A New Paradigm for Prostate Cancer Treatment
All men 50 and over should have regular PSA tests
In 2003, I attended the American Society of Clinical Oncology (ASCO) meeting in Chicago. I was paying particular attention to how oncologists at this ASCO meeting viewed the treatment of prostate cancer because one of the companies we cover had just released important news about a drug targeted for the treatment of this disease
I also had a personal stake in attending several prostate cancer sessions. My father, Jack, had been recently diagnosed by his doctor as having late-stage prostate cancer. Let's just say I was motivated to see what the best oncologists in the world had to say about treating the disease.
To cut a long story short, that ASCO meeting was a revelation to me -- especially where prostate cancer was concerned. I realized that most oncologists had an overly simplistic view of the disease due to a fundamental disconnect between the stages of the disease, patient demands for quality of life, and oncologists' detrimental focus on chemotherapy as a one-size-fits-all tool for treating cancer.
I came back from ASCO and penned a story on the subject for our June 2003 Newsletter. It has proven to be the most popular issue we've ever published - and perhaps our most influential. I've seen its concepts appear in CEO presentations at investor conferences, heard doctors talking about it at scientific conferences, and listened to market analysts discuss its merits.
I wanted to share the basics of this article with the Minyanville community for a couple of reasons. First, I think anyone who invests in a company developing a treatment for prostate cancer without first understanding the implications of this article is investing with both hands tied behind his/her back. Second, it is likely prostate cancer has touched the lives of about half of everyone reading this article. I have received feedback that the way our firm looks at this disease has helped prostate cancer patients understand their disease better. Any day I can write something that gets a two-fer of helping people make better decisions and better choices when faced with a scary disease is a good day.
What appears below is a shortened (and updated) version of this article. Those interested in reading the whole thing can access it either by purchasing the single issue ($60) or by becoming a six- or twelve-month subscriber to our research. I should note here that Minyanville is an educational site, so it does not endorse my firm's stock-specific research appearing in that issue nor the opinions we derive from it.
Prostate cancer kills
Prostate cancer is the most frequently diagnosed cancer in men and second only to melanoma as the leading killer among cancers. Breast cancer is third. Over one million men are currently living with prostate cancer with an expected 221,000 new cases to be diagnosed this year. Nearly 32,000 men will die of prostate cancer in 2004. This is a significant potential market, so many oncology companies have a prostate cancer drug in clinical trials or in the planning stages.
Prostate cancer is most often caught by a PSA test during a routine physical. PSA tests are usually only given to men over 55. The second most common way is an exam when a man complains of changes in urination patterns. I can tell you from family experience, when changes in urination patterns happen - especially when combined with increased fatigue or pain when moving (particularly lower back and hips) - insist that your doctor give you a PSA test no matter what your age or medical condition. If he/she won't, find another doctor fast.
For men who are in otherwise good health, surgery (removal of the prostate) and hormone treatments are the treatment of choice to halt the advance of prostate cancer. Current leading-edge treatment has the hormone therapy given in cycles -- three months on, three months off. Most patients are still treated with continuous monthly doses, however. The reason hormone treatments are used is prostate cancer feeds off male hormones (androgens). Block those hormones and the cancer stops growing.
The disease progresses very quickly without post-surgical treatment of some sort. Only 50% of men are stable at week 12, falling to 25% at week 30 and 10% at the one-year mark. Hormone treatments dramatically extend these otherwise bleak numbers, with some men successfully receiving hormone treatment for a decade or more.
At some point for all men, prostate cancer becomes "hormone refractory" -- which is a fancy way of saying the hormone treatments no longer work as evidenced by rising PSA levels. Once the disease progresses to this stage, as it does in every patient who doesn't die of something else first, it is always fatal with 50% of men dying within 15 months despite treatment shifting to radiation and chemotherapy. Something around 65% of patients have the disease metastasize. When prostate cancer metastasizes, it usually does so to the bone (hence my caution about joint pain above). These bone tumors are particularly painful as they essentially cause the bone to split from the inside. They also mildly interfere with the production of red and white blood cells, which causes the fatigue common for prostate cancer patients.
Prostate-Specific Antigen (PSA) is the accepted bloodstream marker for the existence of prostate cancer. PSA tests are simple, inexpensive, and widely given to men over the age of 50 or 55. It is how most prostate cancers are detected.
PSA is used throughout the disease cycle (diagnosis to death) to gauge how the patient is responding to treatment. A PSA falling to the low single digits generally means the treatment is working. Rising PSA generally means the treatment is not working and it is time to move on to the next stage of treatment.
PSA is a quirky measurement. For example, a move in PSA from a reading of 2.0 to 1.0 is a much more positive development than a move from 200 to 100. There is certainly a relationship between the direction of PSA and the progression of the disease. However, that relationship is not linear. Dropping PSA levels by 40% does not mean there is 40% less cancer in the body. Some researchers argue any drop in PSA over 50% shows clinical efficacy, but few agree. The FDA refuses to consider a drop in PSA as evidence of clinical efficacy for purposes of drug approval, putting an end to the argument as far as biotech investors are concerned. A recent scientific panel convened by the FDA allowed that the velocity of change of PSA (i.e. how fast it doubles) might work as a surrogate endpoint, but the FDA will seek additional input at the end of 2004 before making a final decision.
The treatment of cancer is (supposed to be) all about balancing the stage of the disease, treatment options, and a patient's demands for a specific quality of life. Understanding the stages of any disease is crucial to understanding how doctors want to treat the disease and how patients will allow themselves to be treated. As such, understanding disease stages is crucial for evaluating the market potential of prostate cancer drugs.
The crux of my argument here is there are really three stages of prostate cancer, not the two traditionally seen by oncologists. The "missing" step is a huge sweet spot for new drug development that has largely been ignored by big pharma until very recently.
Classic treatment steps
The classic treatment steps are based upon a view of prostate cancer as a two-stage disease -- a hormone sensitive stage and a hormone refractory stage.
Urologists and oncologists are broadly familiar with these stages and they are firmly entrenched in the medical community.
Immediately after diagnosis, the urologist (or, rarely, an oncologist) embarks upon the primary therapy regime. This most often involves some method of eliminating the cancerous cells from the prostate either by complete removal (radical prostatectomy) or partial removal (other methods), or radiation. Increasingly, the patient does not want to suffer the side effects of direct treatment of the prostate, so "watchful waiting" (doing nothing until symptoms get worse) is an alternate primary therapy.
After the primary therapy, most men start hormone therapy. Drugs that block the body's ability to produce or absorb androgens are given. Many men see sexual dysfunction and other side effects from androgen deprivation therapy. As such, "watchful waiting" has multiple meanings in this stage of the disease. It can mean no action at all until the disease gets worse or no action after surgery until the disease gets worse to avoid the side effects inherent in hormone therapy.
Just to complicate things even more, older men and/or men with other serious health problems are often not considered a candidate for surgery. Don't let a doctor tell you that means they are not a candidate for therapy. Almost all men with other serious diseases can tolerate hormone therapy even if they cannot tolerate surgery. Just hormone therapy alone can make a big difference to the quality and length of life.
Once hormones fail, the patient is said to have "hormone refractory" disease. At this point, only palliative treatments are available. "Palliative" means to moderate the intensity of - specifically, moderate the intensity of the side effects inherent to prostate cancer. The goal here is not to extend life to any significant degree. The goal is to make the months the prostate cancer patient has left more comfortable.
Quality of life considerations now become paramount since treatments are only designed to extend life by weeks or months, reduce existing pain, or extend the time until pain begins -- all quality of life considerations.
Drugs currently used in this treatment step are largely toxic chemotherapeutics and radiation. Side effects from these treatments significantly decrease quality of life, making it very difficult for doctors and patients to balance side effects with the likely outcomes.
A big development at ASCO 2004 was the presentation of data showing Taxotere could extend the life of the hormone-refractory patient by about two months after seven weeks of therapy. While oncologists were positively giddy about this, I strongly suspect patients will have other ideas about whether they want to live the final months of their life with the toxic side effects of chemotherapy.
Something important to realize is the fine line between competition and cooperation between urologists and oncologists in the treatment of prostate cancer. In the first stage of the disease, the patient is almost certainly seeing an urologist. When the disease progresses to the hormone-refractory stage, the urologist passes the patient (and the associated revenue stream) to the oncologist. During the plenary session commentary about the Taxotere data, the speaker exhorted urologists to send them patients earlier now that "we have something to help extend their lives."
A reality-based treatment paradigm
As a general rule, men don't like doctors and they don't like feeling sick. All patients exhibit these traits, but studies prove prostate cancer patients are especially concerned with quality of life considerations. Understand that a newly hormone refractory patient may have been living with prostate cancer for a number of years. When his PSA starts rising (denoting the failure of hormone treatment), he often has no other symptoms. Therefore, it is very hard for a man to convince himself the side effects connected with chemotherapy and radiation are worth it.
Recognizing this reality, we have to divide the treatment of prostate cancer into three steps.
The new stage is populated by men who have rising PSA values (therefore, hormone refractory) but no other symptoms. These asymptomatic patients are in a period of "watchful waiting" - waiting for additional symptoms to appear. For most men, this stage of the disease lasts a couple of months. Lucky men have it last a year or longer.
This relatively new way of looking at prostate cancer is a direct result of patient attitudes. Men simply don't want to undergo the terrors of chemotherapy and radiation when they have no symptoms.
Herein lies the problem for patients/doctors and an opportunity for companies developing treatments for prostate cancer: Currently, there is no treatment suitable for asymptomatic, hormone-refractory prostate cancer (stage two of the disease). Conversations with leading-edge prostate cancer experts reveal a significant unmet demand for something to prescribe for these patients. Similar demand comes from prostate cancer patients in this stage of the disease.
I firmly believe that for all the considerable spinning and marketing from Sanofi/Aventis, Taxotere is not the answer for treating second-stage disease. Taxotere is an immensely important improvement in therapy for third-stage disease and we are grateful we have an FDA-approved option that extends survival.
In June 2003, only a handful of people looked at prostate cancer treatment as a disease of three stages. In June 2004, the number of people who understand that prostate cancer is a three-stage disease has grown significantly. It is very clear to us, however, large numbers of oncologists do not think about prostate cancer in exactly this fashion. Sure, they all are aware of asymptomatic, hormone-refractory disease -- but they simply don't seem to understand the treatment impact. Urologists have been the quickest to understand this distinction because the concept of watchful waiting is less foreign to them.
There is no question in our minds the first drug targeted to asymptomatic, hormone-refractory disease (stage two disease) will be groundbreaking in its effect on the treatment of prostate cancer. The first drug out of the gate will likely see rapid adoption and very high usage rates. It will create its own treatment niche, giving it a significant chance of reaching blockbuster status. Because of this, it will also attract significant competition.
Here is the important part for investors:
Any drug targeted to this second disease stage must have essentially no side effects. Let me say this again because it is perhaps the most important thing you can take away from this article. Any drug targeted to second-stage prostate cancer must have essentially no side effects.
This rules out all drugs that depend on combination use with chemotherapeutics. It rules out Taxotere, despite the hubbub at ASCO 2004. Simply having fewer side effects than chemotherapy will not cut it. Drugs will need to have side effects comparable to what the patient is feeling when they first enter stage two disease -- which typically isn't much.
Efficacy in this stage will be measured in time to onset of pain and time to disease progression. Survival, while certainly important, is really a secondary consideration. Remember, this disease stage was created by patient demand for quality of life, so postponement of pain will be a central driver here.
By the end of this decade, effectively treating patients with asymptomatic disease will be an important goal for patients and doctors. It will also be most lucrative for drug companies who get the message and deliver drugs with few or no side effects. Therefore, smart investors will evaluate all potential prostate cancer drugs for their ability to fit this disease stage. Smart investors will also use the three stages I've outlined above to segregate existing and future treatments into the proper competitive categories.
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