OnCo
ideasIdea

Evolution-guided 'adaptive therapy' dosing tested in randomised phase 2 trials

Rather than hitting the tumour as hard as possible, adaptive therapy uses just enough drug to keep it in check, letting drug-sensitive cells suppress resistant ones. A small prostate cancer pilot was promising; randomised trials are needed.

Adaptive therapy modulates dosing on tumour burden (PSA, imaging or ctDNA), pausing when burden falls below a threshold and resuming when it rises, to maintain a population of sensitive cells that compete with resistant clones. A pilot in metastatic castration-resistant prostate cancer using abiraterone showed prolonged time to progression versus historical controls with roughly half the cumulative drug. The proposal is randomised phase 2 trials in prostate, melanoma and ovarian cancer with pre-specified adaptive algorithms.

Hypothesis
Adaptive dosing will extend time to progression by at least 30 percent relative to continuous dosing in at least one of three settings tested, with lower cumulative drug exposure.
Rationale
Evolutionary game theory and mathematical models of competition between sensitive and resistant clones predict that maximum-dose therapy selects fastest for resistance; the pilot data are consistent with the model.
What would test it
Three randomised phase 2 trials (n about 100 each) of adaptive versus continuous dosing with time to progression as the primary endpoint and cumulative dose and QoL as secondaries.
Maturity
early clinical
Who has to act
research
Cost to try
Medium ($1M to $50M)
Years to first evidence
4
Bottlenecks it attacks
  • Wrong doses · Most drug doses were chosen as the highest a person can tolerate, which is often more than they need.
  • Acquired resistance to every therapy · Nearly every targeted therapy stops working within months to a few years as the tumour adapts.

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