COMMENTARY

ASCO 2009: Expert Video Perspective on Prostate Cancer

Christopher J. Logothetis, MD

Disclosures

June 29, 2009

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Dr. Christopher Logothetis: Hello, my name is Christopher Logothetis. I'm a physician at M.D. Anderson [Cancer Center] and lead the Prostate Cancer Research Program in that institution. I'm reporting from the site of the annual ASCO [American Society of Clinical Oncology] meeting in Orlando, Florida, on behalf of Medscape Oncology, and I'd like to share some of my observations on the advances in prostate cancer reported here that confirm our overall impression that exists in the research community that we're on the threshold of major changes in the understanding of human prostate cancer and an increase in the number of treatment options available to patients.

Now, some of the studies that are most promising are those that are related to a new understanding of androgen signaling. Until very recently, we were governed by the dogma that production of male hormones in one organ, the gonads or the adrenal gland, was responsible for regulating prostate cancer. Reports at this meeting[1] have confirmed that switching from the production of male hormones from the adrenal glands and the gonads to the cancer itself producing its own androgens, driving its growth, may be central to the progression of this disease. Most important, it is clear that this concept applies to human disease and is of clinical relevance.

At least 2 new drugs have been introduced in the clinic with profound effects in individual patients, altering the course of their illness. The basic biology that underlies this is now well understood and has been associated in human studies presented here, demonstrating that it is linked to the disease as it progresses in humans.

This leads us immediately to the second point, and that is: not only does this lead to new therapy, but it also allows us to individualize the therapy to a given patient and allows us to determine the aggressiveness of the individual cancer. As many of you know, there is a great controversy on PSA [prostate-specific antigen] screening. While the data strongly favor [the idea] that PSA screening prolongs survival and [results in] cures for selected patients, PSA screening also exposes many patients to increased risk for therapy and side effects that may not be necessary. PSA screening, therefore -- if it were linked to an understanding of which disease was aggressive and justified intervention and can be distinguished from [disease] that is unaggressive and could be observed and spare the patient the side effects of therapy[2] -- would be more easily applied and more accepted by the community.

The understanding of androgen signaling, when applied to these groups of patients, may provide a tremendous amount of insight into understanding how aggressive the disease is and distinguishing those patients who we can actually cure and, in fact, those who need curing. So while PSA screening helps, it is very clear that understanding which one of those patients [is likely to] benefit from the therapy and which one can avoid it is going to be a critical next step to the wide acceptance of this approach. The understanding of androgen signaling is contributing to this dissection of these patients into different categories and promises to change the landscape of the approach to prostate cancer.

One can extend the observations and underlying biology, and the fruits that come from that, to what we'll call rationally developed drugs. There have been medications that have been presented in the clinic -- one from the Vancouver group -- that have been striking. They have targeted a protein called clusterin,[3] which is responsible for allowing the cancer to become aggressive and grow independent of the male hormone. They have demonstrated that the concept applies to human disease and that the drug they've developed modifies this protein in a way that then changes the cancer to be consistent with a favorable outcome. Preliminary data presented at this meeting by Dr. Kim Chi favor this finding, which is very important. We look forward to the further studies that are ongoing.

An equally interesting study revealed why some of the agents that we all believed would work actually do not work. Studies presented from the Johns Hopkins group[4] demonstrate that blocking the mTOR pathway can be achieved in human prostate cancer; however, the expected favorable outcome in the patients was not seen. This suggests that the complex system that results in human prostate cancer may require tweaking of multiple pathways. While it would not be considered important by most to understand how a drug fails, in reality it will keep us from reproducing the same mistakes and will form the foundation for the next combination therapy. I regard this [ie, a drug failure] as an equally profound finding that applies our biology specifically to disease. I think in prostate cancer, we have now arrived at the era of rationally developed drugs that are applied to individual patients based on understanding of the specific features of that individual cancer.

For many, the most exciting finding is within vaccines. There are no adult solid tumors where vaccines have had antitumor activity that has been significant once the cancer has established itself. The observation of the previously reported trial by Dendreon,[5] the vaccine called Provenge® [sipuleucel-T], impacting survival, and a most recent report by Dr. Phil Kantoff at this meeting[6] suggesting that there is a survival advantage when giving the vaccine is astounding. And this is astounding for 2 reasons. The first is that neither of these vaccines actually makes the cancer regress. Furthermore, in the current crude way in which we determine how long the cancer remains under control, they also appear not to affect the rate of recurrence of the cancer. However, they do appear to affect the rate of growth and the aggressiveness of the cancer, which impact survival. This is a tremendous shift in how one approaches therapy for prostate cancer because it suggests that these vaccines may work, that these vaccines benefit patients in ways that are not fully understood, and that understanding these mechanisms is going to be critical to the efficient development of combinations of vaccines with other drugs. So while it poses a challenge, the observation that these vaccines may alter the survival of patients with prostate cancer increases the prospect that these new agents will be introduced in the clinic very soon and it also makes us reassess our preconceived biases on how these drugs worked and will, hopefully, lead to combinations of vaccines with other agents or combined immunotherapies.

The overall impression of the meeting is that much of the science that has been developed over the last decade in prostate cancer is now being applied to human disease, is having an effect on human disease, and is providing an understanding of human prostate cancer that will allow us to personalize treatment and select the proper therapy for the individual patient. In addition, the observation with vaccines makes us re-examine our previous biases and question these dogmas that have governed the development of these therapies that will enlighten us further. Overall, this has been a very encouraging meeting, and I think the fruits of the labors of many of the scientists who have worked at this disease for years are now manifesting themselves. Thank you very much, on behalf of Medscape Oncology, and thank you for your attention.

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