Figure 3. Adaptive Strategies for Metastatic Castration-Sensitive Prostate Cancer.

Computer simulations of treatment outcomes using methods outlined in Gallaher et al¹⁹ and similar to the models used to design ongoing clinical trials.¹¹ The subpopulations are color coded, and the area of each simulation represents total tumor burden. The model assumes a newly presented prostate cancer metastasis with different initial distributions of resistant and sensitive subpopulations. A, A pretreatment biopsy finds that 95% of the cancer cells express androgen receptor (AR) but not CYP17A, 3% are both AR and CYP17A1 positive, and 2% are AR negative. The frequency of the cell populations suggests that the fitness of the AR-positive phenotype is much higher than AR-negative or CYP17A phenotypes. In the top row, continuous androgen deprivation therapy (ADT) rapidly selects for resistant populations with the dominant clones overexpressing CYP17A, leading to tumor progression. An alternative approach replaces continuous ADT with the protocol used in Zhang et al.¹¹ Androgen deprivation therapy is administered until the tumor burden is reduced by half (based on prostate-specific antigen measurements) and then withdrawn. In the absence of therapy, the fitness advantage of the AR-positive cells allows them to grow at the expense of the resistant populations, thus prolonging tumor control with ADT. B, The initial biopsy shows the AR-positive phenotype to be 65% of the cells, with 35% CYP17A1 and 10% AR negative. Because the relative fitness advantage of the AR-positive cells is not as great as in A (based on the higher relative fractions of AR-negative and CYP17A1 phenotypes), the adaptive strategy in A will not be as successful (simulation not shown). An alternative evolutionary strategy in the lower row alternates treatments directed against AR-positive (ADT) and CYP17A1 (abiraterone) cells, as well as treatment holidays to control the AR-positive and CYP17A1 populations while maximally reducing the growth of the AR-negative cells. Many other strategies (eg, addition of docetaxel) are available, and similar simulations can allow the treating physician to devise a patient-specific protocol that optimizes outcomes. Each arrowhead represents a treatment period. The drug used is above the arrowhead (red arrowheads indicate ADT; blue arrowheads, abiraterone). No specified drug indicates a treatment holiday (black arrowheads).