title: Correlation between Prostate-Specific Antigen Kinetics and Overall Survival in Abiraterone Acetate-Treated Castration-Resistant Prostate Cancer Patients.
abstract: OBJECTIVE
  We constructed a biomarker-survival modeling framework to explore the relationship between prostate-specific antigen (PSA) kinetics and overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC) patients following oral administration of 1,000 mg/day of abiraterone acetate (AA).
  
  
  METHODS
  The PSA-survival modeling framework was based on data from two phase III studies, COU-AA-301 (chemotherapy pretreated, n = 1,184) and COU-AA-302 (chemotherapy naïve, n = 1,081), and included a mixed-effects tumor growth inhibition model and a Cox proportional hazards survival model.
  
  
  RESULTS
  The effect of AA on PSA kinetics was significant (P < 0.0001) and comparable between the chemotherapy-naïve and -pretreated patients. PSA kinetics [e.g., PSA nadir, PSA response rate (≥30%, 50%, and 90%), time to PSA progression, PSA doubling time (PSADT)] were highly associated with OS in both populations. The model-based posttreatment PSADT had the strongest association with OS (HR ∼0.9 in both populations). The models could accurately predict survival outcomes. After adjusting for PSA kinetic endpoints, the treatment effect of AA on survival was no longer statistically significant in both studies, and the Prentice criteria of surrogacy were met for the PSA kinetic endpoints. A strong correlation was also observed between PSA and radiographic progression-free survival.
  
  
  CONCLUSIONS
  The analysis revealed a consistent treatment effect of AA on PSA kinetics and strong associations between PSA kinetics and OS in chemotherapy-pretreated and -naïve patients, thereby providing a rationale to consider PSA kinetics as surrogacy endpoints to indicate clinical benefit in AA-treated patients with mCRPC regardless of chemotherapy treatment.
authors.affiliation: Janssen Research & Development, Raritan, New Jersey. sxu26@its.jnj.com.
authors.forename: Xu S
authors.initials: XS
authors.lastname: Xu
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California.
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Ryan
authors.affiliation: Janssen Research & Development, Beerse, Belgium.
authors.forename: Kim
authors.initials: K
authors.lastname: Stuyckens
authors.affiliation: Harvard Medical School, Massachusetts General Hospital Cancer Center, Boston, Massachusetts.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Smith
authors.affiliation: University of Montreal, Montreal, Quebec, Canada.
authors.forename: Fred
authors.initials: F
authors.lastname: Saad
authors.affiliation: Janssen Research & Development, Los Angeles, California.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Griffin
authors.affiliation: Janssen Research & Development, Raritan, New Jersey.
authors.forename: Youn C
authors.initials: YC
authors.lastname: Park
authors.affiliation: Janssen Research & Development, Los Angeles, California.
authors.forename: Margaret K
authors.initials: MK
authors.lastname: Yu
authors.affiliation: Janssen Research & Development, Beerse, Belgium.
authors.forename: An
authors.initials: A
authors.lastname: Vermeulen
authors.affiliation: Janssen Research & Development, Beerse, Belgium.
authors.forename: Italo
authors.initials: I
authors.lastname: Poggesi
authors.affiliation: Janssen Research & Development, Raritan, New Jersey.
authors.forename: Partha
authors.initials: P
authors.lastname: Nandy
mesh_terms: D000069501:Abiraterone Acetate / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000097:blood*; D004311:Double-Blind Method; D019008:Drug Resistance, Neoplasm; D006801:Humans; D053208:Kaplan-Meier Estimate; D007700:Kinetics; D008297:Male; D016016:Proportional Hazards Models; D017430:Prostate-Specific Antigen / Q000097:blood*; D064129:Prostatic Neoplasms, Castration-Resistant / Q000097:blood / Q000188:drug therapy* / Q000401:mortality
chemical_list: D000970:Antineoplastic Agents; D018931:Antineoplastic Agents, Hormonal; D014408:Biomarkers, Tumor; D017430:Prostate-Specific Antigen; D000069501:Abiraterone Acetate