Key Points 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. (Question 1) Who participated 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. (Question 2) What were the results of the PCPT? Men taking the drug finasteride developed 25 percent fewer prostate cancers than men not taking the drug. (Question 10)

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 Prostate Cancer Prevention Trial?

The 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 was funded by the National Cancer Institute (NCI), which gave $73 million in grants to the Southwest Oncology Group (SWOG). SWOG, a network of cancer researchers at medical centers around the U.S., coordinated and carried out 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.

2. Who participated 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?

They didn't. Men joining the trial had to have a digital rectal exam or DRE (where the doctor feels the prostate through the rectum to find hard or lumpy areas) that showed no sign of prostate cancer and a prostate-specific antigen, or PSA, blood level of 3.0 nanogram/ milliliter (ng/ml) or less. PSA is a substance made by the prostate gland. In 1993, when the PCPT began, men with a PSA level of 4.0 ng/ml or less were considered to be at very low risk of prostate cancer. To further reduce the chance that a man might enter the trial with an early, undiagnosed prostate cancer, a cutoff level of 3.0 ng/ml was chosen.

The only way to know for sure that a man has prostate cancer is to examine cells from his prostate under a microscope. This can be 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.

4. 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.

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.

5. 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, and the corrected number was used.

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 at least six small pieces of prostate tissue. The samples were then examined under a microscope to check for cancer. These were called end-of-study biopsies.

6. 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. 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. The method most often used for 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) are more likely to grow quickly and spread beyond the prostate than lower-grade tumors. Gleason scores from biopsies give a preliminary assessment of overall grade because biopsies provide only a sample of the prostate tissue. Evaluation of the whole prostate after prostatectomy is the best assessment of tumor grade.

About Finasteride

7. What is finasteride and how does it work?

Finasteride is a drug that 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. The prostate gland of men taking finasteride shrinks.

Finasteride works by blocking the action of an enzyme, 5-alpha reductase, which 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.

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®.

8. Why was finasteride tested to prevent prostate cancer?

9. 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 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

10. What were the initial results of the PCPT?

The PCPT was the first study to show that a drug can reduce a man's chances of developing prostate cancer. Men randomized 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) there was a slight increase in high-grade disease among men in the finasteride arm (6.4 percent of men in the finasteride group vs. 5.1 percent of men in the placebo group). High-grade tumors (Gleason score 7-10) are more likely to grow quickly and spread beyond the prostate than lower-grade tumors.

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

In the initial analysis, ten men died from prostate cancer during the study; five of these men were assigned to take finasteride and five were assigned to placebo.

12. How many prostate cancers were diagnosed by the end-of-study biopsy, and were these cancers similar to 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 suspicious DRE or an elevated PSA. Prostate cancers found at end-of-study biopsy were similar to cancers found during the trial.

13. 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.

Other Concerns

14. 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.

15. 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.

The drug dutasteride (sold as Avodart® by GlaxoSmithKline, UK), is also prescribed for BPH and works similarly to finasteride. The manufacturer of this drug began a study in 2004 called REDUCE (Reduction by Dutasteride of Prostate Cancer Events) in men with suspicious PSA levels and negative biopsies, who may be at increased risk for developing prostate cancer (ClinicalTrials.gov identifier: NCT00056407). Results from this study are not yet available.

16. 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.

17. 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.

Additional Research

18. What else has been found in the PCPT data about prostate cancer and finasteride since the trial ended?

• Finasteride improves detection of prostate cancers. Finasteride has several effects on the prostate that allow better detection of prostate cancers. The drug shrinks the prostate, reducing its size and volume and increasing the chance that a biopsy will find existing cancers. This is true for all grades of prostate cancer, including high-grade disease. In addition, detection of overall cancers by DRE is also improved.
• Men taking finasteride may not have an increased risk of high-grade prostate cancer. Adjusting for the known effects that finasteride has on prostate cancer detection, investigators estimated that high-grade tumors (Gleason scores 7-10) were no more likely in the men taking finasteride than in the men taking placebo. However, because very few prostate cancers were detected at Gleason scores of 8 to 10, it is difficult to draw conclusions about this group.
• Finasteride prevents cancer for which treatment would be recommended. Men receiving end-of-study biopsies in the PCPT would not have been diagnosed with prostate cancer outside of the trial. Some experts questioned if it was necessary to try to prevent them. Analysis of biopsy specimens from the PCPT indicate that the majority (75 percent) of all cancers in the PCPT, and 60 percent of tumors with a Gleason score of 6 or less (the cancers finasteride is known to prevent) were found to be 'clinically significant', meaning that most doctors would recommend a patient receive treatment.
• Finasteride decreases risk of a precursor to prostate cancer. One kind of microscopic change in the prostate known as high-grade prostatic intraepithelial neoplasia (PIN) may be a precursor to prostate cancer. Finasteride significantly decreased the overall risk of high-grade PIN in men on the PCPT at about the same rate that it decreased risk for prostate cancer.
• Prostate cancer, including high-grade cancer, can be present even when PSA levels are 4.0 ng/ml or less. About 15 percent of men on placebo who had PSA levels of less than 4.0 ng/ml were found to have prostate cancer at the end-of-study biopsy. Of the men with cancer, nearly 15 percent had tumors with a Gleason score of 7 or higher (2.3 percent of all the men who had an end-of-study biopsy). These results do not mean that the PSA level at which a physician recommends biopsy should be lowered, but rather highlight the difficulty of treating any PSA level as a yes/no test.

19. 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 men diagnosed with prostate cancer during the trial were 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 is looking 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.

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

NCI is conducting 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 recruited more than 35,000 men throughout the United States, including Puerto Rico, and in Canada.

Additional materials and resources:

For more information on PCPT, call the National Cancer Institute's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237) for information in English or Spanish. Or visit http://www.cancer.gov/pcpt.

For a press release about the initial PCPT results, please go to http://cancer.gov/newscenter/pressreleases/PCPTresults.

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