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Management of BPH

Pharmacotherapy

Drug therapy for BPH has increased in popularity because of the improvement in the medical treatments available and the limitations associated with surgical procedures, such as potential serious morbidity, failure to achieve a successful outcome consistently, a frequent need for retreatment and patients' preference. There are two major classes of drugs with proven efficacy in the treatment of patients with BPH. The a-blockers provide rapid symptom relief, but do not reduce the risk of serious outcomes of BPH progression such as AUR and BPH-related surgery.

The 5ARIs do not act as rapidly, but do reduce the size of the prostate, provide longterm symptom relief and lower the risk of detrimental long-term outcomes associated with disease progression.

a-Blockers
a-blockers relieve the symptoms of BPH by causing smooth muscle relaxation through blockade of the a₁-adrenoceptors in the prostate, the base of the bladder and proximal urethra. Several a₁-adrenoceptor subtypes have been identified, including a_1A, a_1B and a_1D, with a_1A being the predominant subtype localised in the prostate. This smooth muscle relaxation results in an increase in urinary flow rate and an improvement in LUTS. Several a-blockers selective for a₁-adrenoceptors are currently available for the treatment of BPH, including prazosin, indoramin, alfuzosin, doxazosin, terazosin and tamsulosin.

Meta-analyses of alfuzosin, doxazosin, tamsulosin and terazosin studies have demonstrated statistically significant improvements compared with placebo in symptom scores, with no significant difference between the agents on direct comparison.^52,53 Data for the slow-release form of alfuzosin, unavailable at the time of these analyses, have shown a similar degree of efficacy.⁵⁴ Typically, the a-blockers provide a 2-4 point decrease in AUA-SI versus placebo, with symptom improvement being observed within 1-2 weeks and maintained for up to 48 months.^51,55 They are also associated with improvements in Q_max, quality of life and BPH Impact Index (BII).¹⁶ Despite the improved symptom relief provided by a-blockers, they have no demonstrable effect in reducing prostate volume or lowering the long-term risk of AUR and BPH-related surgery in large-scale randomised studies.¹⁶

Differences in selectivity for a₁-adrenoreceptor subtypes may, however, translate into differences in tolerability between the a-blockers. Tamsulosin is more selective for the a_1A and a_1D subtypes than the earlier a-blockers - prazosin, doxazosin and terazosin - resulting in a more favourable cardiovascular adverse event profile. The sustained-release, once-daily formulation of alfuzosin has a similar cardiovascular adverse event profile to tamsulosin.

Prazosin, doxazosin and terazosin
Treatment with prazosin - the first selective a-blocker to be developed - resulted in an improvement in LUTS, but this effect was not sustained and the incidence of adverse effects was high.⁵⁶ The need for twice-daily dosing with prazosin also adversely affects patient compliance.

The next selective a-blockers to be developed were doxazosin and terazosin. These have fewer adverse effects and the advantage of once-daily dosing.^56,57

However, all of these drugs are associated with hypotension (particularly after the first dose), sedation and dizziness. Treatment must therefore be initiated with a low dose taken at bedtime and titrated upwards over a few weeks.

Tamsulosin and sustained-release (SR) alfuzosin
Tamsulosin is more specific in action than the earlier agents, selectively blocking the a_1A- and a_1D-adrenoceptor subtypes.⁵⁸ Consequently, it rarely causes a clinically significant reduction in blood pressure, and thus does not require early dose titration. However, placebo-controlled trials,^58-60 and open-label extension studies,⁶¹ have demonstrated an increased incidence of retrograde or delayed ejaculation with tamsulosin.

Although the specific a1-adrenoceptor target for SR alfuzosin has not been confirmed,it appears to be uroselective.⁵⁵ As a result, it also has a low risk of first-dose hypotension, eliminating the need for dose titration.^55,62

5a-reductase inhibitors

There are two types of 5a-reductase (5ARIs). The type 2 isoenzyme is located primarily in stromal tissue of the prostate, and is critical for the normal development of the prostate; it is also involved in the development of BPH. The type 1 isoenzyme converts testosterone into DHT in peripheral tissues such as the skin and liver, but is also present in the prostate, in lower concentrations than the type 2 isoenzyme. Finasteride inhibits type 2 only, however dutasteride inhibits both type 1 and type 2.

5a-reductase (5ARIs) act specifically to inhibit the enzyme 5a-reductase, which converts testosterone to the active intra-prostatic hormone dihydrotestosterone (DHT). The reduced level of DHT in the prostate leads to a decrease in prostate volume and an associated increase in urinary flow rate, improvement in LUTS, a reduced risk of AUR and a decreased need for BPH - related surgery over the long term.

Finasteride
Finasteride (Proscar) - the first 5ARI to be used for the treatment of BPH - inhibits the type 2 isoenzyme of 5a-reductase resulting in approximately 70% reduction in DHT levels (see Development of BPH for more detailed information on the role of DHT in BPH). The Proscar Long-term Efficacy and Safety Study (PLESS)was a double-blind, randomised study involving 3,040 men with moderate-to-severe LUTS and enlarged prostates. Patients were treated with finasteride 5.0mg daily for 4 years. At the conclusion of the trial, finasteride was associated with an 18% reduction in prostate volume, a 3.3 point improvement in symptom score and a 1.9ml/s improvement in urinary flow rate. Patients treated with placebo exhibited continued prostate growth in 90% of cases, with an average prostate volume increase of 14% over 4 years.⁶³

A meta-analysis of six studies to evaluate the use of finasteride in BPH demonstrated that finasteride is most effective in men with large prostates (³40cc).⁶⁴ Guidelines recommend finasteride for 'clinically enlarged prostates',⁹ or prostates larger than 40cc. The adverse effects observed with finasteride are primarily related to sexual function, and include impotence, decreased libido and ejaculation abnormalities.

Dutasteride Summary of Product Characteristics

Dutasteride

Dutasteride inhibits both type 1 and type 2 isoenzymes of 5a-reductase, leading to near maximal suppression of DHT production of 85% after 1 week and 90% after 2 weeks. DHT suppression of greater than 93% is seen following 1 and 2 years of treatment. (Click here for more detailed information on the role of DHT in BPH). The effect of dutasteride on the treatment and progression of BPH has been evaluated in three controlled, double-blind, phase III studies. Since all three studies had similar designs and endpoints data were pooled for analysis. 4,325 men aged over 50 with a moderate to severe BPH (AUA-SI >12, Q_max =15ml/sec), a prostate volume of =30cc (assessed by TRUS) and a PSA greater than 1.5 and less than 10ng/ml participated in the studies.

Significant reductions in prostate volume (relative to placebo) were observed as early as 1 month after the initiation of treatment with dutasteride and continued throughout the studies (p<0.001). The mean decrease in total prostate volume from baseline with dutasteride was 23.6% at month 12 and 25.7% after 24 months.

Patients receiving dutasteride achieved statistically significant improvements in symptoms (relative to placebo) as early as 3 months in one study, and by 6 months in the pooled data from all three studies. At month 24, the mean change in AUA-SI score across all three studies was -4.5 points for dutasteride compared with -2.3 points for placebo (p<0.001).

Pooled data from three pivotal efficacy studies show a decrease in AUA-SI scores from baseline (at visit values)

Significant improvements in urinary flow (Q_max relative to placebo) were achieved within 1 month of therapy and continued throughout the study (p<0.001). At month 24, the adjusted mean increase in Q_max was 2.2ml/s in the dutasteride-treated patients, compared with 0.6ml/s for placebo. This represents a mean difference of 1.6ml/s.

Pooled data from three pivotal efficacy studies show a mean increase in Q_max over 24 months (at visit data)

The reduction in prostate volume and improved Q_max achieved with dutasteride therapy was associated with a significant reduction in both the risk of AUR (57% reduction in risk at 2 years) and the need for BPH related surgical intervention (48% risk reduction at 2 years).

Pooled data from three pivotal efficacy studies show a reduction in risk of acute urinary retention over 24 months (Kaplan-Meier curve for first episode of acute urinary retention)

Pooled data from three pivotal efficacy studies show a reduction in risk of BPH-related surgery over 24 months (Kaplan-Meier curve for first episode of surgery)

A significant improvement in BII score was seen from month 6 in patients receiving dutasteride and this was sustained through to the end of the study at 2 years⁶⁸ These data show that the impact of dutasteride therapy on DHT levels and clinical parameters - such as symptoms, risk of AUR and prostate size - translate into improvements in quality of life for patients.

Efficacy assessments according to baseline prostate volume
Dutasteride is effective at reducing prostate volume and symptoms, improving Q_max, and lowering the risk of AUR and BPH-related surgery in men with a prostate volume ³30-<40cc and ³40cc. Of the 4307 patients randomised to treatment with dutasteride or placebo who had baseline prostate volume recorded, 1223 had a baseline prostate volume ³30-<40cc and 3084 had a baseline prostate volume ³40cc. Demographics and other baseline clinical characteristics were generally comparable between patients with baseline prostate volumes ³30-<40cc and ³40cc, and between the dutasteride and placebo groups. Dutasteride significantly reduced prostate volume compared with placebo from month 1 to month 24 for patients with a prostate volume ³30-<40cc and ³40cc (p<0.001) and was significantly more effective than placebo at reducing the risk of AUR regardless of baseline prostate volume. Among patients with a baseline prostate volume ³30-<40cc and ³40cc, dutasteride reduced the risk of AUR by 85% and 55% respectively and the risk of BPH-related surgical intervention by 35% and 52% respectively. Dutasteride significantly increased Q_max, and decreased symptom scores and BII scores, versus placebo within each baseline prostate volume subgroup.⁸³

Dutasteride Long-Term Efficacy - 4-year data⁶⁹

The phase IIIa efficacy studies for dutasteride had an optional 2 year open label extension period in which patients initially receiving dutasteride in the double-blind phase were maintained on dutasteride (D/D group), whilst those initially receiving placebo were converted to dutasteride (P/D group). Patients who completed the 2 years of double-blind phase were eligible to participate in the open-label phase. Participation in the open-label phase was optional with consent obtained from each patient on entry to this phase of the trial. A total of 2,340 patients participated in the open-label phase (1188 to the D/D group, 1152 to the P/D group)

DHT suppression of greater than 93% was maintained over 4 years for the D/D group. Patients in the P/D had a 95.4% decrease from baseline to 4 years. At 4 years 87% of patients in the D/D group and 89% of patients in the P/D group had a reduction in DHT ³90%.

Effect on prostate volume
From baseline to month 24, patients treated with dutasteride had a mean reduction in prostate volume of 26.0% compared with a mean increase of 1.4% for placebo-treated patients. (p<0.001 between treatment groups, see below).

Mean change (%) in total prostate volume from baseline over 48 months.

At month 48, prostate volume in the P/D group was reduced 21.7% from baseline, which was a significant decrease from month 24 (p<0.001). Although prostate volume continued to decrease during the open-label phase in the D/D group, this decrease was not statistically significant from month 24. However, the overall reduction in prostate volume from baseline to month 48 in D/D-treated patients was significantly greater than that observed in P/D patients (-27.3%, p<0.001).⁶⁹

Symptomatic relief
Patients in the D/D group had a mean reduction in AUA-SI score of 4.4 points versus 2.5 points for placebo-treated patients at month 24 (p<0.001 between treatment groups, see below).

Mean change in AUA-SI scores from baseline over 48 months.

At month 48, patients in the P/D group had experienced a mean improvement in AUA-SI score of 5.6 points (p<0.001 versus Month 24). AUA-SI score also decreased significantly from months 24-48 for D/D-treated patients (p<0.001), with the overall reduction from baseline significantly greater than that observed in patients from the P/D group (6.5 points, p<0.001).⁶⁹ Over 48 months of treatment, the magnitude of symptom improvement with dutasteride (6.5) was in excess of that defined as clinically significant (³3.0).⁸²

Improvement of urinary flow
Patients treated with dutasteride had a mean improvement in Q_max of 2.2ml/s versus 0.6ml/s for placebotreated patients at month 24 (p<0.001 between treatment groups, see below).

Mean change in Qmax from baseline over 48 months.

At month 48, patients in the P/D group had a mean improvement in Q_max of 1.9ml/s that was significant versus month 24 (p<0.001). Patients in the D/D group also showed significant improvements in Q_max between months 24-48 (p=0.007), with the overall improvement from baseline significantly greater than that observed in patients from the P/D group (2.7ml/s versus 1.9ml/s respectively, p=0.042).⁶⁹

Effect on AUR and BPH related surgery
AUR and BPH-related surgery occurred in a small percentage of men during the open-label phase at rates consistent with those seen in dutasteride-treated patients during the double-blind phase. In the open-label phase, D/D-treated patients had a lower risk of AUR versus P/D-treated patients, although this did not reach statistical significance (1.2% versus 1.9%, p=0.14). For BPH-related surgery, the incidence rates were similar for the two groups in the open-label phase (0.8% in each group).⁶⁹

Reduction of risk of Prostate Cancer

• Besides the improvement in BPH outcomes 5 alfa reductase inhibitors could have a role in the reduction of risk of Prostate Cancer.
• The PCPT trial (Prostate cancer prevention trial) represents the largest body of evidence to-date on the benefit/risk profile of 5α-reductase inhibitors (5ARIs) in the chemoprevention. This study showed that finasteride treatment reduced the risk of prostate cancer by 24.8% relative to placebo over a seven-year period (95 percent confidence interval, 18.6 to 30.6%; p<0.001). (Thompson et al.¹⁾
• Retrospective analyses of the incidence of prostate cancer performed on data from 3 randomised, double blind, 2-year studies evaluating the efficacy and tolerability of 0.5 mg dutasteride daily and placebo in subjects with BPH demonstrated that the crude incidence rate of prostate cancer (recorded as an adverse event after the 27 months of follow up) was 50% lower in the dutasteride group than in the placebo group (1.2% vs 2.5%, p<0.002) (Andriole et al.²).
• To prospectively investigate these findings a large-scale randomised study, the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial is in progress (Andriole et al.³).
• The REDUCE trial is a 4-year, randomised, placebo-controlled study involving over 8000 men at increased risk of developing prostate cancer, by virtue of an elevated serum PSA (3.5-10). It was initiated in 2003 to examine the effect of dutasteride on the primary endpoint of biopsy-detectable prostate cancer. (Andriole et al.³).

Drug-related adverse events

Pivotal efficacy studies
In placebo-controlled studies, adverse events relating to the reproductive system were the most commonly reported drug class-related adverse events occurring more often with dutasteride therapy than with placebo. The vast majority of patients (81% of patients receiving dutasteride versus 86% receiving placebo) did not report any drug-related adverse events (see table below). These drug-related adverse events relating to the reproductive system are the most common category of drug-related adverse events reported with this therapeutic class.

Investigator-judged, drug-related adverse events (in ³1% of the total intent-to-treat population) from data pooled from three pivotal efficacy studies⁸⁵

The onset of the majority of drug related adverse events occurred within the first year of treatment. The incidence of drug-related adverse events in the dutasteride-treated group decreased over time and was therefore lower in the second year of the study (first year 15.5%, second year 5.7%).⁴

Only 3% of individuals in the placebo group and 4% of the dutasteride-treated patients withdrew from the study owing to drug-related adverse events.

Long-term (4 year) safety and tolerability
The most commonly reported drug-related adverse events during long-term treatment with dutasteride were anticipated sexual events (impotence, decreased libido and ejaculation disorders) and gynaecomastia (including breast tenderness and breast enlargement) (see below).

The onset of most new drug-related sexual adverse events occurred within the first 6 months of therapy. Throughout the 48 month study period the incidence of new reports of most drug-related sexual adverse events (impotence, decreased libido and ejaculation disorders) decreased with duration of dutasteride treatment. The incidence of drug-related gynaecomastia was low and remained constant over the treatment period. Among patients who received dutasteride in the open-label phase only, the incidence of events was comparable with those experienced by D/D-treated patients at the start of double-blind therapy. The incidence of newly reported events in the P/D group also declined after one year of dutasteride therapy. The incidence of drug-related sexual function adverse events that led to withdrawal was <1% in the open-label phase.⁶⁹

Effect on prostate-specific antigen and prostate cancer detection
The concentration of serum prostate-specific antigen (PSA) is strongly correlated to prostate volume. PSA is also an important marker for the detection of prostate cancer; a serum PSA level of above 4ng/ml warrants further investigation. Thus, the impact of dutasteride on PSA levels has important implications for monitoring the risk of prostate cancer.

Data from the pivotal efficacy studies confirmed that dutasteride reduces serum PSA concentration significantly in the first year of treatment. In these studies, PSA values stabilised to a new baseline level of approximately half that of the pre-treatment value, and this was achieved within 6 months of initiating dutasteride therapy (see figure).

Mean change from baseline PSA levels in dutasteride-treated patients (pooled data from three pivotal efficacy studies)

In the open-label phase of the pivotal efficacy studies, serum PSA decreased by a mean of 52.9% from baseline in the D/D group at month 24 and by 57.2% at month 48. Patients in the P/D group experienced a mean increase in PSA of 15.0% from baseline to month 24. Following initiation of dutasteride treatment at month 24, serum PSA levels decreased by a mean of 48.4% at month 48 compared with baseline.⁶⁹

In view of these findings, one management strategy is to establish a new baseline PSA concentration for dutasteride-treated patients after 6 months of treatment. PSA levels can then still be used to accurately determine potential prostate cancer-related increases in antigen concentration. To interpret an isolated PSA value in a man treated with dutasteride for 6-24 months, the PSA value should be doubled for comparison with normal values in untreated men.⁶⁷

The free-total PSA ratio remains constant in dutasteride-treated patients.^67,87 Therefore, changes in this ratio can be used to aid detection of potential prostate cancer without adjustment.

Combination therapy
Therapy with an a-blocker and a 5ARI combines the benefit of the rapid symptom relief of a-blockers with the long-term symptom benefits, effect on prostate volume, and reduction in the risks of AUR and BPH - related surgery, of 5ARIs.

The National Institutes of Health clinical study MTOPS was a double-blind, randomised trial in which 3,047 men with BPH (mean prostate volume 36.3cc) were given finasteride 5.0mg, doxazosin 4.0mg or 8.0mg, a combination of finasteride and doxazosin, or placebo, and followed up for an average of 4.5 years.¹⁶ The objective of the study was to determine whether medical therapy prevents or delays the clinical progression of BPH as defined by one of the following: a ³4-point rise in baseline AUA-SI score, AUR, renal insufficiency due to BPH, recurrent urinary tract infection, urosepsis or incontinence. Combination therapy significantly reduced the risk of clinical progression and produced improvements in both symptom score and urinary flow rate when compared with each drug therapy alone. Compared with placebo, the overall reduction in risk of clinical progression of BPH was 66% with combination therapy, 34% with finasteride and 39% with doxazosin (see below).¹⁶

The results of the MTOPS study¹⁶

The Symptom Management After Reducing Therapy (SMART-1) study was initiated to examine short-term dutasteride and tamsulosin combination therapy followed by dutasteride monotherapy in 327 men with BPH. This study demonstrated that, in the majority of men with mild-tomoderate symptoms (77%), withdrawal of the a-blocker after 6 months of combination therapy did not result in any significant deterioration in symptoms. Of those subjects with more severe symptoms(baseline IPSS ³20) in whom a-blocker therapy was withdrawn at Week 24, 42.5% reported worsening of their symptoms compared with 14% of patients who remained on combination therapy.⁷⁰ This defines a role for the addition of short-term (6 months) a-blocker therapy, to cover the lag in onset of symptom relief seen with 5ARI monotherapy. Such short-term combination use would be optimal in providing symptomatic improvement among patients who require rapid symptom relief, while also reducing the risk of subsequent AUR or BPH-related surgery in men who are at greater risk of disease progression. A small proportion of patients with severe baseline symptoms may benefit from longer-term combination treatment.⁷⁰

The AUA guidelines on the management of BPH state that combination therapy is an appropriate and effective treatment option for patients with LUTS associated with demonstrable prostatic enlargement.⁵³ The findings of MTOPS support this recommendation and the results of SMART-1 help to define those patients most likely to benefit from short-term combination therapy.

The COMBination of Avodart and Tamsulosin (CombAT) trial is designed to investigate the effects of combination therapy with the 5ARI, dutasteride, and the α-blocker, tamsulosin, on symptoms and disease progression in patients with moderate-to-severe BPH. Measures of progression include symptom scores, AUR, and the need for surgery. Eligible patients are men over 50 years old with prostates ≥30 cc and prostate-specific antigen levels ≥1.5 ng/ml. Patients with larger prostates are more at risk of clinical progression and are, therefore, more likely to benefit from combination therapy. CombAT is a 4-year, global, multicentre, randomised, double-blind, parallel group study, which has enroled 4844 patients.

Enrolment in MTOPS began in 1993, before baseline PSA and PV were widely recognised as key prognostic factors for BPH progression. In contrast with the MTOPS study and other combination therapy studies, entry thresholds for PV (≥30 cc) and PSA ≥1.5 ng/ml) in the CombAT trial have been used to select patients with moderate-to-severe BPH , and who are thus at higher risk of clinical progression of BPH.

Additional References:
1. Thompson et al. The Influence of Finasteride on the Development of Prostate Cancer. The new england journal of medicine 2003; 349:3
2.Andriole, GL et al. Effect of dutasteride on the detection of prostate cancer in men with benign prostatic hyperplasia. Journal of Urology 2004; 64(3)
3.Andriole, GL et al. Chemoprevention of prostate cancer in men at high risk: rationale and design of the reduction by dutasteride of prostate cancer events (REDUCE) trial. Journal of Urology 2004; 172, 1314-1317.