Abiraterone acetate (AA) has been proven effective for metastatic castration-resistant prostate cancer (mCRPC), and it has been proposed that adaptive AA may reduce toxicity and prolong time to progression, when compared to continuous AA. We developed a simple quantitative model of prostate-specific antigen (PSA) dynamics to evaluate prostate cancer (PCa) stem cell enrichment as a plausible driver of AA treatment resistance. The model incorporated PCa stem cells, non-stem PCa cells and PSA dynamics during adaptive therapy. A leave-one-out analysis was used to calibrate and validate the model against longitudinal PSA data from 16 mCRPC patients receiving adaptive AA in a pilot clinical study. Early PSA treatment response dynamics were used to predict patient response to subsequent treatment. We extended the model to incorporate metastatic burden and also investigated the survival benefit of adding concurrent chemotherapy for patients predicted to become resistant. Model simulations demonstrated PCa stem cell self-renewal as a plausible driver of resistance to adaptive therapy. Evolutionary dynamics from individual treatment cycles combined with metastatic burden measurements predicted patient response with 81% accuracy (specificity=92%, sensitivity=50%). In those patients predicted to progress, simulations of the addition of concurrent chemotherapy suggest a benefit between 1% and 11% reduction in probability of progression when compared to adaptive AA alone. This study developed the first mCRPC patient-specific mathematical model to use early PSA treatment response dynamics to predict subsequent responses to adaptive AA, demonstrating the putative value of integrating mathematical modeling into clinical decision making.

醋酸阿比特龙 (AA) 已被证明对转移性去势抵抗性前列腺癌 (mCRPC) 有效，并且有人提出，与连续性 AA 相比，适应性 AA 可降低毒性并延长进展时间。我们开发了一个简单的前列腺特异性抗原 (PSA) 动力学定量模型，以评估前列腺癌 (PCa) 干细胞富集作为 AA 治疗抗性的可能驱动因素。该模型在适应性治疗期间结合了 PCa 干细胞、非干 PCa 细胞和 PSA 动力学。在一项试点临床研究中，使用留一法分析来校准和验证来自 16 名接受适应性 AA 的 mCRPC 患者的纵向 PSA 数据的模型。早期 PSA 治疗反应动力学用于预测患者对后续治疗的反应。我们扩展了模型以纳入转移负担，并研究了为预计会产生耐药性的患者添加同步化疗的生存益处。模型模拟表明，PCa 干细胞的自我更新是对适应性治疗产生耐药性的可能驱动因素。个体治疗周期的进化动力学与转移性负担测量相结合，以 81% 的准确度预测患者反应（特异性 = 92%，敏感性 = 50%）。在那些预计会进展的患者中，与单独的适应性 AA 相比，添加同步化疗的模拟表明进展概率降低了 1% 至 11%。本研究开发了第一个 mCRPC 患者特异性数学模型，使用早期 PSA 治疗反应动力学来预测对适应性 AA 的后续反应，