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A population K-PD model analysis of long-term testosterone inhibition in prostate cancer patients undergoing intermittent androgen deprivation therapy

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Abstract

Intermittent androgen deprivation therapy with gonadotropin-releasing-hormone (GnRH) agonists can prevent or delay disease progression and development of castration resistant prostate cancer for subpopulations of prostate cancer patients. It may also reduce risk and severity of side effects associated with chemical castration in prostate cancer (PCa) patients. One of the earliest comprehensively documented clinical trials on this was reported in a Canadian patient population treated with leuprorelin preceded by a lead-in with cyproterone acetate. A systems-based mixed effect analysis of testosterone response in active and recovery phases allows inference of new information from this patient population. Efficacy of androgen deprivation therapy is presumed to depend on a treshold value for testosterone at the nadir, below which no additional beneficial effects on PSA reponse can be expected, and occurance of testosterone breakthroughs during active therapy. The present analysis results in a mixed effect model, incorporating GnRH receptor activation, testosterone turnover and feedback mechanisms, describing and predicting testosterone inhibition under intermittent androgen deprivation therapy on the individual and population level, during multiple years of therapy. Testosterone levels in these patients decline over time with an estimated first order rate constant of 0.083 year−1(T1/2 = 8.4 y), with a substantial distribution among this patient population, compared to the general population. PCa patients leaving the trial due to unmanageble PSA relapse appear to have slightly higher testosterone levels at the nadir than sustained responders. These findings are expected to contribute to an increased understanding of the role of testosterone in long term disease progression of prostate cancer.

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References

  1. Morote J, Planas J, Salvador C et al (2009) Individual variations of serum testosterone in patients with prostate cancer receiving androgen deprivation therapy. BJU Int 103:332–335. https://doi.org/10.1111/j.1464-410X.2008.08062.x

    Article  CAS  PubMed  Google Scholar 

  2. Oefelein MG, Resnick MI (2003) Effective testosterone suppression for patients with prostate cancer: is there a best castration? Urology 62:207–213. https://doi.org/10.1016/S0090-4295(03)00331-5

    Article  PubMed  Google Scholar 

  3. Spitz A, Young JM, Larsen L et al (2012) Efficacy and safety of leuprolide acetate 6-month depot for suppression of testosterone in patients with prostate cancer. Prostate Cancer Prostatic Dis 15:93–99. https://doi.org/10.1038/pcan.2011.50

    Article  CAS  PubMed  Google Scholar 

  4. Cornford P, Bellmunt J, Bolla M et al (2017) EAU-ESTRO-SIOG guidelines on prostate cancer. Part II: treatment of relapsing, metastatic, and castration-resistant prostate cancer. Eur Urol 71:630–642. https://doi.org/10.1016/j.eururo.2016.08.002

    Article  PubMed  Google Scholar 

  5. Pickles T, Hamm J, Morris WJ et al (2012) Incomplete testosterone suppression with luteinizing hormone-releasing hormone agonists: does it happen and does it matter? BJU Int 110:E500–E507. https://doi.org/10.1111/j.1464-410X.2012.11190.x

    Article  CAS  PubMed  Google Scholar 

  6. Crawford ED, Moul JW, Sartor O, Shore ND (2015) Extended release, 6-month formulations of leuprolide acetate for the treatment of advanced prostate cancer: achieving testosterone levels below 20 ng/dl. Expert Opin Drug Toxicol. https://doi.org/10.1517/174252551073711

    Article  Google Scholar 

  7. Keating NL, O’Malley AJ, Smith MR (2006) Diabetes and cardiovascular disease during androgen deprivation therapy for prostate cancer. J Clin Oncol 24:4448–4456. https://doi.org/10.1200/JCO.2006.06.2497

    Article  CAS  PubMed  Google Scholar 

  8. Shaw GL, Wilson P, Cuzick J et al (2007) International study into the use of intermittent hormone therapy in the treatment of carcinoma of the prostate: a meta-analysis of 1446 patients. BJU Int 99:1056–1065. https://doi.org/10.1111/j.1464-410X.2007.06770.x

    Article  CAS  PubMed  Google Scholar 

  9. Klotz L, Toren P (2012) Androgen deprivation therapy in advanced prostate cancer: is intermittent therapy the new standard of care? Curr Oncol 19:13–21. https://doi.org/10.3747/co.19.1298

    Article  Google Scholar 

  10. Hussain M, Tangen C, Higano C et al (2016) Evaluating intermittent androgen-deprivation therapy phase III clinical trials: the devil is in the details. J Clin Oncol 34:280–285. https://doi.org/10.1200/JCO.2015.62.8065

    Article  CAS  PubMed  Google Scholar 

  11. Romero E, Velez De Mendizabal N, Cendrós JM et al (2012) Pharmacokinetic/pharmacodynamic model of the testosterone effects of triptorelin administered in sustained release formulations in patients with prostate cancer. J Pharmacol Exp Ther 342:788–798. https://doi.org/10.1124/jpet.112.195560

    Article  CAS  PubMed  Google Scholar 

  12. Snelder N, Drenth HJ, Riber Bergmann K et al (2019) Population pharmacokinetic–pharmacodynamic modelling of the relationship between testosterone and prostate specific antigen in patients with prostate cancer during treatment with leuprorelin. Br J Clin Pharmacol 85:1247–1259. https://doi.org/10.1111/bcp.13891

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Gries JM, Munafo A, Porchet HC, Verotta D (1999) Down-regulation models and modeling of testosterone production induced by recombinant human choriogonadotropin. J Pharmacol Exp Ther 289:371–377

    CAS  PubMed  Google Scholar 

  14. Feldman BJ, Feldman D (2001) The development of androgen-independent prostate cancer. Nat Rev Cancer 1:34–45. https://doi.org/10.1038/35094009

    Article  CAS  PubMed  Google Scholar 

  15. Klotz L, O’Callaghan C, Ding K et al (2015) Nadir testosterone within first year of androgen-deprivation therapy (ADT) predicts for time to castration-resistant progression: a secondary analysis of the PR-7 trial of intermittent versus continuous ADT. J Clin Oncol 33:1151–1156. https://doi.org/10.1200/JCO.2014.58.2973

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Bruchovsky N, Klotz L, Crook J et al (2006) Final results of the canadian prospective phase II trial of intermittent androgen suppression for men in biochemical recurrence after radiotherapy for locally advanced prostate cancer: clinical parameters. Cancer 107:389–395. https://doi.org/10.1002/cncr.21989

    Article  PubMed  Google Scholar 

  17. Bruchovsky N, Klotz L, Crook J, Goldenberg SL (2007) Locally advanced prostate cancer - biochemical results from a prospective phase II study of intermittent androgen suppression for men with evidence of prostate-specific antigen recurrence after radiotherapy. Cancer 109:858–867. https://doi.org/10.1002/cncr.22464

    Article  CAS  PubMed  Google Scholar 

  18. Jacqmin P, Snoeck E, Van Schaick EA et al (2007) Modelling response time profiles in the absence of drug concentrations: definition and performance evaluation of the K-PD model. J Pharmacokinet Pharmacodyn 34:57–85. https://doi.org/10.1007/s10928-006-9035-z

    Article  CAS  PubMed  Google Scholar 

  19. Bruchovsky N (2013) dataTanaka.zip. http://nicholasbruchovsky.com/dataTanaka.zip. Accessed 16 May 2018

  20. Thompson IM (2001) Flare associated with LHRH-agonist therapy. Rev Urol 3(Suppl 3):S10–S14

    PubMed  PubMed Central  Google Scholar 

  21. Tod M (2008) Evaluation of drugs in pediatrics using K-PD models: perspectives. Fundam Clin Pharmacol 22:589–594. https://doi.org/10.1111/j.1472-8206.2008.00649.x

    Article  CAS  PubMed  Google Scholar 

  22. Beal S, Sheiner LB, Boeckmann A, Bauer RJ 2009 NONMEM user’s guides (1989-2009) Ellicott City, MD, USA

  23. R Core Team 2013 R: a language and environment for statistical computing. Vienna, Austria. Available from http://www.R-project.org/. Accessed 30 Oct 2019

  24. RStudio Team 2015 RStudio: integrated development environment for R. Boston, MA Available from http://www.rstudio.com/. Accessed 30 Oct 2019

  25. Lindbom L, JEN Pihlgren P (2005) PsN-toolkit–a collection of computer intensive statistical methods for non-linear mixed effect modeling using NONMEM. Comput Methods Programs Biomed 79(3):241–257. https://doi.org/10.1016/j.cmpb.2005.04.005

    Article  PubMed  Google Scholar 

  26. Gibiansky L, Gibiansky E, Bauer R (2012) Comparison of nonmem 7.2 estimation methods and parallel processing efficiency on a target-mediated drug disposition model. J Pharmacokinet Pharmacodyn 39:17–35. https://doi.org/10.1007/s10928-011-9228-y

    Article  PubMed  Google Scholar 

  27. Bonate PL (2011) Pharmacokinetic-pharmacodynamic modeling and simulation. Springer Available from https://www.springer.com/gp/book/9781441994844. Accessed 6 Jan 2016

  28. Petersson KJF, Hanze E, Savic RM, Karlsson MO (2009) Semiparametric distributions with estimated shape parameters. Pharm Res 26:2174–2185. https://doi.org/10.1007/s11095-009-9931-1

    Article  CAS  PubMed  Google Scholar 

  29. Nguyen THT, Mouksassi MS, Holford N et al (2017) Model evaluation of continuous data pharmacometric models: metrics and graphics. CPT Pharmacometrics Syst Pharmacol 6:87–109. https://doi.org/10.1002/psp4.12161

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Kapoor A, Wu C, Shayegan B, Rybak AP (2016) Contemporary agents in the management of metastatic castration-resistant prostate cancer. J Can Urol Assoc 10:E414–E423. https://doi.org/10.5489/cuaj.4112

    Article  Google Scholar 

  31. Xu X, Chen X, Hu H et al (2015) Current opinion on the role of testosterone in the development of prostate caer: a dynamic model. BMC Cancer 15:1–8. https://doi.org/10.1186/s12885-015-1833-5

    Article  CAS  Google Scholar 

  32. Yamaguchi K, Izaki H, Takahashi M et al (2014) Changes in levels of prostate-specific antigen and testosterone following discontinuation of long-term hormone therapy for non-metastatic prostate cancer. J Med Investig 61:35–40. https://doi.org/10.2152/jmi.61.35

    Article  Google Scholar 

  33. Kuo KF, Hunter-Merrill R, Gulati R et al (2015) Relationships between times to testosterone and prostate-specific antigen rises during the first off-treatment interval of intermittent androgen deprivation are prognostic for castration resistance in men with nonmetastatic prostate cancer. Clin Genitourin Cancer 13:10–16. https://doi.org/10.1016/j.clgc.2014.08.003

    Article  PubMed  Google Scholar 

  34. Crawford ED, Heidenreich A, Lawrentschuk N et al (2019) Androgen-targeted therapy in men with prostate cancer: evolving practice and future considerations. Prostate Cancer Prostatic Dis 22:24–38. https://doi.org/10.1038/s41391-018-0079-0

    Article  PubMed  Google Scholar 

  35. Klotz L, Breau RH, Collins LL et al (2017) Maximal testosterone suppression in the management of recurrent and metastatic prostate cancer. J Can Urol Assoc 11:16–23. https://doi.org/10.5489/cuaj.4303

    Article  Google Scholar 

  36. Klotz L, Shayegan B, Guillemette C et al (2018) Testosterone suppression in the treatment of recurrent or metastatic prostate cancer — a canadian consensus statement. J Can Urol Assoc 12:30–37. https://doi.org/10.5489/cuaj.5116

    Article  Google Scholar 

  37. Cabarkapa S, Perera M, Sikaris K et al (2018) Reporting and ideal testosterone levels in men undergoing androgen deprivation for prostate cancer—time for a rethink? Prostate Int 6:1–6. https://doi.org/10.1016/j.prnil.2017.05.003

    Article  PubMed  Google Scholar 

  38. Rouleau M, Lemire F, Déry M et al (2019) Discordance between testosterone measurement methods in castrated prostate cancer patients. Endocr Connect 8:132–140. https://doi.org/10.1530/EC-18-0476

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Ferraldeschi R, Sharifi N, Auchus RJ, Attard G (2013) Molecular pathways: Inhibiting steroid biosynthesis in prostate cancer. Clin Cancer Res 19:3353–3359. https://doi.org/10.1158/1078-0432.CCR-12-0931

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. González-Sales M, Barrière O, Tremblay PO et al (2016) Modeling testosterone circadian rhythm in hypogonadal males: effect of age and circannual variations. AAPS J 18:217–227. https://doi.org/10.1208/s12248-015-9841-6

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. LAP&P Consultants BV, Archimedesweg 31, 2333 CM, Leiden, The Netherlands

    Joost DeJongh, Maurice Ahsman & Nelleke Snelder

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  2. Maurice Ahsman
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All authors contributed to the model analysis results. The first draft of the manuscript was written by JD and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Joost DeJongh.

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Conflict of interest

Nelleke Snelder, Maurice Ahsman and Joost DeJongh were paid consultants for Takeda Development Centre Europe Ltd. before the conduct of the analysis.

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DeJongh, J., Ahsman, M. & Snelder, N. A population K-PD model analysis of long-term testosterone inhibition in prostate cancer patients undergoing intermittent androgen deprivation therapy. J Pharmacokinet Pharmacodyn 48, 465–477 (2021). https://doi.org/10.1007/s10928-020-09736-7

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