A long way from actual clinical applicability, but interesting anyway …


There was an intriguing paper in the November 2013 issue of the journal Prostate suggesting that intermittent dosing with testosterone in between doses of androgen deprivation therapies may actually help men in the early stages of castration resistance to respond better to treatment over time.

Let’s be very clear that the data published by Thelen et al. are based on in-vitro and mouse models, and no one has actually done this in a human being (as yet, as far as we know). However, what the authors are suggesting (and they have provided additional information about this on the UroToday web site) is that such testosterone dosing MAY (please note the degree of emphasis) be able to act like a “reset” button — to some extent — in the management of androgen receptor (AR) expression to resist castration.

So what’s going on here?

When patients are treated with androgen deprivation therapy (ADT), their prostate cancer cells gradually acquire an increasing level of castration resistance over time as a result of AR over-expression. (This happens quickly in some men and much more slowly in others.) Such amplification of the expression of ARs sensitizes these cells to testosterone concentrations at even normal physiological levels. Some current evidence seems to suggest that, when ARs are over-expressed, and AR function is facilitated by other AR abberations, prostate cancer growth actually depends on relatively low levels of testosterone.

Thelen et al. were able to show, using in-vitro and in-vivo models, that when they boosted testosterone levels in certain types of castration-resistant prostate cancer (CRPC) tissue, tumor cells were eliminated to a greater degree than they were by androgen withdrawal in androgen-tolerant cells … and that there was an associated “down-regulation” of AR expression.

What might this mean for the treatment of men with early stage CRPC?

Well, one thing it could, perhaps, mean, is that men showing early signs of castration resistance should have complete withdrawal of ADT for a period of time, i.e., stop the use of any antiandrogen like bicalutamide, let the PSA drop (if it is going to), then stop the use of any LHRH therapy, and then give the patient a tetsosterone boost to return his testosterone level to something approaching a normal physiological level before simply re-starting the LHRH agonist therapy. It is also possible that this could be part of a long-term strategy for intermittent ADT.

Now it is clear that this idea is going to need a lot of testing before anyone starts actually recommending this as a clinical practice, and The “New” Prostate Cancer InfoLink thinks it is highly unlikely to work for all patients because we suspect that genomic variation will profoundly impact response to this type of strategy … so it might only work for a subset of men (if it actually works for any at all).

On the other hand, the nice thing about this idea (if it does actually work — even if it is only in a subset of patients) is that it would be easy and cheap to implement. All we need are to accumulate some data to show that it is safe and that it actually works in real men with real prostate cancer (but that may be easier said than done).

4 Responses

  1. Mike,

    I understand that a small, Phase II study entitled “Bipolar androgen-based therapy for prostate cancer (BAT)” is ongoing in humans under the sponsorship of the Sidney Kimmel Comprehensive Cancer Center (at Johns Hopkins). The trial information states that:

    “The purpose of this study is to determine the safety and clinical effects of alternating androgen deprivation therapy with testosterone therapy in men with recurrent prostate cancer as first line hormonal therapy, to assess the effect of alternating therapy on quality of life and metabolic changes associated with androgen-deprivation therapy.”

    The trial is fully enrolled with just 33 patients.

    I also understand that this has been done by more than one medical oncologist that exclusively treats prostate cancer using the biphasic nature of testosterone to either suppress or kill prostate cells.

  2. As usual Ralph … You’re one step ahead of most of the rest of us! However, I do note that this study is being done in hormone-naive patients as opposed to castration-resistant ones.

    :O)

  3. Mike (and others),

    Please have a look at

    (1) Isaacs JT, et al. Adaptive auto-regulation of androgen receptor provides a paradigm shifting rationale for bipolar androgen therapy (BAT) for castrate resistant human prostate cancer. Prostate. 2012;72:1491–1505.

    (2) Feltquate D, et al. Rapid androgen cycling as treatment for patients with prostate cancer. Clin Cancer Res. 2006;12:7414-7421.

    LowRoad

  4. Sounds similar to my intermittent HT strategy currently, given my testosterone in the 800s, although I think I am still a hormone-sensitive patient at this point. I wouldn’t imagine that they would give testosterone at higher levels than that? (Honestly, not familiar with testosterone dosing.)

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