. University of Minnesota and Masonic Cancer Center, Minneapolis, MN, USA

    Charles J. Ryan

  2. Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, NC, USA

    Sandipan Dutta & Susan Halabi

  3. Thomas Jefferson University, Philadelphia, PA, USA

    William K. Kelly

  4. University of California-San Francisco Helen Diller Comprehensive Cancer Center, San Francisco, CA, USA

    Carly Russell & Eric J. Small

  5. Memorial Sloan Kettering Cancer, New York, NY, USA

    Michael J. Morris

  6. Dana-Farber/Partners Cancer Care, Harvard Medical School, Boston, MA, USA

    Mary-Ellen Taplin

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  1. Charles J. Ryan
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From The Alliance for Clinical Trials in Oncology Genitourinary Committee

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Ryan, C.J., Dutta, S., Kelly, W.K. et al. Androgen decline and survival during docetaxel therapy in metastatic castration resistant prostate cancer (mCRPC). Prostate Cancer Prostatic Dis 23, 66–73 (2020). https://doi.org/10.1038/s41391-019-0152-3

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