Prostate cancer and treatment with immune checkpoint inhibitors

Immune checkpoint inhibitors include drugs like ipilimumab (Yervoy), pembrolizumab (Keytruda), nivolumab (Opdivo), and others that can have dramatic effects on the survival of some groups of patients with advanced forms of some cancers.

The problem is that treatment with such drugs can also come with significant risk for serious side effects, and despite their dramatic effects in some patients, they seem to have little to no benefit at all in other groups of patients. On top of these risk/benefit issues, as yet we have almost no really good evidence as regards their value in the treatment of advanced forms of prostate cancer. However, …

Today, a paper in the journal Nature has reported data from a study by Patel et al. (from the National Cancer Institute here in the US) suggesting that the authors have been able to identify particular genes that must be expressed by a tumor if immune checkpoint inhibitor antibodies are going to work well in a particular patient with a particular type of cancer. (See also this article in the journal The Scientist that discusses the paper by Patel et al. in some detail.)

The use of this type of genetic testing may be very important to prostate cancer patients and their doctors (and to patients with other types of cancer too) in knowing whether they want to risk treatment with immune checkpoint inhibitor antibodies, which, in addition to being associated with significant risk for side effects, are also very expensive. There is little doubt that insurance companies and other payers will also be looking closely at this paper to see if they can justify requiring patients to have such genetic testing prior to any decision about whether they will cover the costs associated with immune checkpoint inhibition.

In the case of prostate cancer, we can reasonably expect that future clinical trials are going to be testing patients who undergo treatment with immune checkpoint inhibitors to see whether or not these patients are actually expressing specific proteins programmed by specific genes at high enough levels. While the screening test developed by the group at the National Cancer Institute (based on the so-called genome-wide CRISPR technology) has provided a hypothetical rationale for why some patients treated with immune checkpoint inhibitors do really well and others don’t, we will still need to see if this hypothesis turns out to be true in clinical practice.

4 Responses

  1. This was in melanoma cells. Ipilimumab and Keytruda have already proven a survival advantage in melanoma — so they are finding the exceptional cells that do not respond. Prostate cancer, on the other hand, has not responded to ipilimumab, and the jury’s still out on whether it responds to the PD-1/PD-L1 inhibitors. It may someday turn out that there are peculiar prostate cancer variants that will respond, but as a class, so far, we have no data. Hopefully, they will. I also remain hopeful about targeted immune therapies like CAR-T.

  2. I worked with a man last year who exhibited MLH1 and a high level of micro-satellite instability (MSI); both indicated pembrolizumab. Unfortunately the actionable gene was discovered too late to determine if pembrolizumab was effective.

  3. Dear Allen:

    I would point out that there were clear signs of activity of ipilimumab in mCRPC in the Phase III trial data when they were finally published, and the authors noted that, “The observed increases in progression-free survival and prostate-specific antigen response rates suggest antitumor activity in a patient subset.”

    This might well correlate with a genetically definable group of prostate cancer patients.

  4. Anecdotal evidence only, and to the best of my [increasingly faulty] recollection:

    In recent conversation with a well-known prostate oncologist, I learned that he has tried adding pembrolizumab (Keytruda) to the treatment regimens of 20 of his patients whose PSA was rising on fourth-generation treatments like Xtandi. With Keytruda added, he observed slowing or even reversal of PSA progression in eight of the twenty.

    Of course, this is neither random, double-blind, nor anything other than anecdotal.

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