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Efficacy and safety exposure–response relationships of apalutamide in patients with metastatic castration-sensitive prostate cancer: results from the phase 3 TITAN study

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Abstract

Purpose

Apalutamide plus androgen-deprivation therapy (ADT) has been approved for treatment of patients with metastatic castration-sensitive prostate cancer (mCSPC) based on data from phase 3 TITAN study. This analysis was conducted to describe pharmacokinetics of apalutamide and N-desmethyl-apalutamide and explore relationships between apalutamide exposure and selected clinical efficacy and safety observations.

Methods

1052 patients were randomized to apalutamide + ADT (n = 525) or placebo + ADT (n = 527). A previously developed population pharmacokinetic model was applied. Cox regression analysis investigated the relationships between apalutamide exposure and overall survival (OS; n = 1004) and radiographic progression-free survival (rPFS; n = 1003). Logistic regression analysis assessed the relationships between apalutamide exposure and selected clinically relevant adverse events (n = 1051).

Results

Apalutamide + ADT treatment was efficacious in extending rPFS and OS versus placebo + ADT. Within a relatively narrow apalutamide exposure range (coefficient of variation: 22%), no statistical association was detected between rPFS, OS and apalutamide exposure quartiles. Incidence of skin rash and pruritus increased significantly with increasing apalutamide exposure.

Conclusions

Differences in apalutamide exposure were not associated with clinically relevant differences in rPFS or OS in patients with mCSPC. Patients with increased apalutamide exposure are more likely to develop skin rash and pruritus. Dose reductions may improve these adverse events, based on an individual risk–benefit approach.

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Availability of data and material

The data sharing policy of Janssen Pharmaceutical Companies of Johnson & Johnson is available at https://www.janssen.com/clinical-trials/transparency. As noted on this site, requests for access to the study data can be submitted through Yale Open Data Access [YODA] Project site at http://yoda.yale.edu.

References

  1. Rawla P (2019) Epidemiology of prostate cancer. World J Oncol 10(2):63

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Damodaran S, Lang JM, Jarrard DF (2019) Targeting metastatic hormone sensitive prostate cancer: chemohormonal therapy and new combinatorial approaches. J Urol 201(5):876–885. https://doi.org/10.1097/ju.0000000000000117

    Article  PubMed  Google Scholar 

  3. Hahn AW, Higano CS, Taplin ME, Ryan CJ, Agarwal N (2018) Metastatic castration-sensitive prostate cancer: optimizing patient selection and treatment. Am Soc Clin Oncol Educ Book Am Soc Clin Oncol Ann Meet 38:363–371. https://doi.org/10.1200/edbk_200967

    Article  Google Scholar 

  4. James ND, Sydes MR, Clarke NW, Mason MD, Dearnaley DP, Spears MR, Ritchie AW, Parker CC, Russell JM, Attard G, de Bono J, Cross W, Jones RJ, Thalmann G, Amos C, Matheson D, Millman R, Alzouebi M, Beesley S, Birtle AJ, Brock S, Cathomas R, Chakraborti P, Chowdhury S, Cook A, Elliott T, Gale J, Gibbs S, Graham JD, Hetherington J, Hughes R, Laing R, McKinna F, McLaren DB, O’Sullivan JM, Parikh O, Peedell C, Protheroe A, Robinson AJ, Srihari N, Srinivasan R, Staffurth J, Sundar S, Tolan S, Tsang D, Wagstaff J, Parmar MK (2016) Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet (London, England) 387(10024):1163–1177. https://doi.org/10.1016/s0140-6736(15)01037-5

    Article  CAS  Google Scholar 

  5. Fizazi K, Tran N, Fein L, Matsubara N, Rodriguez-Antolin A, Alekseev BY, Özgüroğlu M, Ye D, Feyerabend S, Protheroe A, De Porre P, Kheoh T, Park YC, Todd MB, Chi KN (2017) Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer. N Engl J Med 377(4):352–360. https://doi.org/10.1056/NEJMoa1704174

    Article  CAS  PubMed  Google Scholar 

  6. James ND, de Bono JS, Spears MR, Clarke NW, Mason MD, Dearnaley DP, Ritchie AWS, Amos CL, Gilson C, Jones RJ, Matheson D, Millman R, Attard G, Chowdhury S, Cross WR, Gillessen S, Parker CC, Russell JM, Berthold DR, Brawley C, Adab F, Aung S, Birtle AJ, Bowen J, Brock S, Chakraborti P, Ferguson C, Gale J, Gray E, Hingorani M, Hoskin PJ, Lester JF, Malik ZI, McKinna F, McPhail N, Money-Kyrle J, O’Sullivan J, Parikh O, Protheroe A, Robinson A, Srihari NN, Thomas C, Wagstaff J, Wylie J, Zarkar A, Parmar MKB, Sydes MR (2017) Abiraterone for prostate cancer not previously treated with hormone therapy. N Engl J Med 377(4):338–351. https://doi.org/10.1056/NEJMoa1702900

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Smith MR, Antonarakis ES, Ryan CJ, Berry WR, Shore ND, Liu G, Alumkal JJ, Higano CS, Chow Maneval E, Bandekar R, de Boer CJ, Yu MK, Rathkopf DE (2016) Phase 2 study of the safety and antitumor activity of apalutamide (ARN-509), a potent androgen receptor antagonist, in the high-risk nonmetastatic castration-resistant prostate cancer cohort. Eur Urol 70(6):963–970. https://doi.org/10.1016/j.eururo.2016.04.023

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Borno HT, Small EJ (2019) Apalutamide and its use in the treatment of prostate cancer. Fut Oncol (Lond, Engl) 15(6):591–599. https://doi.org/10.2217/fon-2018-0546

    Article  CAS  Google Scholar 

  9. Erleada [Internet]. Eur. Med. Agency. 2018. . Available from: https://www.emaeuropaeu/en/medicines/human/EPAR/erleada. Accessed November 15, 2019

  10. ERLEADATM (apalutamide) prescribing information. [Internet]. 2019. . Available from: https https://www.accessdatafdagov/drugsatfda_docs/label/2019/210951s001lblpdf. Accessed December 14, 2019

  11. US Food and Drug administration. FDA approves apalutamide for metastatic castration-sensitive prostate cancer. FDA [Internet]. 2019. Available from: http: // wwwfdagov/drugs/resources-information-approved-drugs/fda-approves-apalutamide-metastatic-castration-sensitive-prostate-cancer Accessed November 15,2019

  12. Lowrance WT, Breau RH, Chou R, Chapin BF, Crispino T, Dreicer R, Jarrard DF, Kibel AS, Morgan TM, Morgans AK, Oh WK, Resnick MJ, Zietman AL, Cookson MS (2021) Advanced prostate cancer: AUA/ASTRO/SUO guideline part I. J Urol 205(1):14–21. https://doi.org/10.1097/JU.0000000000001375

    Article  PubMed  Google Scholar 

  13. de Vries R, Jacobs F, Mannens G, Snoeys J, Cuyckens F, Chien C, Ward P (2019) Apalutamide absorption, metabolism, and excretion in healthy men, and enzyme reaction in human hepatocytes. Drug Metab Dispos 47(5):453–464. https://doi.org/10.1124/dmd.118.084517

    Article  CAS  PubMed  Google Scholar 

  14. Pérez-Ruixo C, Pérez-Blanco JS, Chien C, Yu M, Ouellet D, Pérez-Ruixo JJ, Ackaert O (2020) Population pharmacokinetics of apalutamide and its active metabolite N-desmethyl-apalutamide in healthy and castration-resistant prostate cancer subjects. Clin Pharmacokinet 59(2):229–244. https://doi.org/10.1007/s40262-019-00808-7

    Article  CAS  PubMed  Google Scholar 

  15. Chi KN, Agarwal N, Bjartell A, Chung BH, de Santana P, Gomes AJ, Given R, Juárez Soto Á, Merseburger AS, Özgüroğlu M, Uemura H, Ye D, Deprince K, Naini V, Li J, Cheng S, Yu MK, Zhang K, Larsen JS, McCarthy S, Chowdhury S (2019) Apalutamide for metastatic, castration-sensitive prostate cancer. N Engl J Med 381(1):13–24. https://doi.org/10.1056/NEJMoa1903307

    Article  CAS  PubMed  Google Scholar 

  16. Chi KN, Chowdhury S, Bjartell A, Chung BH, de Santana P, Gomes AJ, Given R, Juárez A, Merseburger AS, Özgüroğlu M, Uemura H, Ye D, Brookman-May S, Mundle SD, McCarthy SA, Larsen JS, Sun W, Bevans KB, Zhang K, Bandyopadhyay N, Agarwal N (2021) Apalutamide in patients with metastatic castration-sensitive prostate cancer: final survival analysis of the randomized, double-blind Phase III TITAN Study. J Clin Oncol. https://doi.org/10.1200/jco.20.03488

    Article  PubMed  Google Scholar 

  17. Agarwal N, McQuarrie K, Bjartell A, Chowdhury S, de Santana P, Gomes AJ, Chung BH, Özgüroğlu M, Juárez Soto Á, Merseburger AS, Uemura H, Ye D, Given R, Cella D, Basch E, Miladinovic B, Dearden L, Deprince K, Naini V, Lopez-Gitlitz A, Chi KN (2019) Health-related quality of life after apalutamide treatment in patients with metastatic castration-sensitive prostate cancer (TITAN): a randomised, placebo-controlled, phase 3 study. Lancet Oncol 20(11):1518–1530. https://doi.org/10.1016/s1470-2045(19)30620-5

    Article  CAS  PubMed  Google Scholar 

  18. Davis ID, Martin AJ, Stockler MR, Begbie S, Chi KN, Chowdhury S, Coskinas X, Frydenberg M, Hague WE, Horvath LG, Joshua AM, Lawrence NJ, Marx G, McCaffrey J, McDermott R, McJannett M, North SA, Parnis F, Parulekar W, Pook DW, Reaume MN, Sandhu SK, Tan A, Tan TH, Thomson A, Tu E, Vera-Badillo F, Williams SG, Yip S, Zhang AY, Zielinski RR, Sweeney CJ (2019) Enzalutamide with standard first-line therapy in metastatic prostate cancer. N Engl J Med 381(2):121–131. https://doi.org/10.1056/NEJMoa1903835

    Article  CAS  PubMed  Google Scholar 

  19. Smith MR, Saad F, Chowdhury S, Oudard S, Hadaschik BA, Graff JN, Olmos D, Mainwaring PN, Lee JY, Uemura H, Lopez-Gitlitz A, Trudel GC, Espina BM, Shu Y, Park YC, Rackoff WR, Yu MK, Small EJ (2018) Apalutamide treatment and metastasis-free survival in prostate cancer. N Engl J Med 378(15):1408–1418. https://doi.org/10.1056/NEJMoa1715546

    Article  CAS  PubMed  Google Scholar 

  20. Perez-Ruixo C, Ackaert O, Ouellet D, Chien C, Uemura H, Olmos D, Mainwaring P, Lee JY, Yu MK, Perez-Ruixo JJ, Smith MR, Small EJ (2020) Efficacy and safety exposure-response relationships of apalutamide in patients with nonmetastatic castration-resistant prostate cancer. Clin Cancer Res 26(17):4460–4467. https://doi.org/10.1158/1078-0432.Ccr-20-1041

    Article  CAS  PubMed  Google Scholar 

  21. Saad F, Cella D, Basch E, Hadaschik BA, Mainwaring PN, Oudard S, Graff JN, McQuarrie K, Li S, Hudgens S, Lawson J, Lopez-Gitlitz A, Yu MK, Smith MR, Small EJ (2018) Effect of apalutamide on health-related quality of life in patients with non-metastatic castration-resistant prostate cancer: an analysis of the SPARTAN randomised, placebo-controlled, phase 3 trial. Lancet Oncol 19(10):1404–1416. https://doi.org/10.1016/s1470-2045(18)30456-x

    Article  CAS  PubMed  Google Scholar 

  22. Beal S SL, Boeckmann A, Bauer R, editors. NONMEM 7.2.0 Users Guides. Ellicott City, MD: Icon Development Solutions; 1989–2011.

  23. R Development Core Team. R: a language and environment for statistical computing. Vienna: R Foundation for Statistical Computing; 2012. . Available from: https: // wwwr-projectorg/ Accessed November 15, 2019

  24. Li Z, Meredith MP, Hoseyni MS (2001) A method to assess the proportion of treatment effect explained by a surrogate endpoint. Stat Med 20(21):3175–3188. https://doi.org/10.1002/sim.984

    Article  CAS  PubMed  Google Scholar 

  25. US Food and Drug administration. Guidance for industry: Exposure-Response Relationships — Study Design, Data Analysis, and Regulatory Applications [Internet]. 2003. Available from: https :// wwwfdagov/media/71277/download Accessed November 15,2019

  26. van Nuland M, Bergman AM, Rosing H, de Vries N, Huitema ADR, Beijnen JH (2019) Exposure-response assessment of enzalutamide and its major metabolites in a real-world cohort of patients with metastatic castration-resistant prostate cancer. Pharmacotherapy 39(12):1137–1145. https://doi.org/10.1002/phar.2339

    Article  CAS  PubMed  Google Scholar 

  27. Joulia ML, Carton E, Jouinot A, Allard M, Huillard O, Khoudour N, Peyromaure M, Zerbib M, Schoemann AT, Vidal M, Goldwasser F, Alexandre J, Blanchet B (2020) Pharmacokinetic/pharmacodynamic relationship of enzalutamide and its active metabolite N-desmethyl enzalutamide in metastatic castration-resistant prostate cancer patients. Clin Genitourin Cancer 18(2):155–160. https://doi.org/10.1016/j.clgc.2019.05.020

    Article  PubMed  Google Scholar 

  28. Benoist GE, van Oort IM, Burger DM, Mehra N, van Erp NP (2020) The impact of patient characteristics on enzalutamide pharmacokinetics and how this relates to treatment toxicity and efficacy in metastatic prostate cancer patients. Cancer Chemother Pharmacol 85(4):753–760. https://doi.org/10.1007/s00280-020-04039-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Rathkopf DE, Morris MJ, Fox JJ, Danila DC, Slovin SF, Hager JH, Rix PJ, Maneval EC, Chen I, Gönen M, Fleisher M, Larson SM, Sawyers CL, Scher HI (2013) Phase I study of ARN-509, a novel antiandrogen, in the treatment of castration-resistant prostate cancer. J Clin Oncol 31(28):3525–3530. https://doi.org/10.1200/jco.2013.50.1684

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors would like to thank the patients, investigators, and their medical, nursing and laboratory staff who participated in the clinical studies included in the present work. Editorial assistance was provided by Akshada Deshpande, PhD (SIRO Clinpharm Pvt Ltd) and Namit Ghildyal, PhD (Janssen Global Services, LLC), funded by Janssen Global Services, LLC.

Funding

The clinical studies were supported by research funding from Janssen Research & Development, and the analyses presented here were supported by Janssen Research & Development.

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Author notes

  1. Huybrecht T’jollyn and Oliver Ackaert contributed equally as first author.

Authors and Affiliations

  1. Clinical Pharmacology and Pharmacometrics, Janssen Research and Development, Turnhoutseweg 30, 2340, Beerse, Belgium

    Huybrecht T’jollyn, Oliver Ackaert, Carlos Perez Ruixo & Juan-Jose Perez Ruixo

  2. Clinical Pharmacology, Hutchison MediPharma International, Florham Park, NJ, USA

    Caly Chien

  3. Janssen Research & Development, Los Angeles, USA

    Angela Lopez-Gitlitz

  4. Janssen Research and Development, Raritan, NJ, USA

    Sharon McCarthy

  5. The Urology Center of Colorado, Denver, CO, USA

    Lawrence Karsh

  6. BC Cancer and Vancouver Prostate Centre, Vancouver, Canada

    Kim Chi

  7. Guy’s, King’s, and St. Thomas’ Hospitals and the Sarah Cannon Research Institute, London, UK

    Simon Chowdhury

  8. Huntsman Cancer Institute, University of Utah, Salt Lake City, USA

    Neeraj Agarwal

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  1. Huybrecht T’jollyn
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Contributions

HT and OA were involved in development of methodology, analysis and interpretation of data and provided administrative, technical, or material support. CC contributed to the conception of the study and interpretation of data. ALG contributed to the conception of the study and supervised the study. SM contributed to the conception of the study. CPR contributed to the analysis and interpretation of data. LK, KC, SC, and NA were involved in acquisition of data. JJPR was involved in development of methodology and analysis and interpretation of data. All authors contributed to drafting, review and/or revisions of the manuscript, and all authors approved the final version of the manuscript for submission and publication.

Corresponding author

Correspondence to Oliver Ackaert.

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Conflict of interest

HT, OA, CC, ALG, SM, JJPR, and CPR: Employees of Janssen Research & Development at time of conduct of the study; CC, ALG, SM, and JJPR: Stock owners of Johnson & Johnson at time of conduct of the study. NA: Consultancy: Astellas, Astra Zeneca, Bayer, Bristol Myers Squibb, Clovis, Eisai, Eli Lilly, EMD Serono, Exelixis, Foundation Medicine, Genentech, Janssen, Merck, Nektar, Novartis, Pfizer, Pharmacyclics, and Seattle Genetics; Research funding: Astra Zeneca, Bavarian Nordic, Bayer, Bristol Myers Squibb, Calithera, Celldex, Clovis, Eisai, Eli Lilly, EMD Serono, Exelixis, Genentech, Glaxo Smith Kline, Immunomedics, Janssen, Medivation, Merck, Nektar, New Link Genetics, Novartis, Pfizer, Prometheus, Rexahn, Roche, Sanofi, Seattle Genetics, Takeda, and Tracon. KC: Honoraria: Novartis, Janssen, Astellas, Sanofi, Astra Zeneca, Roche, Daiichi Sankyo, Pfizer, and Point Biopharma; and Research funding: Novartis, Janssen, Astellas, Sanofi, Astra Zeneca, and Roche. SC: Consultancy: Clovis Oncology, Astellas Pharma, Bayer, Pfizer, and Janssen-Cilag; Honoraria: Clovis Oncology, and Novartis; Speakers’ Bureau: Pfizer; Research funding: Sanofi/Aventis. LK: Stock Owner: Swan Valley Medical; Honoraria: Astellas, Bayer, Janssen, Pfizer and Dendreon; Consultancy: 3D Biopsy, Astellas, Astra-Zeneca, Bayer, Dendreon, Ferring, Janssen, Pfizer, and Vaxiion; Speakers’ Bureau: Astellas, Bayer, Janssen, Pfizer, and Clovis; Travel, Accommodations, Expenses: Astellas, Bayer, Janssen, Pfizer, and Dendreon; Research funding: Astellas, Astra Zeneca, Bayer, BioXcel Therapeutics, Bristol Meyers Squibb, CU Optics, CUSP, Dendreon, Epizyme, Exact Sciences, Ferring, FKD, Genentech/Roche, GenomeDx, Genomic Health, Janssen, Merck, Myovant, Nucleix, OncoCell MDx, Pfizer, Pharmtech/Veru, Precision Med, QED Therapeutics, Siemens, Urogen, and Vaxiion.

Ethical approval

The study was conducted in accordance with principles for human experimentation as defined in the Declaration of Helsinki and was approved by the Human Investigational Review Board of each study center and by the Competent Authority of each country.

Consent to participate

Informed consent was obtained from each subject before enrollment in the study, after being advised of the potential risks and benefits, as well as the investigational nature of the study.

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T’jollyn, H., Ackaert, O., Chien, C. et al. Efficacy and safety exposure–response relationships of apalutamide in patients with metastatic castration-sensitive prostate cancer: results from the phase 3 TITAN study. Cancer Chemother Pharmacol 89, 629–641 (2022). https://doi.org/10.1007/s00280-022-04427-1

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