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Prostate Cancer Lab #7: Drug Combinations and Off-Label Drugs

Meeting Summary

“We have done many simulations on genomic data, and all of them show that using more drugs is better than fewer drugs, and less concentration is better than more concentration.” – Saed Sayad

In our meeting on May 4 we discussed the strengths and weaknesses of using combinations of approved drugs to better fit a patient’s unique molecular profile and thereby achieve better outcomes, and the use of off-label drugs targeted at molecular biomarkers. The main concerns were around toxicity from combinations and the possibility that off-label drugs might behave differently in different disease contexts (something that worked in one cancer might not in another). 

(For more background, please see the notes from our meeting #5 on April 20, where Ally Perlina, Chief Science Officer at CureMatch, presented combinations of approved drugs that are the best fit for advanced prostate cancer patient Brian McCloskey based on his cancer’s unique molecular profile.)

Should a combination of drugs be administered sequentially vs. all at once?

  • Leaving mutations untargeted enables progression.
  • Higher matching results in better outcomes.

Are drug combinations more expensive than monotherapies?

  • Providing the molecular rationale is evidence that can persuade payers to reimburse.
  • Alternative drugs are identified that affect the same pathway. Some will be cheaper yet have the same effect.
  • Dosages for drugs within a combination can be reduced vs. when the drug is administered as a monotherapy.
  • By targeting the molecular profile, better outcomes are achieved, which are cheaper.

Do you have any experience or data in having patients cycle on and off drugs?

  • We don’t.
  • It’s hard enough getting physicians to consider drug combinations.

Do you include therapies that are in clinical trials in your recommendations?

  • We don’t.
  • Adding drugs that are in clinical trials would be too complicated and too risky for most physicians

Is there evidence to support using a MEK inhibitor for a BRAF mutation?

  • I will have to look it up to find the evidence.
  • It depends on the situation whether to use the indirect MEK pathway.

Is off-label use of a drug potentially a mistake? What about the example of a BRAF drug not working in colon cancer?

  • If a drug that targets a mutation didn’t work, it was because the whole molecular picture wasn’t taken into account.

How should a physician manage doses with a novel drug combination?

  • There is dosage advice provided in the report.
  • We will provide report reviews on request.

Brian McCloskey asked about on-off cycling through drugs, an idea promoted by Dr. Bob Gatenby.

Saed Sayad and Dr. John Laird observed that our guidelines, which push to maximum tolerated doses, are driving cancers to resistance – a flawed strategy.

Saed Sayad presented a hypothesis that RCC1 could be a biomarker to predict cancer recurrence after prostate surgery.

Do you have any feedback on drug combinations and off-label uses of approved drugs?

Meeting Recording

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