Modeling the Relationship Between Exposure to Abiraterone and Prostate-Specific Antigen Dynamics in Patients with Metastatic Castration-Resistant Prostate Cancer.
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.



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.



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 (kdec) 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 kdec. 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.



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.
Janssen Research & Development, 920 Route 202, Raritan, NJ, 08869, USA. sxu26@its.jnj.com.
Xu Steven
XS
Xu
Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA.
Charles J
CJ
Ryan
Janssen Research & Development, a Division of Janssen Pharmaceutica NV, Beerse, Belgium.
Kim
K
Stuyckens
Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA.
Matthew R
MR
Smith
University of Montréal, Montréal, QC, Canada.
Fred
F
Saad
Janssen Research & Development, Los Angeles, CA, USA.
Thomas W
TW
Griffin
Janssen Research & Development, 920 Route 202, Raritan, NJ, 08869, USA.
Youn C
YC
Park
Janssen Research & Development, Los Angeles, CA, USA.
Margaret K
MK
Yu
Janssen Research & Development, a Division of Janssen Pharmaceutica NV, Beerse, Belgium.
Peter
P
De Porre
Janssen Research & Development, a Division of Janssen Pharmaceutica NV, Beerse, Belgium.
An
A
Vermeulen
Janssen Research & Development, a Division of Janssen Pharmaceutica NV, Beerse, Belgium.
Italo
I
Poggesi
Janssen Research & Development, 920 Route 202, Raritan, NJ, 08869, USA.
Partha
P
Nandy
D000069501:Abiraterone Acetate / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D004359:Drug Therapy, Combination; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000097:blood; D008297:Male; D008954:Models, Biological; D011241:Prednisone / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D017430:Prostate-Specific Antigen / Q000187:drug effects*; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy*; D012720:Severity of Illness Index; D012959:Socioeconomic Factors; D013739:Testosterone / Q000097:blood
D013739:Testosterone; D007770:L-Lactate Dehydrogenase; D017430:Prostate-Specific Antigen; D000069501:Abiraterone Acetate; D011241:Prednisone