Xu Steven Xu1, Charles J Ryan2, Kim Stuyckens3, Matthew R Smith4, Fred Saad5, Thomas W Griffin6, Youn C Park7, Margaret K Yu6, Peter De Porre3, An Vermeulen3, Italo Poggesi3, Partha Nandy7. 1. Janssen Research & Development, 920 Route 202, Raritan, NJ, 08869, USA. sxu26@its.jnj.com. 2. Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA. 3. Janssen Research & Development, a Division of Janssen Pharmaceutica NV, Beerse, Belgium. 4. Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA. 5. University of Montréal, Montréal, QC, Canada. 6. Janssen Research & Development, Los Angeles, CA, USA. 7. Janssen Research & Development, 920 Route 202, Raritan, NJ, 08869, USA.
Abstract
BACKGROUND AND OBJECTIVES: Recent analysis revealed strong associations between prostate-specific antigen (PSA) dynamics and overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC) and supported PSA dynamics as bridging surrogacy endpoints for clinical benefit from treatment with abiraterone acetate plus prednisone. This analysis aimed to investigate the abiraterone exposure-PSA dynamics relationship in mCRPC. METHODS: Abiraterone pharmacokinetics-PSA models were constructed using data from the COU-AA-301 (chemotherapy-pretreated) and COU-AA-302 (chemotherapy-naïve) trials comparing abiraterone acetate 1000 mg/day plus prednisone 5 mg twice daily with prednisone alone in mCRPC. The drug effect-PSA dynamics relationship was modeled as a function of selected pharmacokinetic measures. The influences of baseline demographic variables, laboratory values, and disease status on PSA dynamics were assessed. RESULTS: A tumor growth inhibition model best described PSA dynamics post-treatment with abiraterone acetate. Abiraterone acetate treatment in chemotherapy-pretreated and chemotherapy-naïve patients increased the PSA decay rate (k dec) to the same extent (1.28-fold, 95 % confidence interval [CI] 0.58-1.98; and 0.93-fold, 95 % CI 0.6-1.27, respectively). Lower baseline lactate dehydrogenase and higher baseline testosterone significantly increased k dec. Findings from our analysis suggest a maximum-effect relationship between abiraterone trough concentration and PSA dynamics in both patient populations. The majority of patients had a steady-state trough concentration greater than the estimated half maximal effective concentration. CONCLUSION: The model appropriately described the exposure-response relationship between abiraterone and PSA dynamics in chemotherapy-pretreated and chemotherapy-naïve patients following oral administration of abiraterone acetate.
BACKGROUND AND OBJECTIVES: Recent analysis revealed strong associations between prostate-specific antigen (PSA) dynamics and overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC) and supported PSA dynamics as bridging surrogacy endpoints for clinical benefit from treatment with abiraterone acetate plus prednisone. This analysis aimed to investigate the abiraterone exposure-PSA dynamics relationship in mCRPC. METHODS:Abiraterone pharmacokinetics-PSA models were constructed using data from the COU-AA-301 (chemotherapy-pretreated) and COU-AA-302 (chemotherapy-naïve) trials comparing abiraterone acetate 1000 mg/day plus prednisone 5 mg twice daily with prednisone alone in mCRPC. The drug effect-PSA dynamics relationship was modeled as a function of selected pharmacokinetic measures. The influences of baseline demographic variables, laboratory values, and disease status on PSA dynamics were assessed. RESULTS: A tumor growth inhibition model best described PSA dynamics post-treatment with abiraterone acetate. Abiraterone acetate treatment in chemotherapy-pretreated and chemotherapy-naïve patients increased the PSA decay rate (k dec) to the same extent (1.28-fold, 95 % confidence interval [CI] 0.58-1.98; and 0.93-fold, 95 % CI 0.6-1.27, respectively). Lower baseline lactate dehydrogenase and higher baseline testosterone significantly increased k dec. Findings from our analysis suggest a maximum-effect relationship between abiraterone trough concentration and PSA dynamics in both patient populations. The majority of patients had a steady-state trough concentration greater than the estimated half maximal effective concentration. CONCLUSION: The model appropriately described the exposure-response relationship between abiraterone and PSA dynamics in chemotherapy-pretreated and chemotherapy-naïve patients following oral administration of abiraterone acetate.
Authors: Daniel C Danila; Michael J Morris; Johann S de Bono; Charles J Ryan; Samuel R Denmeade; Matthew R Smith; Mary-Ellen Taplin; Glenn J Bubley; Thian Kheoh; Christopher Haqq; Arturo Molina; Aseem Anand; Michael Koscuiszka; Steve M Larson; Lawrence H Schwartz; Martin Fleisher; Howard I Scher Journal: J Clin Oncol Date: 2010-02-16 Impact factor: 44.544
Authors: Alison H M Reid; Gerhardt Attard; Daniel C Danila; Nikhil Babu Oommen; David Olmos; Peter C Fong; L Rhoda Molife; Joanne Hunt; Christina Messiou; Christopher Parker; David Dearnaley; Joost F Swennenhuis; Leon W M M Terstappen; Gloria Lee; Thian Kheoh; Arturo Molina; Charles J Ryan; Eric Small; Howard I Scher; Johann S de Bono Journal: J Clin Oncol Date: 2010-02-16 Impact factor: 44.544
Authors: Wilfred D Stein; James L Gulley; Jeff Schlom; Ravi A Madan; William Dahut; William D Figg; Yang-Min Ning; Phil M Arlen; Doug Price; Susan E Bates; Tito Fojo Journal: Clin Cancer Res Date: 2010-11-24 Impact factor: 12.531
Authors: Charles J Ryan; Matthew R Smith; Karim Fizazi; Fred Saad; Peter F A Mulders; Cora N Sternberg; Kurt Miller; Christopher J Logothetis; Neal D Shore; Eric J Small; Joan Carles; Thomas W Flaig; Mary-Ellen Taplin; Celestia S Higano; Paul de Souza; Johann S de Bono; Thomas W Griffin; Peter De Porre; Margaret K Yu; Youn C Park; Jinhui Li; Thian Kheoh; Vahid Naini; Arturo Molina; Dana E Rathkopf Journal: Lancet Oncol Date: 2015-01-16 Impact factor: 41.316
Authors: Rong Hu; Thomas A Dunn; Shuanzeng Wei; Sumit Isharwal; Robert W Veltri; Elizabeth Humphreys; Misop Han; Alan W Partin; Robert L Vessella; William B Isaacs; G Steven Bova; Jun Luo Journal: Cancer Res Date: 2009-01-01 Impact factor: 12.701
Authors: Gerhardt Attard; Alison H M Reid; Timothy A Yap; Florence Raynaud; Mitch Dowsett; Sarah Settatree; Mary Barrett; Christopher Parker; Vanessa Martins; Elizabeth Folkerd; Jeremy Clark; Colin S Cooper; Stan B Kaye; David Dearnaley; Gloria Lee; Johann S de Bono Journal: J Clin Oncol Date: 2008-07-21 Impact factor: 44.544
Authors: C J Ryan; W Peng; T Kheoh; E Welkowsky; C M Haqq; D W Chandler; H I Scher; A Molina Journal: Prostate Cancer Prostatic Dis Date: 2014-03-18 Impact factor: 5.554
Authors: B Ribba; N H Holford; P Magni; I Trocóniz; I Gueorguieva; P Girard; C Sarr; M Elishmereni; C Kloft; L E Friberg Journal: CPT Pharmacometrics Syst Pharmacol Date: 2014-05-07
Authors: Guillemette E Benoist; Eric van der Meulen; Floor J E Lubberman; Winald R Gerritsen; Tineke J Smilde; Jack A Schalken; Jan H Beumer; David M Burger; Nielka P van Erp Journal: Biomed Chromatogr Date: 2017-05-16 Impact factor: 1.902
Authors: Emmy Boerrigter; Guillemette E Benoist; Joanneke K Overbeek; Rogier Donders; Niven Mehra; Inge M van Oort; Rob Ter Heine; Nielka P van Erp Journal: Br J Clin Pharmacol Date: 2021-10-08 Impact factor: 3.716
Authors: Guillemette E Benoist; Maarten J van der Doelen; Rob Ter Heine; Nielka P van Erp; Niven Mehra Journal: Br J Clin Pharmacol Date: 2018-02-21 Impact factor: 4.335
Authors: Floor J E Lubberman; Guillemette E Benoist; Winald Gerritsen; David M Burger; Niven Mehra; Paul Hamberg; Inge van Oort; Nielka P van Erp Journal: Cancer Chemother Pharmacol Date: 2019-09-12 Impact factor: 3.333
Authors: Emmy Boerrigter; Guillemette E Benoist; Inge M van Oort; Gerald W Verhaegh; Onno van Hooij; Levi Groen; Frank Smit; Irma M Oving; Pieter de Mol; Tineke J Smilde; Diederik M Somford; Niven Mehra; Jack A Schalken; Nielka P van Erp Journal: Mol Oncol Date: 2021-05-29 Impact factor: 6.603