Multidrug cancer therapy in metastatic castrate-resistant prostate cancer: An evolution-based strategy

Abstract

Purpose: Integration of evolutionary dynamics into system-Results: Simulations from the mathematical model demic therapy for metastatic cancers can prolong tumor control onstrate that the primary–secondary approach increases time compared with standard maximum tolerated dose (MTD) to progression (TTP) compared with conventional strategies in strategies. Prior investigations have focused on monotherapy, which drugs are administered without regard to evolutionary but many clinical cancer treatments combine two or more dynamics. We apply our model to an ongoing adaptive ther-drugs. Optimizing the evolutionary dynamics in multidrug apy clinical trial of evolution-based administration of abir-therapy is challenging because of the complex cellular inter-aterone to treat metastatic castrate-resistant prostate cancer. actions and the large parameter space of potential variations in Model simulations, parameterized with data from individual drugs, doses, and treatment schedules. However, multidrug patients who progressed, demonstrate that strategic applica-therapy also represents an opportunity to further improve tion of docetaxel during abiraterone therapy would have outcomes using evolution-based strategies. significantly increased their TTP. Experimental Design: We examine evolution-based strat-Conclusions: Mathematical models can integrate evolu-egies for two-drug therapy and identify an approach that tionary dynamics into multidrug cancer clinical trials. This divides the treatment drugs into primary and secondary roles. has the potential to improve outcomes and to develop clinical The primary drug has the greatest efficacy and/or lowest trials in which these mathematical models are also used to toxicity. The secondary drug is applied solely to reduce the estimate the mechanism(s) of treatment failure and explore resistant population to the primary drug. alternative strategies to improve outcomes in future trials.