The proposed REALITY trial and the impact of statins on prostate cancer

As a mentioned earlier this week, a new article by Moyad and Klotz has suggested that it may be possible to carry out a randomized clinical trial to evaluate the impact of statin therapy on the progression of early stage prostate cancer.

The idea that statins might affect the development and progression of prostate cancer goes back many years. However, there has never been a specific, randomized clinical trial designed and implemented to assess the impact of statin therapy on the progression or the initial development of prostate cancer. All currently published data come from retrospective analysis of (sometimes large) data sets.

The potential trial outlined by Moyad and Klotz (the so-called REALITY trial) is relatively straightforward. Men meeting specific criteria and enrolled on an active surveillance protocol would be randomized to receive either a cholesterol lowering agent or a placebo. The study endpoint would be disease progression — as normally assessed for men on active surveillance (an increase in the Gleason score from 3 + 3 = 6 to 3 + 4 = 7 or higher on a follow-up biopsy or a clear and rapid increase in the patient’s PSA level over time).

The one possible problem with the proposed trial is that rather than using an actual statin (atorvastatin, rosuvastatin, pravastatin, etc.), the authors are suggesting the use of a dietary supplement called red yeast rice (RYR). There certainly appear to be data indicating the statin-like impact of RYR on cholesterol levels. However, the quality control of any over-the-counter dietary supplement tends to be much lower than the quality control of products manufactured as prescription drugs.

The proposed trial is to be conducted under the supervision of the authors in Toronto, Canada. Patients will be given either RYR at a dose of 3,600 mg/day or an equivalent placebo. This dose of RYR is expected to equate to a 25 to 35 percent reduction in serum levels of LDL cholesterol (based on data from other trials of RYR). Patients would be followed for a minimum of 1 year and would receive at least two biopsies during this time frame.

While The “New” Prostate Cancer InfoLink would want to encourage and thank Drs. Moyad and Klotz for their determination to bring a trial of this type to fruition, it is perhaps distressing that such a trial cannot be carried out by using a standard cholesterol lowering agent that is widely prescribed today in North America. One would have hoped that a pharmaceutical company would have been willing to offer free drug and a placebo to encourage the conduct of what is clearly still going to be a small, pilot study.

We should also point out that there is no mention of the proposed REALITY trial on the web site at this time. Exactly when this trial is going to be initiated has yet to become evident.

2 Responses

  1. Trial Planning

    Ideally, to test the effect of red yeast rice on progression, the REALITY trial would focus on just those men in the Klotz active surveillance (AS) series whose cancer was going to progress and not include any of those who were not going to progress. Of course that is not knowable up front, and therefore the trial group of patients must include both men who are never going to progress, or who will progress at a time many years in the future, as well as the men who will progress within a few years. This necessity creates a couple of trial planning challenges in the particular Klotz AS series setting, as I see it, and I hope the protocol will deal with them.

    First, in view of the fact that the trial participants will be randomized from Dr. Klotz’s long-running series of AS patients, there needs to be thoughtful attention to duration of follow-up to make detection of an impact (or not) with confidence more likely. It is known that a substantial majority of men in the Klotz series will not experience either biopsy-detected progression or a telltale PSA increase for many years or ever. Moreover, even for those men headed for determination of progression in the Klotz series, a large portion will make it through the first year of AS free of progression, and a somewhat smaller portion will make it through at least the second year free of progression. Therefore, the minimum of just 1 year of follow-up in the protocol is a concern. Perhaps the protocol calls for removing patients who do not make it to 1 year before progressing, which would be consistent with a reasonable assumption that pretreatment influences were driving the progression of such early progressors. However, unless median follow-up is at least several years long, it is hard to imagine that there will be enough difference visible between the groups even if there is an underlying real difference in progression caused by the red yeast rice. As I recall previous reports from the Klotz series, much of the progression that does occur is evident at around the second or third year and tails off substantially thereafter, so getting average follow-up of 3 years or so would have some appeal as a protocol objective.

    Second and similarly, regarding detectability in the Klotz AS series, in view of the fact that a clear majority of men in the trial are highly likely not to progress, the number of men in the trial needs to be high enough so that a real but possibly undramatic difference in incidence of progression between the red yeast rice arm and the placebo arm of the study will not be drowned out by a large number of men in each arm who do not progress because, regardless of consuming red yeast rice, they are not going to progress at all or will progress only after many years. However, REALITY is a pilot study, and pilot studies tend to have relatively small numbers of patients. If that is the plan for the REALITY trial, then would that not make it likely that only a dramatic difference in progression would show up? I am not thoroughly familiar with research on statins and prostate cancer, but my impression is that evidence is encouraging regarding statins and reducing metastatic and lethal prostate cancer, but not yet encouraging regarding the overall incidence of prostate cancer or progression. If that impression is correct, then a difference in progression that could be detected by a small pilot study would seem less likely.

    Of course, the follow-up duration and trial size factors work together. The most challenging case — the one least likely to detect a real impact — would be a trial with short median follow-up, say just 1 or 2 years, and a small number of participants. Satisfactory follow-up or size would be an improvement, but a trial satisfactory in both follow-up and size would have the best chance of overcoming these challenges.

    Is the trial going to be double-blinded so that the medical staff interacting with the patients do not know who is getting the red yeast rice and the placebo? I’m assuming that is so. It is certainly desirable to avoid a potential placebo effect, but it is not yet clear.

    Does anyone know whether the researchers have thought through the follow-up duration and study size issues?

  2. Dear Jim:

    I think we can safely assume that researchers with the experience of Dr. Klotz and Dr. Moyad understand the implications of the issues you have raised. Perhaps a more fundamental question (in the current economic environment) is whether they can get a grant large enough to do much more than demonstrate that a larger trial is feasible.

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