Range-Bounded Adaptive Therapy in Metastatic Prostate Cancer

SIMPLE SUMMARY: The success of adaptive therapy (AT), whereby treatment is cycled on and off using patient-specific treatment triggers, is hypothesized to be due to the competitive suppression of the resistant population by the sensitive population. There may exist a subset of patients who might benefit from slight modifications to AT, whereby treatment is initially delayed and subsequently cycled to remain between predetermined, patient-specific bounds, i.e., range-bounded adaptive therapy (RBAT). Here, we investigate the potential benefit of RBAT using a previously calibrated and validated model of stem cell and prostate-specific antigen dynamics. Simulations show that RBAT can further extend time to progression, while reducing the cumulative dose received. By delaying treatment, competition is further leveraged between the sensitive and resistant populations and treatment response can be prolonged. ABSTRACT: Adaptive therapy with abiraterone acetate (AA), whereby treatment is cycled on and off, has been presented as an alternative to continuous therapy for metastatic castration resistant prostate cancer (mCRPC). It is hypothesized that cycling through treatment allows sensitive cells to competitively suppress resistant cells, thereby increasing the amount of time that treatment is effective. It has been proposed that there exists a subset of patients for whom this competition can be enhanced through slight modifications. Here, we investigate how adaptive AA can be modified to extend time to progression using a simple mathematical model of stem cell, non-stem cell, and prostate-specific antigen (PSA) dynamics. The model is calibrated to longitudinal PSA data from 16 mCRPC patients undergoing adaptive AA in a pilot clinical study at Moffitt Cancer Center. Model parameters are then used to simulate range-bounded adaptive therapy (RBAT) whereby treatment is modulated to maintain PSA levels between pre-determined patient-specific bounds. Model simulations of RBAT are compared to the clinically applied adaptive therapy and show that RBAT can further extend time to progression, while reducing the cumulative dose patients received in 11/16 patients. Simulations also show that the cumulative dose can be reduced by up to 40% under RBAT. Through small modifications to the conventional adaptive therapy design, our study demonstrates that RBAT offers the opportunity to improve patient care, particularly in those patients who do not respond well to conventional adaptive therapy.