Integrating evolutionary dynamics into treatment of metastatic castrate-resistant prostate cancer

Nat Commun. 2017 Nov 28;8(1):1816. doi: 10.1038/s41467-017-01968-5.


Abiraterone treats metastatic castrate-resistant prostate cancer by inhibiting CYP17A, an enzyme for testosterone auto-production. With standard dosing, evolution of resistance with treatment failure (radiographic progression) occurs at a median of ~16.5 months. We hypothesize time to progression (TTP) could be increased by integrating evolutionary dynamics into therapy. We developed an evolutionary game theory model using Lotka-Volterra equations with three competing cancer "species": androgen dependent, androgen producing, and androgen independent. Simulations with standard abiraterone dosing demonstrate strong selection for androgen-independent cells and rapid treatment failure. Adaptive therapy, using patient-specific tumor dynamics to inform on/off treatment cycles, suppresses proliferation of androgen-independent cells and lowers cumulative drug dose. In a pilot clinical trial, 10 of 11 patients maintained stable oscillations of tumor burdens; median TTP is at least 27 months with reduced cumulative drug use of 47% of standard dosing. The outcomes show significant improvement over published studies and a contemporaneous population.

Trial registration: NCT02415621.

Publication types

  • Clinical Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androgens
  • Androstenes / administration & dosage
  • Androstenes / pharmacology*
  • Androstenes / therapeutic use*
  • Disease Progression
  • Humans
  • Male
  • Models, Theoretical
  • Neoplasm Metastasis / drug therapy
  • Pilot Projects
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms, Castration-Resistant / drug therapy*
  • Steroid 17-alpha-Hydroxylase
  • Testosterone
  • Time Factors
  • Treatment Failure
  • Treatment Outcome


  • Androgens
  • Androstenes
  • Testosterone
  • CYP17A1 protein, human
  • Steroid 17-alpha-Hydroxylase
  • abiraterone

Associated data