Can prostate cancer be prevented?

Principal investigator Ian Thompson, M.D., sorts out the Prostate Cancer Prevention Trial’s findings and outlines finasteride’s risks and benefits

For men diagnosed with prostate cancer, the question of what to do next is probably foremost in their minds. Surgery? Radiation? Wait to see how quickly the tumor grows? But somewhere in the midst of all the soul-searching, many inevitably wonder, “Is there anything I could have done to prevent prostate cancer in the first place?”

In 1993, a group of researchers embarked on the first large-scale, population-based study to try to find an answer. Nearly 19,000 men, ages 55 and older, enrolled in a seven-year landmark study, dubbed the Prostate Cancer Prevention Trial (PCPT), to determine whether the drug finasteride (Proscar) could prevent prostate cancer. The choice of finasteride, typically prescribed for the relief of urinary symptoms associated with an enlarged prostate, was based on two observations:

1. Male hormones, or androgens, drive the development of prostate cancer. Two common androgens are testosterone and the more powerful dihydrotestosterone (DHT).
2. Men deficient in an enzyme called 5-alpha-reductase type 2 don’t develop an enlarged prostate (also called benign prostatic hyperplasia, or BPH) or prostate cancer. Without 5-alpha-reductase type 2, testosterone can’t be converted into DHT, which promotes prostate growth. (See “Two enzyme types,” below.)

Because finasteride tamps down 5-alpha-reductase type 2, researchers hypothesized that it would lower DHT levels and help prevent prostate cancer.

Researchers randomly assigned the 18,882 participants, who had a normal digital rectal examination (DRE) and a prostate-specific antigen (PSA) level of 3 ng/ml or lower, to take either 5 milligrams (mg) of finasteride or a placebo daily. In addition, participants had annual DREs and PSA tests. If the DRE was abnormal, or if the PSA or PSA level adjusted for finasteride had climbed above 4 ng/ml, a prostate biopsy was recommended. (See “Finasteride’s effect on PSA,” below.)

Fifteen months before the trial was scheduled to end, the independent Data and Safety Monitoring Committee, which tracks the health of participants, stopped the study because the evidence to that point was so striking: among those who took finasteride, the prevalence of prostate cancer was reduced by 24.8%. But the excitement was tempered by the fact that a higher percentage of men taking finasteride had aggressive tumors than men in the placebo group — 6.4% versus 5.1%. (See “Initial PCPT findings,” below.) Given the divergent findings, few doctors prescribed finasteride for prostate cancer prevention.

Researchers wondered, however, if perhaps the finasteride wasn’t making the tumors more aggressive, but simply making them easier to find. Their thinking hinged on the fact that finasteride shrinks the prostate. When doctors perform a prostate biopsy, they usually remove a set number of tissue samples, or cores — often eight to 12; at least six were required in the PCPT. If the same number of samples is taken from a relatively small prostate and from a relatively large one, the likelihood of finding an aggressive cancer is greater in the smaller gland (see Figure 1).

Researchers went back to the data. Pathologists carefully examined each of the 528 cancerous prostate glands that had been removed during the study. They also compared those specimens, and the cancers lurking inside them, to the original biopsy samples that were used to diagnose the cancers.

The conclusion, according to two separate groups of researchers who simultaneously published their findings in August 2008 in Cancer Prevention Research: finasteride was indeed making the aggressive tumors easier to find, not causing them. The other notable finding was that finasteride reduced the risk of all tumors — from indolent, slow-growing varieties to aggressive fast-growing ones — by 30%. In fact, the risk of a high-grade tumor dropped by 27%. (See “Recent PCPT findings.”)

Even with the newest findings, skeptics of finasteride’s ability to prevent cancer remain. They argue that the authors of the recent scientific papers are merely trying to erase their earlier findings and encourage more urologists to prescribe the drug. They suggest that men will be lulled into a false sense of security when they see their PSA levels drop while taking finasteride and perhaps bypass a biopsy, which may have detected a life-threatening cancer. They also point out that the drop in the risk of a positive biopsy between men on placebo and men on finasteride was only 10%, which was not statistically significant.

To learn more about the PCPT and the varying interpretations of the findings, editors at Harvard Health Publishing spoke with Dr. Ian Thompson, chairman of the Department of Urology at the University of Texas Health Science Center at San Antonio and the principal investigator for the PCPT. [Note: Dr. Thompson serves as a consultant to two companies and directs the proceeds of his work from them to the University of Texas Health Science Center at San Antonio. He also receives grant support from the National Cancer Institute.]

Finasteride findings

One of the original findings of the PCPT was that finasteride reduces prostate cancer risk by 25%. What else did you discover?

For the men who took it, finasteride reduced the risk of BPH-related events, such as urinary urgency, frequency, and retention, as well as the need for surgery, by about 30% to 50%, depending on the symptom. There was also a reduction in prostatitis, which is an interesting observation. A lot of people now use finasteride or dutasteride (Avodart) to ease symptoms such as perineal pain. Men taking finasteride also had fewer urinary tract infections.

One question we still want to answer is whether the men who reduced their risk for prostate cancer are the same ones who reduced their risk for BPH. This is a question I don’t know the answer to. I have a suspicion that the man who benefits from finasteride for preventing prostate cancer is probably not the same man who benefits from a BPH standpoint, but I don’t know.

Did men taking finasteride experience any sexual or hormonal changes?

While they did better in terms of genitourinary effects, men taking finasteride were more likely to experience erectile dysfunction, a reduced volume of ejaculate, loss of libido, and gynecomastia [breast enlargement] than men taking a placebo. Although statistically significant, the actual differences between the groups weren’t that large. In the finasteride group, for example, the rate of gynecomastia was 4.5% versus 2.8% in the placebo group, so the marginal increase was about 1.7%.

How did you measure changes in sexual function?

We measured changes in sexual function using a questionnaire called the Sexual Activity Scale. It preceded the International Index of Erectile Function, which is often used today, but they are both validated instruments and correlate very nicely. Scores on the Sexual Activity Scale range from 0 to 100, with higher scores corresponding to more sexual dysfunction. On average, the scores of men who took finasteride were 3.21 points higher than those reported for men taking the placebo. Interestingly, when you assess sexual function in more than 17,000 patients, that’s a statistically significant finding, but it’s less than the day-to-day variation in sexual function that an individual man experiences. We also found that the impact of the drug on sexual dysfunction decreased over time. So the effect of finasteride on sexual function was really minimal for most men. [For more details, see “Sexual function and the PCPT,” below.]

So the potential impact on sexual function hasn’t really deterred men from using finasteride?

I don’t think so. If it caused sexual dysfunction, the patient would stop taking the medication and sexual function would come back. The principal deterrent for its use has really been the initial finding related to high-grade disease.

To what do you attribute the difference in high-grade disease between the two groups?

The high-grade effect is probably best understood when you understand that a diagnosis of prostate cancer requires two things: First, it requires a physician to suspect that cancer is present. Second, when a biopsy is done, the needle must strike the cancer. So, if you walk into the doctor’s office with a Gleason 5 + 5 prostate cancer, but you have a normal DRE and your PSA is less than 4 ng/ml, you don’t have prostate cancer because the doctor has no reason to suspect that it’s there. Similarly, if you have a Gleason 5 + 5 prostate cancer with a volume of 1 cubic centimeter, and the doctor does a biopsy and misses it, you don’t have prostate cancer. Thus the risk of prostate cancer becomes the likelihood that the doctor suspects it times the likelihood that a biopsy finds it. What drives a doctor’s suspicion of cancer? The PSA and the DRE, both of which are highly affected by finasteride.

Let’s start with PSA. (I’m going to use the term elevated PSA here, although that’s a bit of a misnomer because PSA is a continuous variable.) Most people with an elevated PSA don’t have prostate cancer. If you put a man with an elevated PSA on finasteride, his PSA goes down. But if that man has prostate cancer, which is responsible for more PSA production, and you put him on finasteride, his PSA won’t really go down that much. So the group of men taking finasteride who have the highest levels of PSA is rich with cancer cases, and because PSA is directly proportional to the risk of high-grade disease, you have more cases of high-grade disease.

So a prostate cancer patient’s PSA level is not affected by finasteride?

The PSA is less affected than it would be in a man without prostate cancer. If you compare a man whose PSA level does not change when he’s on finasteride to a man whose PSA level falls by 65% or more while on finasteride, you’ll find that the risk of prostate cancer and of high-grade disease is three times less in the man whose PSA level falls. It’s a stepwise phenomenon, so for someone whose PSA drops by 50% to 64%, the risk is about 2.3 times less. I haven’t published these findings yet, but I have presented them — and they may have clinical implications. If a man walks into his doctor’s office with a higher PSA, the doctor could put him on finasteride and see what happens rather than immediately subject him to a potentially unnecessary prostate biopsy.

How does finasteride affect a DRE?

It turns out that the DRE is significantly more sensitive for cancer detection in someone on finasteride than in someone who isn’t. DRE sensitivity was also greater for detecting high-grade disease, but not statistically so, because DRE is such an imprecise test and because there are relatively few high-grade cancers. [See “Finasteride and DRE,” below.]

So finasteride shrinks benign glandular tissue and leaves the cancer unchecked, making it easier to feel any nodules?

Yes. And it turns out that if there is high-grade cancer in the prostate, the likelihood that a biopsy will find it is greater in men taking finasteride than in those who don’t. That’s simply because there is less normal tissue surrounding that cancer; in the PCPT participants, finasteride reduced prostate volume by an average of 24%.

As part of the PCPT, our pathology lab examined radical prostatectomy specimens from 528 participants — 222 from the finasteride group and 306 from the placebo group. (There were more of them in the placebo arm than in the finasteride arm simply because there were more cancers in the placebo arm.) With the samples from radical prostatectomy, we could determine the true grade of the cancer because we had the whole gland. With biopsies, you just get small tissue samples. When high-grade disease was present in the prostatectomy sample, we compared that finding to the biopsy sample. For men in the placebo arm, the biopsy found high-grade cancer about 50% of the time. For men in the finasteride arm, the biopsy found it 70% of the time. That means finasteride increased the sensitivity of biopsies for the detection of high-grade disease.

So that explains the original finding — that there were more cases of high-grade tumors in the finasteride group?

We think so, and our group and another group at the NCI [National Cancer Institute] have published reports of studies that support these conclusions. One study looked at how biases affected risk. If we adjust for the PSA bias, the DRE bias, and the biopsy bias that I just described, the risk of prostate cancer with finasteride drops by 30%, instead of 25%. For low-grade disease (Gleason 6 or less), it’s a 34% risk reduction, and for high-grade disease (Gleason 7 or higher), it turns out to be a 27% risk reduction.

Does finasteride do anything to developing precancerous lesions, or high-grade prostatic intraepithelial neoplasia (PIN)?

Well, we don’t know for sure that high-grade PIN [see Figure 2]  is a precursor to all prostate cancers, but we think that it is in at least a subset of cases. As part of the PCPT, we looked at the impact of finasteride on the diagnosis of high-grade PIN by biopsy. It turns out that the men in the finasteride arm of the study had a 21% lower risk of high-grade PIN on biopsy.

As we point out in one of our papers, how finasteride reduced the risk of prostate cancer in the PCPT isn’t well understood. But one possibility is that it reduces the chances of high-grade PIN in tissue, thus making prostate cancer less likely. The other possibility is that finasteride targets both prostate cancer and high-grade PIN.

How do you respond to those who aren’t convinced by the reanalysis of the PCPT data and discourage the use of finasteride for the prevention of prostate cancer?

Well, I think the numbers speak for themselves. If you look at the lifetime risk of prostate cancer, it’s about 16%. With finasteride, there’s a 25% relative risk reduction, which translates to an absolute risk reduction of 4%. So we need to treat 25 men to prevent one prostate cancer. Let’s compare that to the value of taking statins for the prevention of a fatal heart attack. Statins have an absolute risk reduction of about 1%. So in terms of the public health impact, taking finasteride for prostate cancer prevention is right up there with the other things that we do for disease prevention. [Note: The American Society of Clinical Oncology and the American Urological Association issued a guideline for the use of 5-alpha-reductase inhibitors in February 2009, after this interview with Dr. Thompson took place. For a summary of the recommendations and additional information, see “Clinical practice guideline for 5-alpha-reductase inhibitors,” below.]

Finasteride’s image

If finasteride can lessen pain and other symptoms of an enlarged prostate and reduce the likelihood of prostate cancer, why isn’t it routinely prescribed?

If a friend tells you not to go to a particular restaurant because they serve the food cold, you won’t go there even if it is the best restaurant in the world. It’s like that with finasteride. People have heard that it causes high-grade disease, so despite the new findings, they say, “I’d never use it.” You’ve got one chance to make a good impression. The other problem is that finasteride is now a generic drug.

That means pharmaceutical companies aren’t promoting brand-name versions of finasteride. With generic versions available, there’s no opportunity for them to make money on it and no financial reason to promote it, right?

That’s right. I’ve been to an international meeting where people from Europe asked representatives from the NCI why they don’t bring finasteride to the FDA so that it can be officially approved for the prevention of prostate cancer. But the NCI can’t do that. A manufacturer has to take it to the FDA. But you can see that there isn’t any incentive for manufacturers to do that.

The PCPT wasn’t sponsored by Merck?

No, and this is often misunderstood. The pharmaceutical company Merck sells finasteride under the name Proscar. But Merck doesn’t have exclusive rights to finasteride. The company did supply the drug and the placebos for study participants, but it didn’t fund the trial. The company was allowed to have the primary data from the trial if it wanted to take the drug to the FDA, but it wasn’t a Merck trial. It was an NCI trial.

What’s next?

Presumably, researchers will continue to mine data from the PCPT and report their findings. Where can our readers turn for more information in the future?

The National Cancer Institute includes information about the PCPT on its Web site, as well as links to published papers and general information on prostate cancer. To access that information, log on to www.cancer.gov/pcpt.

What are some of the ideas that have emerged from the PCPT that researchers are now pursuing?

Well, we have an ongoing project related to BPH. We gathered supplemental information related to diet, and we are analyzing that. We are also looking at the genetics of prostate cancer. For example, there can be variations in a gene that codes for 5-alpha-reductase type 2, potentially altering the effectiveness of finasteride. We have DNA from a lot of the men in the trial, so we are looking at androgen and estrogen levels and their impact on prostate cancer and their interactions with genes and finasteride.

Our goal is to figure out how prostate cancers, including high-grade cancers, develop and to better understand how finasteride reduces a man’s risk for them. The ideal would be to know who is going to get prostate cancer, and of those men, who should take finasteride to prevent it. That’s what we’d really love to know.

Originally published April 1, 2009; last reviewed April 7, 2011.