Is there a subset of CRPC patients who may respond well to checkpoint inhibition?

A paper in the journal Oncotarget has suggested that patients who have progressed on treatment with enzalutamide (Xtandi) may be good candidates for treatment with one of the checkpoint inhibitors like pembrolizumab (Keytruda), nivolumab (Opdivo), or even ipilimumab (Yervoy).

What the authors of this paper (by Bishop et al.) have actually shown is that

  • Clinically relevant targets for checkpoint inhibitors (e.g., PD-1, PD-L1, PD-L2, and CTLA-4) seem to be “upregulated” in patients who have castration-resistant prostate cancer (CRPC) and who have progressed after treatment with enzalutamide.
  • In a pre-clinical animal (mouse) model, there were significantly higher levels of circulating PD-L1/2-positive dendritic cells in the mice that had enzalutamide-resistant tumors compared to just castration-resistant tumors (along with other supportive findings).

Now it is reasonable, on the basis of these findings, to think that men who carry enzalutamide-resistant tumors might be more responsive to treatment with checkpoint inhibitors than men who have CRPC but have not been treated with enzalutamide. However, we also know that things that one observes in the laboratory all too often do not seem to “translate” into actual clinical practice.

Before we start to think that (just as an example), men diagnosed with non-metastatic, castration-resistant prostate cancer (nmCRPC), who are treated with enzalutamide, and who progress on such treatment, should then be treated with a drug like pembrolizumab, we are going to need some rather more robust data based from the laboratory and from clinical trials, because there are too many things that we don’t know yet? They include:

  • Whether this finding is unique to enzalutamide or whether it might also occur in patients who are refractory to treatment with the other super-antiandrogen, apalutamide (Erleada)
  • Whether, in men with prostate cancer, there is actually any direct correlation between the levels of expression of targets for checkpoint inhibition and the effectiveness of the currently available checkpoint inhibitors
  • Whether this finding is relevant to all men with CRPC and who are refractory to enzalutamide or only to some of them

BIshop et al. conclude in their article that

The clinical relevance of this observation should be more thoroughly investigated, and future studies that examine the utility of monitoring circulating cell PD-L1 pathway activity vs. tumor intrinsic PD-L1 expression in CRPC patients to predict responsiveness to checkpoint blockade immunotherapy are warranted.

This is an entirely appropriate conclusion based on the currently available data. Indeed, the very first paragraph of the “Discussion” section of their article Bishop et al. are also careful to point out that:

The efficacy of immune checkpoint blockade immunotherapies like ipilimumab and PD-1 pathway inhibitors in CRPC patients remains questionable. Despite one CRPC patient showing a complete response to ipilimumab …, in another study there was no improvement in overall survival for CRPC patients … and no objective responses were observed in 17 CRPC patients treated with anti-PD-L1 antibody.

We still have a ways to go before we will know, with a high degree of certainty, whether there is a subset of prostate cancer patients who really are good candidates for treatment with the checkpoint inhibitors.

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