June 24, 2003 - In the Prostate Cancer Prevention Trial (PCPT), 25 percent fewer men taking the drug finasteride developed prostate cancer than men not taking the drug. However, men who developed prostate cancer while taking finasteride were more likely to have high-grade cancers, which can spread quickly even if the tumors are small.

Background and Study Design

1. What was the purpose of the Prostate Cancer Prevention Trial?

The Prostate Cancer Prevention Trial, or PCPT, was a study designed to see whether the drug finasteride (trade name Proscar®) could prevent prostate cancer in men ages 55 and older. The study began in October 1993 at 221 sites across the United States. The PCPT was expected to continue until May 2004, but was stopped in June 2003 when an analysis showed that finasteride reduced the risk of developing prostate cancer by 25 percent.

The PCPT is funded by the National Cancer Institute (NCI) and coordinated by researchers with the Southwest Oncology Group (SWOG), a group of cancer researchers at medical centers around the country.

2. Who could participate in the PCPT?

Men 55 years of age and older who were in good health and who showed no evidence of prostate cancer could enroll in the trial. Some 18,882 men joined the study over three years.

Characteristics of the Participants:

Age: 31 percent were ages 55-59, 31 percent were 60-64, and 38 percent were ages 65 and older when they joined the study.

Race: 92 percent were white, 4 percent were African American, and 4 percent were from other racial and ethnic backgrounds.

Family history: 15 percent had a brother, father, or son who had prostate cancer.

3. How did the investigators know that the men did not have prostate cancer at the beginning of the study?

Men joining the trial had to have a digital rectal exam (DRE) that showed no sign of prostate cancer and a prostate-specific antigen (PSA) blood level of 3.0 nanogram/ milliliter (ng/ml) or less. A PSA level of 4.0 ng/ml or less is considered normal, but a cutoff level of 3.0 ng/ml was chosen to reduce the chance that a man might enter the trial with early, undiagnosed prostate cancer. (See also Question 11.)

The only way to know for sure that a man has prostate cancer is to examine cells from his prostate under a microscope. This is done with a prostate biopsy, which involves removing small samples of prostate tissue with a needle and examining the samples under a microscope to check for cancer. When the PCPT was designed, the researchers decided that a normal DRE plus a PSA level of less than 3.0 ng/ml were sufficient evidence of being cancer-free and would be more acceptable to the participants than a biopsy at the beginning of the study.

4. Why did the participants have to be 55 years of age or older?

The vast majority of prostate cancers occur in men ages 55 and older. While all men are at some risk for prostate cancer, the risk of developing this disease increases with age. (See also Question 10.)

5. Did every man receive finasteride?

No. The PCPT was a randomized, placebo-controlled clinical trial. The men in the PCPT were randomized (selected by chance) to receive either finasteride or a placebo (an inactive pill that looks like finasteride). Half of the men in the study took finasteride, and half took a placebo. Neither the participant nor his PCPT physician knew which pill the participant was receiving. Setting up a study in this way allows researchers to see the true benefits and side effects of an intervention (in this case, finasteride) without the influence of other factors such as the expectations of participants or researchers.

6. What was the dose of finasteride and how long was it given?

All men in the study were assigned to take one pill per day for seven years, either a 5 milligram dose of finasteride or a placebo.

7. How were the men monitored for side effects and for prostate cancer?

PCPT participants visited the study site twice a year and were contacted by phone twice a year to monitor their health and the occurrence of side effects. Participants were asked about side effects and were encouraged to call the study site any time they had concerns or symptoms they thought might be related to the study.

Monitoring included a yearly physical exam, including a DRE and a PSA blood test. If a PSA screening or DRE suggested any problem, a prostate biopsy to check for cancer was recommended. Because finasteride lowers the level of PSA in the blood, a calculation was done to correct the reading.

At the end of seven years in the study, each participant who had not been diagnosed with prostate cancer was asked to have a prostate biopsy. The biopsy involved using a needle to remove six small pieces of prostate tissue. The samples were then examined under a microscope to check for cancer.

About Prostate Cancer

8. What is the prostate?

The prostate is a small gland in a man's reproductive system that produces a component of semen. The prostate gland is about the size of a walnut, and is located below the bladder and in front of the rectum. It surrounds the upper part of the urethra, the tube that empties urine from the bladder. If the prostate grows too large, the flow of urine can be slowed or stopped.

9. Is prostate cancer a major public health problem?

Yes. With the exception of skin cancer, cancer of the prostate is the most common cancer in American men. Nearly 221,000 men in the United States will be diagnosed with prostate cancer in 2003. In most men with prostate cancer, the disease grows very slowly. Many men will not die from their prostate cancer, but rather will live with it until they eventually die of some other cause. However, a significant number of men will experience progression of disease and a difficult death. Prostate cancer is the second leading cause of cancer death in men. Common treatments for prostate cancer can cause impotence (difficulty achieving an erection) and incontinence (not being able to hold in urine) in some men, greatly decreasing their quality of life.

10. Who is at risk for prostate cancer?

All men are at some risk for prostate cancer. The strongest risk factor is age. More than 92 percent of prostate cancers occur in men ages 55 and older.

African-American men have a higher risk than white men. Dramatic differences in the incidence of prostate cancer are also seen in different countries, and there is some evidence that a diet high in fat, especially animal fat, may increase risk for prostate cancer, and may account for some of these differences. Genetic factors also appear to play a role, particularly for families in which the disease occurs in men under age 60. The risk for prostate cancer rises with the number of close relatives who have the disease.

11. How is prostate cancer detected?

Two tests are commonly used to check for prostate cancer in men who have no symptoms of the disease. One is the digital rectal exam (DRE), in which a doctor feels the prostate through the rectum to find hard or lumpy areas. The other is a blood test used to detect a substance made by the prostate called prostate specific antigen (PSA). Both tests are used to determine if a man should have a prostate biopsy; the only way to know for sure that a man has prostate cancer is to examine cells from his prostate under a microscope.

Currently, NCI is supporting research to learn more about using screening tests for prostate cancer. At present, it is unclear whether routine screening of men who are not at unusually high risk will prove to save lives and outweigh the complications of therapy for patients, many of whom will not have aggressive or life-threatening tumors.

12. When prostate cancer is diagnosed, how is it described?

Prostate cancer is described by both stage and grade. Stage refers to how far the cancer has spread, and grade describes how abnormal the tumor cells appear.

Stage: Early prostate cancer, stages I and II, has not spread outside the prostate gland. Stage III prostate cancer, often called locally advanced disease, extends outside the gland into the seminal vesicles or lymph nodes. Stage IV means the cancer has spread to other tissues or organs.

Grade: Based on the microscopic appearance of tumor tissue, pathologists may describe it as a low-, medium-, or high-grade cancer. One way of grading prostate cancer is the Gleason system, which uses scores of 2 to 10. The pathologist studies samples of tissue from the prostate and grades the appearance of the tumor tissues on a scale of 1 to 5 to indicate how different they are from normal prostate tissue. The two most common grade patterns or the most common and the worst (most abnormal) grade patterns are added together to make a Gleason score. The higher the score, the higher the grade of the tumor. High-grade tumors (Gleason score 7-10) can grow more quickly and are more likely to spread than lower-grade tumors.

About Finasteride

13. What is finasteride?

In 1992, the U.S. Food and Drug Administration (FDA) approved the use of a 5 mg dose of finasteride, taken by mouth as a pill, for treating benign prostatic hyperplasia (BPH), a noncancerous enlargement of the prostate that can block the flow of urine. Finasteride is marketed as Proscar for this use. At a much lower dosage (1 mg), finasteride is used to prevent hair loss and promote hair growth and is marketed as Propecia®.

14. How does finasteride work?

Finasteride shrinks the prostate gland. The drug reduces levels of dihydrotestosterone (DHT) in the blood and the prostate gland. DHT is a male hormone that is important in normal and abnormal prostate growth. DHT plays a key role in noncancerous growth of the prostate (benign prostate enlargement or BPH) and is also involved in the development of prostate cancer.

Finasteride works by blocking the action of an enzyme, 5-alpha reductase, that is needed to change the hormone testosterone into DHT. Finasteride has a chemical structure similar to the structure of testosterone, which lets it attach to 5-alpha reductase, making the enzyme unavailable to change testosterone to DHT.

15. Why was finasteride tested to prevent prostate cancer?

The development of prostate cancer is strongly influenced by male hormones. DHT in particular is known to promote the growth of prostate cells. Because finasteride reduces levels of DHT, researchers believed the drug might prevent the cellular changes that can lead to prostate cancer. In support of this hypothesis, finasteride had already been shown to inhibit the growth of prostate cancer cells in laboratory experiments. Also, studies had shown that men with very low levels of 5-alpha reductase due to an inherited deficiency are not able to convert testosterone to DHT, and do not develop prostate cancer.

16. Can finasteride cause side effects?

Yes. Like most medications, whether over-the-counter drugs, prescription drugs, or drugs in medical studies, finasteride may cause side effects. Decreased sexual desire, impotence (difficulty achieving an erection), and decreased ejaculate volume are known side effects of this drug. There are treatments available that may lessen these side effects. Participants in the PCPT were regularly asked about side effects and were encouraged to call the study site any time they had concerns or symptoms they thought might be related to the study.

In the PCPT, men taking finasteride reported more sexual side effects, such as decreased sexual desire and episodes of impotence, than men on the placebo. However, men on finasteride were also less likely to experience urinary symptoms such as urgency/frequency of urination or incontinence.

Study Results

17. What were the results of the PCPT?

The PCPT is the first study to show that a drug can reduce a man's chances of developing prostate cancer. Men assigned to take finasteride were 25 percent less likely to develop prostate cancers than men in the placebo group.

Almost all the prostate cancers in men on the PCPT were found in an early stage. However, although men taking finasteride had fewer prostate cancers overall (18 percent of men in the finasteride group developed prostate cancer vs. 24 percent of men in the placebo group), the cancers in the finasteride group were of a higher grade (37 percent of cancers in the finasteride group were high-grade vs. 22 percent of the cancers in the placebo group). High-grade prostate cancers may be more aggressive and are more likely to spread outside the prostate. (See also Questions 12, 18, 19, 20, and 31).

18. Can the results be described in a way that relates to the general population?

Yes. If you start with 1,000 men age 63, it is estimated that after seven years, 60 of those men would develop prostate cancer. Of those 60 men with prostate cancer, 18 would have high-grade disease. If you take those same 1,000 men and treat them with finasteride for seven years, only 45 men would get prostate cancer. Of those 45 men with prostate cancer, 22 would have high-grade disease.

(These calculations are done using estimates of developing prostate cancer from NCI's Cancer Surveillance Program and data on outcomes from the PCPT.)

19. Why did men taking finasteride get more high-grade prostate cancers than men taking the placebo?

We don't know. Researchers are uncertain how to explain this finding, although they are considering several possibilities. One possibility is that there may be a false estimate of tumor grade because finasteride affects the appearance of prostate cancer cells. Another possible explanation is that finasteride truly causes more aggressive tumors to develop - either by preventing only low-grade tumors, or by making the prostate gland more favorable to high-grade tumors. Follow-up studies will help explain the findings. (See also Question 36.)

20. Are men more likely to die from a high-grade cancer than a low-grade cancer even if the disease is diagnosed at an early stage?

Yes. High-grade prostate cancers can be more aggressive, regardless of the stage of disease. Although some men with early-stage prostate cancers have their cancers monitored instead of receiving treatment (a process called "watchful waiting"), most physicians feel a high-grade cancer is more likely to require treatment than a low-grade cancer, even at an early stage.

21. Did any men on the PCPT die from their prostate cancers?

Ten men died from prostate cancer during the study; five of these men were assigned to take finasteride and five were assigned to placebo.

22. Were cancers diagnosed by the end-of-study biopsy different from cancers found during regular monitoring?

About half of the prostate cancers found during the PCPT were diagnosed at the end-of-study biopsy instead of after a biopsy prompted by a problem with their DRE, an elevated PSA, or symptoms. These men are a very unusual population because most men in the United States would not have a prostate biopsy if they had no signs of cancer from a DRE and a PSA level below 4.0 ng/ml. Additional research will help determine if cancers diagnosed by end-of-study biopsy are different from cancers found during regular monitoring. (See also Question 36.)

23. Did any group of men benefit more from finasteride than others?

The reduction in prostate cancer risk from finasteride was seen regardless of age, race/ethnicity, family history of prostate cancer, and PSA level at entry into the study. Research is in progress to determine whether a particular group of men would be more (or less) likely to benefit from finasteride based on other biological and molecular factors.

24. Why was the trial stopped early?

As part of the study design, the PCPT data were regularly reviewed by an independent Data and Safety Monitoring Committee (DSMC). On March 3, 2003, the DSMC notified the chair of SWOG that the primary goal of the trial had been met: finasteride reduced the risk of prostate cancer by 25 percent and it was extremely unlikely that continuing the trial would change that finding. The DSMC recommended that the trial be stopped early and that the men and their physicians be told what pills the participants had been taking (finasteride or placebo).

Representatives from SWOG and NCI met on March 12, 2003, and both groups agreed with the DSMC's recommendation. All parties agreed that the results of the study should be made known to the participants in the study and to all men concerned about prostate cancer.

To make the study findings available to the medical community, a report on the study findings was submitted to the New England Journal of Medicine on March 24 for expedited review. The report was published in the online version of the journal on June 24, 2003, and will appear in the print journal on July 17, 2003.

25. Have the men in the study been told the results?

Yes. Before the study was reported in the New England Journal of Medicine, the Southwest Oncology Group sent letters to the participants about the study's results. The participants will receive a second letter in one to two weeks to tell them whether they were taking finasteride or the placebo.

26. What do the participants do now?

Men who were still taking study pills were told to stop and return their pills to their study site. Those men who have not yet had an end-of-study prostate biopsy may have one without charge through October 31, 2003. All men in the PCPT have been asked to participate in long-term monitoring of their health. Participants without prostate cancer may also eligible to take part in another prostate cancer prevention trial known as SELECT. (See also question 37.)

Other Concerns

27. Should all men take finasteride?

Finasteride will not be appropriate for every man. All men who are concerned about getting prostate cancer should talk with their health care provider about the potential benefits and possible risks of taking finasteride.

28. How does a man decide if he should take finasteride?

As with any medical procedure or intervention, the decision to take finasteride is an individual one in which both the benefits and risks must be considered. The balance of these benefits and risks will vary depending on a man's health history and how he weighs the benefits and risks. Men considering finasteride to reduce their risk of prostate cancer should talk with their health care provider.

29. Would it be beneficial for men to take finasteride for more than seven years?

We do not know whether taking finasteride for more than seven years would be beneficial. We do not know if there is an ideal time period to take the drug to have the best prostate cancer prevention effect. We also do not know the benefit of taking it for less than seven years. Finasteride is commonly given for indefinite periods of time to treat BPH.

30. Do other drugs that treat BPH have the same cancer prevention effect as finasteride?

The most commonly prescribed drugs for BPH are alpha blockers, including terazosin (sold as Hytrin®), doxazosin (sold as Cardura®), and tamsulosin (sold as Flomax®). These drugs don't work in the same way as finasteride. Alpha blockers help BPH by relaxing the muscles in the prostate and neck of the bladder to allow better urine flow. They do not affect hormone levels the way finasteride does. It is unlikely that they would have an effect on prostate cancer risk, although these drugs have not been studied for this purpose.

A new drug, dutasteride (sold as Avodart®), is also prescribed for BPH and works similarly to finasteride. The manufacturer of this drug recently began testing it for the prevention of prostate cancer.

31. Are men using finasteride for BPH at risk for developing high-grade prostate cancer?

All men are at risk for developing prostate cancer, and some men will develop high-grade disease whether or not they use finasteride. In the PCPT, 5.1 percent of all men taking the placebo developed high-grade prostate cancer, and 6.4 percent of all men taking finasteride developed high-grade prostate cancer. Men taking finasteride for BPH should talk with their physicians about the PCPT study results and about their risk for developing prostate cancer with or without finasteride. (See also Questions 17, 18, and 19.)

32. Does Propecia prevent prostate cancer?

We don't know. The PCPT evaluated only the 5 mg dose of finasteride, not the 1 mg dose marketed as Propecia.

33. What proportion of men in the study were African-American?

About 4 percent of the men in the PCPT were African-American. PCPT investigators made strong efforts to invite African-American men to participate in this trial, but participation was voluntary and investigators did not succeed in enrolling a large number of African-Americans. Prostate cancer is a critical issue for African-American men, who have the highest rates of this disease in the world. Finasteride was shown to be as effective in reducing prostate cancer risk among African-American men as in men of other races.

34. How much does a standard dose of finasteride cost?

Finasteride is a prescription drug. A one-month supply costs about $60 to $98.

35. How much did the study cost?

The PCPT was funded by the National Cancer Institute, which gave $73 million in grants to the Southwest Oncology Group for the trial. In addition, Merck and Co., of Whitehouse Station, N.J., the manufacturer of finasteride, provided both the finasteride and the placebo without charge, and paid for distributing the pills to the study sites.

36. What follow-up studies are being done in the PCPT?

Two types of studies are under way: Investigators are continuing to follow participants, and they are conducting laboratory studies using the blood and prostate tissue samples collected from participants during the trial.

All participants in the trial are encouraged to take part in a long-term follow-up study in which PCPT researchers continue to contact them to collect additional information about the effects of finasteride use, prostate cancer, and survival.

Using the blood and tissue samples collected during the trial, a comprehensive program of additional laboratory studies will look at the molecular biology of prostate cancer to try to determine who is at risk for developing this disease and who might benefit most from finasteride. Initial studies will focus on:

• How variations in the genes for 5-alpha reductase (the target of finasteride), the androgen (male hormone) receptor, and enzymes that control androgen metabolism affect risk for prostate cancer;
• How variations in genes affect how finasteride works in the body and how people respond to the drug (pharmacogenomics);
• How levels of insulin-like growth factors, substances that stimulate cell division in many organs including the prostate, affect development of prostate cancer;
• The role of diet in prostate cancer risk; and
• How oxidative damage, DNA repair mechanisms, and inflammation affect prostate cancer development.

37. What other research is being done to try to prevent prostate cancer?

NCI is spending more than $310 million this year on research related to the prevention, detection, diagnosis, and treatment of prostate cancer. The largest prevention project under way is the Selenium and Vitamin E Cancer Prevention Trial (SELECT), a study to determine whether selenium and vitamin E, taken separately or together, can prevent prostate cancer. The study is recruiting men throughout the United States, including Puerto Rico, and in Canada.

For more information about SELECT and a list of participating centers:

In the United States (including Puerto Rico), call the National Cancer Institute's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237) for information in English or Spanish. The number for callers with TTY equipment is 1-800-332-8615.

In Canada, call the Canadian Cancer Society's Cancer Information Service at 1-888-939-3333 for information in English or French.

For more information about the Selenium and Vitamin E Cancer Prevention Trial, visit NCI's Web site at http://cancer.gov/select or visit SWOG's Web site at http://swog.org and choose SELECT.

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