Does “AR gain” affect responses to drugs like abiraterone in men with CRPC?

Perhaps unsurprisingly, it appears to be true that “AR gain” (see below) does indeed lower overall survival (OS) and progression-free survival (PFS) rates among men with castration-resistant prostate cancer (mCRPC).

So-called “AR gain” is defined as an increase in the number of androgen receptors detectable in the cell-free DNA (cfDNA) of men with prostate cancer. It has long been hypothesized that AR gain could potentially be used to predict treatment response to androgen receptor signaling inhibitors (ARSIs; i.e., drugs like abiraterone acetate / Zytiga and enzalutamide / Xtandi) in  men with CRPC.

Tolmeijer et al. reviewed the available data to see if they were able to provide insight into the potential of cfDNA-based AR gain as a predictive biomarker to guide the appropriate choice of therapy for selected patients with CRPC. To do this, they carried out a meta-analysis of data from 16 studies, all published prior to November 2019 and including more than 1,000 patients.

Here is a summary of the key results of their analysis.

When the patients were treated with one or more ARSIs …

  • PFS and OS were significantly worse for the patients who had AR gain compared to those who had no AR gain
    • For PFS, the hazard ratio (HR) = 2.33 (P < 0.0001)
    • For OS, HR = 3.83
  • This result was independent of the line and type of ARSI used

When the patients had been treated with first-line docetaxel or second-line or third-line cabazitaxel chemotherapy …

  • PFS and OS appeared to have been unaffected by AR gain, despite a higher disease burden in patients with AR gain
  • AR gain was associated with reduced response when patients were treated with later lines of docetaxel

Tolmeijer et al. conclude that

In patients with CRPC, cfDNA-based AR gain is associated with a worse response to ARSIs. The effect on patients who are receiving taxane chemotherapy seems to be dependent on the type and line, although data are limited. Future prospective studies are essential to assess the true potential of cfDNA-based AR gain as a minimally invasive biomarker to guide therapy choice.

The authors’ conclusion makes two key points. First, that there does appear to be good evidence that AR gain is associated with  less good responses to ARSIs. Second. that in order to confirm this, it will be important to conduct appropriately designed, prospective, randomized clinical trials. We point this out solely to emphasize the way in which clinical “science” actually works:

  1. Define an idea (an hypothesis) that you would like to test and then confirm.
  2. See if there are data that can be used to support this hypothesis already.
  3. Confirm the hypothesis by conducting well designed and implemented trials.

Tolmeijer and her colleagues have carried out steps 1 and 2 above. When and how step 3 can be conducted may prove more difficult — unless the FDA or some other regulatory authority insists that it be built into trials of some future, new ARSI.

3 Responses

  1. More and more I hear about men with more advanced disease considering rechallenging their disease with drugs that have previously failed them … even with first-line anti-androgens like bicalutamide. And talk about how the AR receptors may be rejuvenated by chemo treatment.

    Does anyone know of evidential studies on “rechallenging”?

  2. The only studies I know of are at Johns Hopkins. They are trying to use BAT to rechallenge (the RESTORE trial). They found that it only works with enzalutamide but not much with abiraterone:

    They also observed that taxanes can sometimes reverse AR-V7 mutations (in 6 of 14 patients):

    Niclosamide has been proposed as a co-therapy to prevent resistance to Xtandi. Researchers at the University of Washington (in Seattle) were unable to find an effective dose, but the University of California at Davis has a couple of ongoing trials of a new formulation:

    There is also a novel drug, CPI-1205, in trial:

    And indomethacin is also being tested in a clinical trial at UCDavis:

  3. Tx Allen … very helpful!

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