New drugs for the prostate

Content provided by the Faculty of the Harvard Medical School

New drugs for the prostate

Medicine is a rapidly changing field. New discoveries in basic research continue to uncover the body’s innermost secrets, explaining how it works in health and what goes wrong in disease. New diagnostic techniques allow doctors to recognize abnormalities with more precision than ever before. And a steady stream of new treatments continues to improve the outlook for patients with a broad range of problems.

This progress is wonderful, but many challenges remain and new ones continue to arise. Although the need for further advances is great, sometimes even urgent, science usually progresses in evolutionary stages rather than revolutionary breakthroughs. It’s particularly true of medications; some new drugs are indeed unique and novel, but many are modifications of existing drugs.

Developing, testing, and marketing new medications is expensive — and a business. That means drug manufacturers are likely to advertise the possible advantages of new products with great vigor. Those advantages may be substantial or minimal; and even when a new medication has real merit, it’s often offset by a higher price. And because clinical experience is limited when a drug is first approved, it takes time to learn if the benefits hold up and to recognize any side effects.

The drug treatment for prostate disorders has come a long way. As of spring 2005, new prescription medications are available for the two leading diseases, benign prostatic hyperplasia (BPH) and prostate cancer. Although the medications do not represent dramatic breakthroughs, they can be helpful. Men with prostate problems should understand what’s behind the names scribbled on their doctor’s prescription form.

Benign prostatic hyperplasia

Although it’s usually called “enlargement of the prostate,” BPH is actually a bit more complex. It begins with tiny microscopic nodules in the transition zone of the prostate. The location is important because the transition zone surrounds the urethra, the tube that carries urine from the bladder through the prostate, then out through the penis. Over time, the nodules of BPH enlarge and become macroscopic nodules. This slow process starts in midlife and continues at a steady pace; nearly all men who live to the age of 85 have macroscopic nodules of BPH. But the nodules won’t cause any trouble unless they press on the urethra, restricting the flow of urine much as a gardener’s foot can pinch a hose. About 25% of all 80-year-old men have symptoms of BPH that are troublesome enough to warrant treatment, and many others have milder symptoms that don’t require medical therapy.

BPH responds to a number of treatments. Many gents with mild to moderate symptoms can manage the problems themselves with simple lifestyle adjustments (see below); others may decide to try herbal preparations such as saw palmetto. But if the symptoms remain bothersome, more effective treatments are available. These symptoms may include a weak, slow urinary stream, a hesitancy and straining to urinate, prolonged voiding, dribbling at the end of urination, an inability to empty the bladder completely, an urgent, sometimes uncontrollable need to void, the frequent passage of small amounts of urine, and nighttime urination (nocturia).

Men with complications such as urinary bleeding, recurrent urinary tract infection, acute urinary retention, and kidney damage due to back pressure from urine (hydronephrosis) need treatment. Fortunately, these problems are relatively uncommon. Men with uncomplicated BPH can reasonably decide to “live with” symptoms that don’t impair their quality of life to a significant degree. And men who are bothered enough to seek treatment can choose between an expanding array of surgical therapies and an increasing number of prescription drugs.

As of the mid-2000s, doctors can use two very different types of drugs to treat BPH, and each category has a new entry. In addition, one study suggests that a combination of medications from each group may help more than either type alone.

Alpha blockers

Alpha blockers don’t change the size or structure of the prostate. Instead, they relax the smooth muscle cells in the bladder neck and in the prostate itself. As the muscles relax, the pressure on the urethra diminishes, allowing urine to flow more freely. About 70% of men with BPH experience benefit from an alpha blocker, usually a mild to moderate reduction in symptoms. The alpha blockers act quickly, taking effect in days to weeks, but their benefits disappear just as rapidly if they are discontinued.

All the alpha blockers work the same way, and all have similar success rates. But they do have different side effects and drug interactions. The difference depends on whether the medications act selectively on the smooth muscle cells in the urinary tract or if they also relax the smooth muscle cells in the walls of arteries throughout the body

The older alpha blockers act on both groups of muscles. In fact, terazosin (Hytrin) and doxazosin (Cardura) were originally developed to treat high blood pressure; they continue to fill that role but are considered third-tier antihypertensive medications. Because they lower blood pressure, the nonselective alpha blockers can produce lightheadedness, dizziness, or even fainting, particularly when men stand up quickly. It also means that they should be used with caution by men with a somewhat low blood pressure, by men taking other antihypertensives, and by men taking sildenafil (Viagra) — and they should not be used at all by men taking vardenafil (Levitra) or tadalafil (Cialis) for erectile dysfunction. Finally, the potential to lower blood pressure means their dosage must be adjusted gradually. Doctors usually start with 1 milligram (mg) of either medication at bedtime, and then gradually increase it as needed to a maximum of 10 mg of terazosin or 8 mg of doxazosin.

The third alpha blocker, tamsulosin (Flomax), is a bit different. It is a selective alpha blocker, which is much more active on the prostate and bladder than the arteries, so it’s much less likely to lower blood pressure. As a result, dosing is simpler: 0.4 or 0.8 mg is taken 30 minutes after dinner. A low dose of tamsulosin can be used cautiously by men taking vardenafil or tadalafil.

The newest alpha blocker for BPH as of 2005 is alfuzosin (Uroxatral). Like tamsulosin, alfuzosin is a selective alpha blocker, so it does not lower blood pressure. Its major advantage is that it appears less likely to cause diminished or retrograde (“dry”) ejaculation, a problem for some men taking tamsulosin. The most common side effect is dizziness, which occurs in about 5% of patients. Uroxatral is a time-release formulation of alfuzosin, so a single 10-mg tablet is taken once a day immediately after a meal. It has not been evaluated in men taking pills for erectile dysfunction, but it’s probably similar to tamsulosin.

Alfuzosin costs about the same as the 0.4-mg dose of tamsulosin, but generic preparations of terazosin and doxazosin are considerably less expensive: Age does, after all, have some advantages.

DHT inhibitors

Unlike the alpha blockers, the second group of drugs for BPH actually shrink the gland. The prostate is stimulated by the male hormone testosterone. But these drugs don’t stop the testicles from producing the male hormone, nor do they reduce the amount in the blood. Instead, they inhibit 5 alpha-reductase, the enzyme that normally converts testosterone to dihydrotestosterone (DHT), the chief male hormone in the prostate. This selective action explains why these medications affect some male traits without changing others. Because DHT is central to testosterone’s action in the prostate and the hair follicles, the inhibitors are active in these regions. But since testosterone can act in other tissues without being converted to DHT, they do not influence other male characteristics such as sperm production, musculature, or voice, and they affect libido and potency only infrequently.

In 1992 the first 5 alpha-reductase inhibitor, finasteride, was greeted enthusiastically when it was marketed in a 5-mg dose as Proscar. Until then, surgery was the only effective treatment for BPH. Some of that enthusiasm has worn off as it has become clear that finasteride does not help all men with BPH and as alpha blockers have proved their worth.

By inhibiting one of the two forms of 5 alpha-reductase, finasteride reduces DHT levels in the blood by about 70% and in the prostate by about 90%. On average, the drug takes three to six months to begin reducing the size of the prostate, and the gland may continue to shrink during the next 12–18 months if treatment is continued. At its maximum, however, finasteride shrinks the gland by only about 20%.

Although finasteride reduces the size of the prostate in most men, it relieves symptoms for only about a third of men with BPH. The men who benefit most are those with the largest prostates. Because prostate size can be estimated with a digital rectal exam (DRE) and measured more accurately with a transrectal ultrasound (TRUS), it is possible to predict which patients are likely to be helped. In general, men with glands smaller than 30–40 ml should not expect to improve. In men with larger glands, though, the drug can reduce symptoms, control urinary bleeding caused by BPH, lower the risk of acute urinary retention, and lower the need for surgery.

The new player in the 5 alpha-reductase-inhibitor game as of spring 2005 is dutasteride (Avodart). It inhibits both forms of 5 alpha-reductase; a 0.5-mg dose reduces DHT levels in the blood by 93%, which is a bit more than finasteride does. Like finasteride, it has no effect on testosterone levels. Dutasteride also acts slowly, producing some reduction in symptoms in as little as one month, with maximum benefit in six months. Over a 2– to 4–year period, dutasteride shrinks the average prostate by about 26%.

Although finasteride and dutasteride have not been compared in head-to-head trials, they seem very similar in their effectiveness. To benefit, however, men must take the medication every day. Even with prolonged use, the drugs appear equally safe. Impotence is the only major side effect, but it develops in just 4%–5% of men, and it diminishes when treatment is discontinued. Both drugs are expensive, costing over $2 a day.

Unlike the alpha blockers, the 5 alpha-reductase inhibitors reduce prostate specific antigen (PSA) levels by about 50%, complicating the screening for prostate cancer. Men who choose to monitor their PSAs should take the test before starting the drug and another after 6–12 months of therapy.

How do the 5 alpha-reductase inhibitors compare to the alpha blockers? Only the older drugs have been investigated to date. A 1996 study of 1,229 men compared terazosin, finasteride, and a combination of the two with a placebo. At the end of a year, terazosin was the clear winner. Combination therapy was no better than the alpha blocker alone. Finasteride was no better than the placebo, but that does not mean the drug is worthless, since many men in the study did not have the large prostates that respond best to finasteride. A one-year trial of doxazosin and finasteride in 1,095 men with BPH reported similar results. However, a major 2003 trial found potentially important benefits for long-term combination therapy. In that study, 3,047 men with BPH were randomly assigned to take doxazosin, finasteride, a combination of the two, or a placebo. After 4½ years of observation, the combination reduced the risk of BPH progression by 66% compared to the placebo’s result, while doxazosin reduced risk by 39%, and finasteride reduced it by 34%. Even more impressive was the finding that single-drug treatment with doxazosin did not prevent acute urinary retention or reduce the need for surgery, while finasteride was effective and combination treatment was somewhat better.

This large study shows that doctors are learning to use old drugs in new ways. But it’s too soon to recommend combination therapy for all men with moderate BPH. For one thing, serious complications were uncommon even in men taking only an alpha blocker. For another thing, the Prostate Cancer Prevention Trial found that finasteride had a mixed effect on risk, reducing the overall incidence of cancer by 25% but increasing the incidence of high-grade cancer.

Similar trials of dutasteride are under way; until results are available, the only apparent differences between the 5 alpha-reductase inhibitors are the greater experience with the older drug and the fact that only finasteride is available in a reduced dose for male pattern baldness (Propecia, which contains 1 mg of finasteride).

Prostate cancer

The treatment of prostate cancer is much more controversial and complex than the treatment of BPH. Men who are diagnosed with early disease still confined to the prostate gland face a choice of surgery, radiotherapy, or watchful waiting. But it’s even more complex than that, since a radical prostatectomy can be performed with the traditional open approach or the new laparoscopic technique, and radiotherapy can be accomplished with external beam treatment or brachytherapy (seed implants) with or without androgen-deprivation medication.

Men with advanced disease usually benefit from androgen-deprivation therapy. Like normal prostate cells, malignant cells are stimulated by testosterone and other male hormones. By sharply reducing the levels of androgens, the growth of prostate cancer cells is halted, often for years.

Androgen-deprivation therapy is hardly new; it dates back to the Nobel Prize–winning work of Huggins and Hodges in 1941. The earliest form of androgen deprivation was orchiectomy, surgical removal of the testicles. It’s still a very effective option but is rarely selected by men today. The second form of treatment, estrogen therapy, has also fallen by the wayside. At present, most men are treated with more specific medications, and that’s where the new drug, abarelix (Plenaxis), fits in. To understand how it works and how it compares to its older rivals, you have to review the lengthy chain of events linking hormones to the prostate (see figure below).

The androgen cascade and prostate drugs BPH drugs DHT blockers inhibit 5 alpha-reductase. Without this enzyme, levels of DHT drop, which in turn can keep prostate cells from enlarging. Prostate cancer drugs LHRH agonists act like the LHRH produced in the body. These drugs flood the pituitary with messages to crank out LH. This causes a temporary rise in levels of testosterone until the receptors in the pituitary are full up and can't respond to further stimulation; then testosterone levels drop sharply. GnRH antagonists surreptitiously act against the body's LHRH. These drugs slip into receptors in the pituitary so that the gland cannot respond to the normal pulses of LHRH from the hypothalamus. Thus, LH and testosterone are suppressed with no initial surge of these hormones.

It all begins in the brain, where the hypothalamus produces the hormone that starts things off. Although it is a single protein, it has two names: gonadotropin-releasing hormone (GnRH) and luteinizing hormone-releasing hormone (LHRH). Hormones are chemicals that are produced in one part of the body before traveling to another part, where they do their work. LHRH is a true hormone, but it does not have to travel very far to do its job. Instead, it acts on another part of the brain, the pituitary gland, where it stimulates the release of two additional hormones, follicle-stimulating hormone (FSH) and luteinizing hormone (LH).

FSH and LH were named by scientists who discovered that they stimulate the female ovary. But they are just as important for men. LH stimulates the Leydig cells in the testicles to produce testosterone, the primary androgen or male hormone. About 95% of a man’s androgens are produced by his testicles, the remainder by his adrenal glands, which are not controlled by LH or FSH.

After testosterone enters the blood, about 95% of the hormone is bound to proteins, while 5% circulates free. The free testosterone acts on the prostate by diffusing into its epithelial cells. Androgens from the adrenal gland also enter prostate cells, where they are converted to testosterone.

After testosterone enters the prostate cells, it is converted to dihydrotestosterone; the enzyme 5 alpha-reductase is responsible for the conversion.

DHT is the final hormone in the long and complex chain from the brain to the prostate. DHT binds to androgen receptors in the prostate cells. The DHT-receptor complex turns on the cells’ DNA, stimulating cellular growth.

It is a complex series of events, but it’s important to all men. It starts the prostate growing in adolescence and causes the additional enlargement of BPH in older men (see above). And it stimulates the growth of malignant cells in men with prostate cancer.

This chain can be interrupted in several ways. At present, the standard medications are the LHRH agonists. These synthetic drugs resemble LHRH, but unlike the real thing, they inhibit the release of LH and FSH by the pituitary, thus reducing testosterone levels as much as orchiectomy. Their side effects are also similar to those of orchiectomy, including a loss of libido, hot flashes, and breast enlargement. The major preparations are goserelin (Zoladex), leuprolide (Lupron, Eligard, Viadur), and triptorelin (Trelstar). All are administered by injection, and all are very expensive.

The new entry in the LHRH agonist field is histrelin. Long used for various pediatric and gynecological disorders, a new preparation of the drug, Vantas, has received FDA approval for advanced prostate cancer. It has the same clinical advantages and side effects as the older LHRH agonists, but it differs in one important respect: convenience. The older members of the group require injections every 1–4 months, but Vantas is administered just once a year. But to gain that advantage, histrelin comes in a hydrogel capsule that is implanted under the skin of the inner surface of the patient’s upper arm in a simple office procedure. To continue therapy, the implant must be replaced every 12 months. Because Vantas is new, experience is limited, but most men find the procedure quick and painless.

The LHRH agonists take about a month to work. By itself, the delay would not be worrisome, but during the first month of therapy, these medications actually increase blood testosterone levels, which could worsen symptoms of prostate cancer. To prevent the early testosterone surge, doctors usually prescribe anti-androgen tablets for about 2–4 weeks. The major preparations are bicalutamide (Casodex), nilutamide (Nilandron) and flutamide (Eulexin). They are expensive, and they may cause breast enlargement and diarrhea.

The new medication for advanced prostate cancer is a GnRH antagonist. Abarelix (Plenaxis) suppresses the production of LH and FSH, reducing testosterone levels. Unlike the older LHRH agonists, however, abarelix does not cause an early surge in testosterone levels, so anti-androgen tablets are not required.

Abarelix is administered by injection on days 1, 15, and 29 and every 28 days thereafter. It is very expensive, and patients must be monitored for at least 30 minutes after each injection because it can cause serious allergic reactions. In addition, since the drug may become less effective over time, blood testosterone levels should be checked every two months. Because of these limitations, abarelix should probably be reserved for men who are not good candidates for LHRH agonists and who decline orchiectomy.

The prostate is a puzzling little organ, and doctors are still learning how to best treat its disorders, both benign and malignant. More advances are sure to follow, and new drugs will be part of the progress. By then, the three medications discussed here will be old hat.

Last updated:	August 21, 2006