To prednisone or not to prednisone? Is that the question?

The past couple of years have seen a resurgence of academic (and clinical) interest in the value of the corticosteroid prednisone in combination with other drugs in the treatment of men with advanced forms of prostate cancer.

Let us be very clear up front. No one has ever approved prednisone (or its close cousin prednisolone) as a treatment for any stage of prostate cancer. However, trials dating back many years now have consistently suggested a palliative effect for prednisone in late stage disease, along with PSA responses in some 15 percent of patients, and prednisone alone may suppress production of testosterone. Conversely, we know that low daily doses of prednisone (and analogous corticosteroids) can counteract the potential benefits of immunotherapy and can induce things like hyperglycemia, bone loss, myopathy, edema, hypertension, and infections.

A newly published paper by Morgan et al. has provided us with a little more insight into this issue through a meta-analysis of data from five large, randomized clinical trials of the treatment of men with metastatic, castration-resistant prostate cancer (mCRPC) that included prednisone in one arm of the study but not in the other. The full text of this paper is available on line from now through March 3, 2014. Support group leaders and other prostate cancer educators may want to save and/or print this document out now for their files.

The paper by Morgan et al. does not resolve the question of when the use of prednisone is most appropriate. Indeed, arguably, it raises more questions than it provides answers. However, one thing is clear from this paper:

  • “There was no difference between the non-P and P groups for severe toxicities (incidence rate ratio [IRR] = 0.82, p = 0.712 …”

In other words, across all five trials, the downsides of administration of prednisone did not outweigh the upsides or vice versa.

The authors correctly point out that a new trial in which, for example, we randomize men with mCRPC to either docetaxel + a placebo in arm A or docetaxel + prednisone in arm B is highly unlikely. There is, however, a different possibility which might have value in some other trial.

Consider the possibility of a new abiraterone-like or enzalutamide-like drug. Why not look at a three-arm trial in which patients were randomized to one of the following three arms:

  • The new drug + predisone
  • The new drug + placebo A (replacing the prednisone)
  • Placebo B (replacing the new drug) + prednisone

Analysis of data from such a trial would allow us to assess the value of the new drug whether or not the patient was getting placebo compared to prednisone alone as well as the relative merits of the three individual arms. Of course there are all sorts of technical questions that would need to be addressed: Could this be done relatively easily? Would this trial structure be acceptable to regulatory authorities like the U.S. Food and Drug Administration? Would the trial structure reduce probability that the new drug would gain approval? How many patients would be needed to get meaningful data? Should this trial exclude all patients with a significant potential for adverse reactions to corticosteroid therapy?

We are reaching the point at which we really do need to know whether long-term, low-dose prednisone is beneficial in the treatment of most men with late stage prostate cancer. We know that it is beneficial for some of them, but if it is only beneficial for about 15 percent of all the potential patients (and therefore non-beneficial in 85 percent), then “Houston, we have a problem!”

3 Responses

  1. Since many men receiving Provenge are likely to take prednisone with either docetaxel or abiraterone (or both), I wonder if it has any impact on the efficacy of the Provenge. I also wonder what difference it may make if the prednisone is taken before or after the Provenge?

  2. It is widely believed that, because corticosteroid therapy and chemotherapy both have immunosuppressive effects, treatment with prednisone or with any form of chemotherapy (docetaxel, cabazitaxel, mitoxantrone, etc.) almost certainly does have impact on the efficacy of sipuleucel-T. However, actual data to substantiate the validity of this belief is hard to come by. The prescribing information for sipuleucel-T states explicitly that, “Use of either chemotherapy or immunosuppressive agents (such as systemic corticosteroids) given concurrently with the leukapheresis procedure or PROVENGE has not been studied.”

    The other factor that is important here is timing of treatment. Prednisone has a relatively short half-life in the body, and has to be taken daily to maintain therapeutic levels. Thus, if a patient had even a relatively brief “wash out” period of perhaps a week or two between his last therapeutic dose of prednisone and the initiation of leukapheresis for preparation of a first therapeutic dose of sipuleucel-T, then it would seem likely that any prior immunosuppressive effect of the prednisone would be minimal. By contrast, starting prednisone treatment during or relatively soon after treatment with sipuleucel-T may well have a very significant impact on the effectiveness of sipuleucel-T. It should also be remembered that the immunosuppressive impact of prednisone may also affect the immunogenic potential of the cells extracted at the time of leukapheresis and used to make the sipuleucel-T in the first place, which is why I would assume that any “wash out” of prednisone would need to occur prior to the initiation of a first cycle of leukapheresis. Since the half-life of a drug like docetaxel is significantly longer than that of prednisone, I would assume that the appropriate wash out period between a last dose of docetaxel and initiation of leukapheresis might need to be more like a couple of months.

    Since we also know that the optimal effects of sipuleucel-T in clinical trials were seen in the men with the lowest PSA levels and tumor burden levels, it would seem likely that for a patient seeking aggressive treatment for early-stage, metastatic, castration-resistant prostate cancer, the optimal form of treatment today may well be sipuleucel-T followed by enzalutamide, thereby avoiding any risks of the immunosuppressive impact of corticosteroid therapy or chemotherapy for as long as possible. However, this comment is pure speculation and is not based on any actual clinical data that I know of.

  3. Tx Mike — speculative as it might be, it helps clarify … we won’t quote you!

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