Janssen Research & Development, Raritan, New Jersey.
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California.
Clin Cancer Res. 2015 Jul 15;21(14):3170-7. doi: 10.1158/1078-0432.CCR-14-1549. Epub 2015 Mar 31.
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).
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.
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.
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.
我们构建了一个生物标志物生存建模框架，以探索在转移性去势抵抗性前列腺癌（mCRPC）患者口服醋酸阿比特龙 1000mg/天后，前列腺特异性抗原（PSA）动力学与总生存（OS）之间的关系。
PSA 生存建模框架基于两项 III 期研究（COU-AA-301，化疗预处理，n=1184；COU-AA-302，化疗初治，n=1081）的数据，包括混合效应肿瘤生长抑制模型和 Cox 比例风险生存模型。
AA 对 PSA 动力学的影响具有统计学意义（P<0.0001），且在化疗初治和预处理患者中具有可比性。PSA 动力学（如 PSA 最低值、PSA 反应率（≥30%、50%和 90%）、PSA 进展时间、PSA 倍增时间（PSADT））在两个人群中与 OS 高度相关。基于模型的治疗后 PSADT 与 OS 相关性最强（两个人群中的 HR 约为 0.9）。模型能够准确预测生存结局。调整 PSA 动力学终点后，AA 对生存的治疗效果在两项研究中均不再具有统计学意义，且 PSA 动力学终点符合替代终点的 Prentice 标准。PSA 与放射性无进展生存期之间也存在很强的相关性。
分析表明 AA 对 PSA 动力学的治疗效果一致，且 PSA 动力学与 OS 在化疗预处理和初治患者之间存在强烈关联，因此为考虑 PSA 动力学作为 AA 治疗 mCRPC 患者的替代终点提供了依据，无论是否接受化疗，均可指示临床获益。
