TY - JOUR
T1 - Correlation between prostate-specific antigen kinetics and overall survival in abiraterone acetate-treated castration-resistant prostate cancer patients
AU - Xu, Xu S.
AU - Ryan, Charles J.
AU - Stuyckens, Kim
AU - Smith, Matthew R.
AU - Saad, Fred
AU - Griffin, Thomas W.
AU - Park, Youn C.
AU - Yu, Margaret K.
AU - Vermeulen, An
AU - Poggesi, Italo
AU - Nandy, Partha
N1 - Publisher Copyright:
© 2015 American Association for Cancer Research.
PY - 2015/7/15
Y1 - 2015/7/15
N2 - Purpose: 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). Experimental Design: The PSA-survival modeling framework was based on data from two phase III studies, COU-AA-301 (chemotherapypretreated, 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.
AB - Purpose: 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). Experimental Design: The PSA-survival modeling framework was based on data from two phase III studies, COU-AA-301 (chemotherapypretreated, 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.
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U2 - 10.1158/1078-0432.CCR-14-1549
DO - 10.1158/1078-0432.CCR-14-1549
M3 - Article
C2 - 25829400
AN - SCOPUS:84942875101
SN - 1078-0432
VL - 21
SP - 3170
EP - 3177
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 14
ER -
