THERAPY

Finding the right niche for BPH therapies

-Charles Bankhead-

In the multicentre Veterans Affairs (VA) Cooperative Study, the ex-blocker terazosin proved superior to the Sex-reductase inhibitor finasteride for the treatment of benign prostatic byperplasia (BPB).l Adding f'masteride to terazosin offered no symptomatic benefits above those obtained with the ex-blocker alone, and f'masteride monotherapy proved not to be statistically better than placebo. Investigators are still trying to clarify the therapeutic niches for a-blockers and for finasteride. This process continued at the recent American Urological Association meeting [San Diego, US; June 1998].

Data from various studies were presented that: • essentially corroborated results of the VA Cooperative

Trial by demonstrating doxazosin's superiority to finasteride

• provided reassurance about the effect of a-blockers and finasteride on sexual function

• indicated that prostate growth and the risk of acute urinary retention correlate with baseline prostate­specific antigen (PSA) levels. which previously has been shown to predict response to finasteride.

Predicting BPH therapy Following the success of terazosin, doxazosin

proved superior to finasteride in the Prospective European Doxazosin in Combination Therapy (PREDICT) trial. Compared with finasteride mono­therapy or placebo. doxazosin alone resulted in significantly more improvement in prostate symptom score and peak flow rate. Combining treatment with finasteride and doxazosin did not improve on results obtained with doxazosin alone. says Dr Claus Roehrborn of the University of Texas Southwestern Medical Center, Dallas, US.

PREDICT investigators randomised approximately 1000 patients to doxazosin, finasteride, a combination of the 2 agents or to placebo. All the patients had lower urinary tract symptoms in association with BPH. Follow-up continued for 1 year.

Among patients treated with doxazosin alone, 81 % had a ~ 30% decrease in International Prostate Symptom Scale score. In contrast, 66, 79 and 57% of those treated with finasteride, combination therapy or placebo, respectively, achieved this endpoint. A similar pattern emerged with respect to improvement in peak flow rate: 50% of doxazosin-treated patients had a ~ 3 mlIsec improvement compared with 33. 57 and 39% of finasteride, combination and placebo recipients, respectively.

Adverse events were more common in the doxazosin and combination arms, but the adverse effect-related discontinuation rate ranged between 10 and 12% in all 4 groups. The most common adverse effects were dizziness (15-16% of doxazosin and combination patients), asthenia (10-11 % with doxazosin and the combination) and upper respiratory infection (10-12% in ali 4 groups).

Synergy lacking Dr Roehrborn believes that these results confirm

the efficacy of doxazosin in the treatment of men with lower urinary tract symptoms and BPH in terms of symptoms and flow rate improvement. The study also confirms the absence of a 'clinically meaningful synergistic effect' of combined therapy with a-blockers and 5-a reductase inhibitors. Similar to

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the VA Cooperative Study, patients treated with finasteride experienced improvement that was not significantly different from placebo.

These results are 'virtually identical to those in the VA Cooperative study', says Dr Herbert Lepor, principal investigator for the VA trial. He adds that the new study should 'put to rest' any questions about the therapeutic superiority of ex-blockers over finasteride in the treatment of most men with BPH.

Sexual function unimpaired in majority Results of a multicentre comparison involving

over 1000 patients randomised to treatment with alfuzosin or finasteride show that the latter agent had a greater impact on erectile function.

The investigators had previously found that alfuzosin also was more effective than finasteride for relief of BPH symptoms, and that combination therapy did not add to the benefits achieved with alfuzosin alone, according to Dr Franz DeBruyne of the University of Nijmegen, The Netherlands.

After 6 months, 2.2% of alfuzosin recipients reported impotence, compared with 6.7% of finasteride recipients and 7.4% of patients treated with the combination. No patient in the alfuzosin group experienced ejaculatory failure. whereas 1.5% of the finasteride group and 0.9% of the combination group reported this problem. Decreased libido was reported by 0.6% of alfuzosin patients, 1.7% of finasteride patients and 2% of the combination group.

No difference after 1 year Investigators in the Proscar Long-Term Evaluation of

Safety and Symptoms (PLESS) trial report that adverse sexual events associated with finasteride do not differ from those experienced with placebo after the first year of therapy. The trial involved 3040 patients with BPH who were randomised to finasteride or placebo therapy. Follow-up has reached 4 years for the entire cohort.

Overall, finasteride was associated with a higher incidence of sexual adverse events (21.6 vs 13.7%, respectively). The sexual effects prompted 3.7% of finasteride patients and 2.1 % of placebo patients to withdraw from the study, says Dr Johnny Roy of the University of Okiahoma, US.

However, differences in sexual adverse events during the first year of treatment accounted for the overall difference. During years 2-4, no differences existed with respect to total sexual adverse events (fr.7%). decreased libido (about 2% in both groups), impotence (5% in both groups). or ejaculatory dis­orders « 0.5% in both groups). Ejaculatory volume was statistically lower in the finasteride cohort during years 2-4 (1.5 vs 0.5%, respectively).

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According to Dr Roy, many patients with BPH have a history of sexual dysfunction. 46% of study participants reported a history of sexual dysfunction at baseline. In this study, very few patients dis­continued treatment as a result of sexual adverse events. Among those who reported sexual adverse events during the study, the events resolved in 12% of cases while patients remained on finasteride and in 19% of cases while patients continued placebo treatment.

Sexual adverse events resolved in 50% of finasteride recipients and 41 % of placebo recipients after discontinuing treatment, which is consistent with the natural history of sexual dysfunction in patients with BPH.

A reduced risk of surgeIY? Another analysis of the PLESS data shows

that the risk of BPH-associated urinary retention remains constant over time, whether spontaneous or precipitated (as by an interventional procedure or surgery). On average, episodes of spontaneous retention occurred 19-20 months after starting treatment. Finasteride significantly reduced the risk of spontaneous retention (20 episodes vs 51 with placebo), says Dr Roehrbom.

Precipitated episodes of urinary retention occurred an average of 22 months after enrolment in PLESS. Finasteride also reduced the risk of precipitated retention (22 vs 47 cases). Overall, 44% of patients who experi­enced urinary retention required surgery (usually in the form of transurethral resection of the prostate). The need for surgical intervention was increased in patients who had spontaneous urinary retention.

According to Dr Roehrbom, 75% of placebo­treated patients who had spontaneous urinary retention required transurethral resection of the prostate. The findings confirm the results of a Scandinavian study showing that finasteride treatment reduces the risk of serious adverse events in BPH, including urinary retention and need for surgery. Placebo-treated patients who had spontaneous episodes of urinary retention had a significantly higher baseline PSA level (4.4 vs 2.7 ng/ml for those who did not develop spontaneous retention).

S~fora~fors~ Dr Roehrbom believes that PSA levels can serve

as a surrogate for prostate size. A meta-analysis of finasteride clinical trials has shown that men with larger prostates are more likely to respond to finasteride therapy.2*

A third study presented by Dr Roehrbom provides new information about the rate of prostate enlarge­ment in BPH among placebo-treated patients in the PLESS trial. During the first year of the study, prostate growth averaged 2.5ml (range 1.7-3.1ml), with the greatest growth occurring in men aged > 70 years. During the 4-year study, average prostate enlargement ranged between 6.1ml for men aged 50-59 years to 9.6ml for those aged> 70 years.

The rate of growth had a significant positive correlation with baseline PSA levels, explains Dr Roehrborn. Moreover, prostate volume did not decrease in any patient who had a baseline PSA level that exceeded 2.5 ng/m1. In contrast, 30% of patients

THERAPY

who had baseline PSA levels of ~ 2.5 ng/m1 experienced a decrease in prostate volume over the 4-year study.

'Baseline serum PSA strongly predicted the change in prostate volume during each year of the study and predicted the percent volume change during years 3 and 4', says Dr Roehrbom. He has previously reported that treatment with terazosin has minimal impact on PSA level, underscoring the differing therapeutic effects of a-blockers and finasteride in the treatment of BPH.3** * See /npharma 1(w): 16, 26 Oct 1996; 8lXJ475Jl5

** See /nphamra 1112: 19, 8 Nov 1997; fHJ624650

1. Lepor H, ct aI. The efficacy of terazosin. fiDasttride, Ill" both in benign proslalic hyperplasia. New England Journal of Medicine 335: 533-539, 22 Aug 1996

2. Boyle p, ct aI. Prostate volume predicts outcome of treatment of benign

prostatic hyperplasia with finasIcride: meta-analysis of nndomizcd cliDical trials.

Urology 48: 398405, Sep 1996 3. Roehrbom eG, et aI. Serial prostate-specific antigen measuremems in men with clinil:ally benign proslalic hyperplasia during

a 12-month placeh<H:ontroUed Sllldy with tcraz.oSin. Urology SO: 556-561,

Oct 1997 1DOOlI'2'

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