Pembrolizumab in treatment of advanced prostate cancer

We finally have some published data — albeit not a lot — on the use of one of the PD-1 inhibitors (pembrolizumab, also known as Keytruda) in the treatment of late-stage prostate cancer.

These data come from a Phase Ib trial of pembrolizumab in patients with multiple different tumor types, and the data were published by Hansen et al. in Annals of Oncology. For details of the original clinical trials, see the trial protocol for the Keynote-028 trial.

The Keynote-028 trial enrolled 23 patients with “common or garden” castration-resistant prostate cancer (CRPC) — i.e., advanced adenocarcinoma of the prostate. All patients showed the presence of a PD-1 ligand in at least 1 percent of tumor or stromal cells.

The patients were all treated with pembrolizumab (at a dose level of 10 mg/kg) every 2 weeks until either disease progression or intolerable toxicity for up to 24 months. (In other words, this was not a trial in which treatment with pembrolizumab was being compared to any other form of known therapy.)

Here are the basic study findings:

  • The average (median) age of the 23 patients was 65 years.
  • 17/23 patients (73.9 percent) had had at least two prior therapies for metastatic prostate cancer.
  • Responses observed included:
    • 4/23 partial responses, for an overall response rate (ORR) of 17.4 percent.
    • 8/23 patients (34.8%) had stable disease.
    • No patient had a complete response.
  • The average (median) duration of response was 13.5 months.
  • Median progression-free survival (PFS) was 3.5 months.
  • Median overall survival (OS) was 7.9 months.
  • The 6-month PFS rate was 34.8 percent
  • The 6-month OS rate was 73.4 percent.
  • After a median follow-up of 7.9 months, 14/23 patients (60.9 percent) experienced treatment-related adverse events (TRAEs), of which nausea was the most common (n = 3, 13.0 percent).
  • 4/23 patients (17.3 percent) experienced different grade 3/4 TRAEs.
  • There were no pembrolizumab-related deaths or discontinuations.

The authors conclude that:

Pembrolizumab resulted in durable objective response in a subset of patients with heavily pretreated, advanced PD-L1–positive prostate cancer, and its side effect profile was favorable.

The “New” Prostate Cancer InfoLink has a somewhat different interpretation of these data, which could be phrased as follows:

  • In a small cohort of patients with metastatic and non-metastatic CRPC, pembrolizumab induced partial responses in a minority of patients.
  • Responses induced in this trial were of limited duration, with median progression-free survival at < 4 months.
  • Treatment-related side effects were observed in the majority of patients within 8 months.

“Word on the street” has, for some time, suggested that this type of immunotherapy seemed to hold limited potential in the treatment of CRPC, and the data above would — unfortunately — appear to support this perception. Whether combining drugs like Keytruda and Opdivo with other therapeutic agents can stimulate higher levels of immune activity will (presumably) still need to explored.

It should be noted that Keytruda may well have a higher level of activity in prostate cancer patients who test positive for metastatic, microsatellite instability-high (MSI-H) or mismatch repair-deficient (MRD) disease. Pembolizumab has been approved here in the US for the treatment of all cancers of this type — prostate cancers specifically included (but these are rare forms of prostate cancer).

5 Responses

  1. There must surely be some context I’m missing that would allow both these two bullet items to be true:

    • The average (median) duration of response was 13.5 months.
    • Median overall survival (OS) was 7.9 months.

    Naively, I would take these two sentences in conjunction to mean that, of the 50% the participants who died within 7.9 months of starting the study, many continued to respond to medication postmortem.

    While this is clearly an erroneous interpretation, perhaps an explanation of the error could be helpful in avoiding future misinterpretations.

  2. Dear Paul:

    I have no explanation for those apparently conflicting findings either … but I would point out that this is a very small data set, which can produce some very odd statistical effects.

    I have not seen the full paper and so the report above is based only on the paper’s abstract. If you want to resolve this issue, the only way to do this would be to get a copy of the full text of the paper and then discuss these data with the authors.

  3. Sitemaster’s point on MSI and MMR occurred to me too before reaching the last paragraph. It would be very interesting to learn how MSI/MMR measurements correlated with outcomes.

    And Paul — I too pondered the same inconsistency!

    I am on my way to visit with Foundation Medicine — on my agenda to discuss is whether they can make an MSI/MMR test available as a subset and at a lower price rather than part of a full genomic sequence as it is right now.

  4. It is worth reminding people that, with drugs like this, there is a possibility of extreme — even life-threatening — auto-immune reactions, and that this can come on with very little warning. I could give more graphic details, but will refrain, since the small number of pembrolizumab patients I have known may not be a representative sample, and I would not want to give an exaggerated view of the risk. Also, in fairness, I must say that a couple of prostate cancer patients I know have had a near-miraculous response to this drug.

    My personal bottom line is that I would be extremely wary of this drug — and probably of all PD-1 inhibitors — until such time as their effects in prostate cancer have been better characterized.

  5. @Tom T … Your observation is true regarding most immune therapies — probably less so with PD-1/PD-L1 inhibitors than CTLA-4 drugs like ipilimumab.

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