Advances in the Medical Treatment of Benign Prostatic Hyperplasia

3. RIU0477_12-14.qxd 12/14/09 5:35 PM Page 181 KOL INTERVIEW Advances in the Medical Treatment of Benign Prostatic Hyperplasia Herbert Lepor, MD New York University School of Medicine, New York, NY [Rev Urol. 2009;11(4):181-184 doi: 10.3909/riu0477] © 2009 MedReviews®, LLC n this KOL (key opinion leader) interview, Herbert Lepor, MD, co–Medical Editor of Reviews in Urology, discusses the medical treatment of benign prostatic hyperplasia (BPH). I RIU: How do -blockers work for the treatment of BPH? Dr. Lepor: -Adrenoceptors are abundant in the bladder neck and prostate and mediate the tension of prostate and bladder neck smooth muscle. Historically, the clinical manifestations of BPH were attributed to bladder outlet obstruction (BOO) caused by the enlarged prostate. The BOO resulted in bladder dysfunction that manifested as lower urinary tract symptoms (LUTS), detrusor instability, and urinary retention. The enlarged prostate caused BOO via both dynamic and static mechanisms. Dynamic BOO, which accounted for the variability of LUTS, is mediated by the tone of the prostate smooth muscle. Static BOO is mediated by the anatomic obstruction directly as a result of the enlarged prostate. Therefore, -blockers and 5-reductase inhibitors (5ARIs) were developed to alleviate dynamic and static BOO, respectively. The observed improvement in LUTS, detrusor instability, and urinary retention were attributed to drug-dependent alleviation of BOO. If the mechanism of action of -blockers is mediated exclusively by smooth muscle relaxation, then those men experiencing the greatest improvement in BOO should derive the greatest clinical benefit. In clinical trials, a poor correlation was observed between changes in LUTS (AUA Symptom Index) and BOO (Qmax), suggesting that other -mediated mechanisms are responsible for the clinical benefit of -blockers for BPH. Therefore, bladder, spinal cord, and central -adrenoceptors must also play a role in the efficacy of these drugs in men with BPH. RIU: Which 1-adrenoceptors mediate the efficacy of -blockers? Dr. Lepor: There are 3 subtypes of the 1-adrenoceptor: 1A, 1B, and 1D. Our laboratory was instrumental in discovering that the 1A subtype mediated the tone of prostate smooth muscle. Interestingly, when 1A subtype–specific antagonists were investigated for BPH, the improvement in LUTS was quite disappointing. These clinical observations provided further evidence that the 1A subtype was not solely, or predominantly, responsible for the LUTS improvement seen with -blockers. The 1B subtype is predominant in the vasculature and likely plays little role in the efficacy of -blockers for BPH. It is conceivable that 1D-adrenoceptors present in the bladder body and spinal cord and nasal passages may play some role in the LUTS improvement mediated by -blockers in BPH. VOL. 11 NO. 4 2009 REVIEWS IN UROLOGY 181 3. RIU0477_12-14.qxd 12/14/09 5:35 PM Page 182 Advances in the Medical Treatment of BPH continued RIU: How would you describe the clinical development of -blockers for BPH? Dr. Lepor: Over the past 35 years, the development of -blockers may be summarized by maintenance of efficacy with improved tolerability and ease of dosing. In 1975, Marco Caine was the first to report on the clinical benefits of an -blocker, phenoxybenzamine, for the treatment of BPH. Although phenoxybenzamine improved LUTS relative to placebo, the drug was associated with significant side effects. In the late 1970s, 2 subtypes of the -adrenoceptor were identified (1 and 2). -Blockers were initially developed for the treatment of hypertension because -receptors are abundant in the vascular smooth muscle. The tension of prostate smooth muscle was observed to be mediated by the 1-adrenoceptor. Prazosin, a selective 1-adrenoceptor blocker approved for the treatment of hypertension, was observed to have the same effectiveness as phenoxybenzamine but was better tolerated, suggesting that the efficacy of -blockers in BPH was mediated by the 1-adrenoceptor and the side effects were primarily mediated by the 2adrenoceptor. Postural hypotension remained a significant problem with prazosin. The next major milestone was the development of the long-acting selective 1-blockers terazosin hydrochloride (Hytrin®; Abbott Laboratories, North Chicago, IL) and doxazosin mesylate (Cardura®; Pfizer Inc, New York, NY). The once-daily dosing of these drugs enhanced convenience and also greatly reduced vascular-mediated adverse events. Dizziness and asthenia remained problematic, and manageable side effects and dose titration were mandatory. In 1987, terazosin became the first US Food and Drug Administration (FDA)–approved -blocker for the treatment of BPH. In the 1990s, 3 subtypes of 1-adrenoceptor were characterized (1A, 1B, and 1D). The 1A subtype was found to mediate prostate smooth muscle tension. Tamsulosin hydrochloride (Flomax®; Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT) was weakly selective for the 1A versus the 1B subtype, but exhibited no selectivity for the 1A subtype versus the 1D subtype. The primary advantage of tamsulosin was that an effective dose (0.4 mg) was administered without requirement for dose titration; however, a much higher incidence of ejaculatory dysfunction was observed. The lack of titration and fewer cardiovascular effects most likely had little to do with the marginal selectivity but rather the slow-release (SR) formulation. The prescribing urology community felt the advantage attributed to the lack of titration outweighed the disadvantages of ejaculatory issues, and tamsulosin quickly became the -blocker of choice. 182 VOL. 11 NO. 4 2009 REVIEWS IN UROLOGY Alfuzosin hydrochloride (Uroxatral®; sanofi-aventis U.S. LLC, Bridgewater, NJ) was the next -blocker approved that lacked any pharmacologic selectivity. Alfuzosin did not require dose titration and did not cause ejaculatory issues. This message of improved tolerability did not resonate with the urology community, suggesting that ejaculatory dysfunction was not perceived to be a major problem by prescribing physicians and affected patients. RIU: Are there any subtype-selective -blockers for BPH? Dr. Lepor: Until recently, there were no -blockers on the market that exhibited pharmacologic -adrenoceptor selectivity. The very modest selectivity of tamsulosin for the 1A subtype versus the 1B subtype is too low to have clinical advantages. Silodosin (Rapaflo®; Watson Pharmaceuticals, Inc., Corona, CA) was recently approved by the FDA for the treatment of BPH. Silodosin has a unique pharmacologic subtype-selectivity profile. The drug is exceedingly selective for the 1A subtype versus the 1B subtype and moderately selective for the 1D subtype. This uniquely selective pharmacologic profile likely explains any unique clinical properties. RIU: Do -blockers affect the corrected QT (QTc) interval? Dr. Lepor: Drugs that prolong the heart QTc interval have been associated with increased risk of polymorphic ventricular tachycardia, or torsades de pointes (TdP), and sudden death. Therefore, beginning in 2005, the FDA required that all new drugs undergo a rigorous evaluation of QTc interval. Therefore, -blockers including terazosin, doxazosin, tamsulosin, and alfuzosin were not subjected to these rigorous QTc interval studies prior to approval. Postmarketing, there was some concern regarding cardiovascular events observed in men on alfuzosin SR, which prompted studies to examine its effect on QTc interval. The Arizona Center for Education and Research Therapeutics lists on its Web site a ranking for the TdP risk of drugs. Alfuzosin is the only -blocker on the list and carries a level 2 risk, which implies a possible risk for TdP. It is important to recognize that other commonly prescribed drugs used for treating urologic conditions, such as levofloxacin and vardenafil hydrochloride, also are listed as level 2 risks. There are also many commonly prescribed drugs that carry a possible risk of TdP. Therefore, elderly men with BPH and cardiovascular comorbidities on polypharmacy are at increasing risk for TdP. 3. RIU0477_12-14.qxd 12/14/09 5:35 PM Page 183 Advances in the Medical Treatment of BPH Silodosin was rigorously examined for its effect on QTc interval as part of its new drug application and was found to elicit no effect on QTc interval. RIU: Is it safe to co-administer -blockers and phosphodiesterase type 5 (PDE-5) inhibitors? Dr. Lepor: Both -blockers and PDE-5 inhibitors may lower blood pressure. Therefore, there are obvious concerns about co-administering these drug classes, especially in normotensive men. One of the advantages of the unique selectivity of silodosin is that it has no measureable effect on blood pressure or pulse rate. In a rigorous combination study, silodosin, when co-administered with either tadalafil or sildenafil citrate, did not increase the incidence of orthostatic hypotension when compared with placebo. The Physicians’ Desk Reference® contains no warnings on the co-administration of silodosin with PDE-5 inhibitors. RIU: Does the unique pharmacologic subtype selectivity profile of silodosin translate into any clinical benefits? Dr. Lepor: There have been no head-to-head comparisons of silodosin with other -blockers. Therefore, insights related to comparative properties can only be gleaned from a comparison of the registered clinical trials that had the same inclusion and exclusion criteria and primary endpoints. Overall, the treatment-related improvements in LUTS and Qmax are of similar magnitude for the various blockers. There is a suggestion that the least efficacious -blocker is alfuzosin. The rate of ejaculatory problems with silodosin far exceeds that of all the other -blockers. Historically, ejaculatory dysfunction was observed only with tamsulosin. In clinical trials and clinical practice, men rarely discontinued treatment with tamsulosin due to ejaculatory side effects. This observation suggests that ejaculatory dysfunction is not perceived to be a major limitation of the drug. Tamsulosin remained the market leader by a far margin despite alfuzosin’s lack of ejaculatory side effects. Roehrborn and colleagues recently reported that the subset of men with ejaculatory dysfunction exhibited the greatest degree of clinical benefit. There appears to be a clinical benefit linked to the ejaculatory side effect. As far as safety, silodosin appears to have the superior cardiovascular safety properties. The drug does not have any impact on blood pressure or heart rate. This may be due to the drug’s very weak affinity for the 1B subtype. Dizziness was also lowest with silodosin. Ultimately, the patient and prescribing physician need to weigh the relative advantages of greater efficacy and lack of cardiovascular adverse events versus ejaculatory dysfunction. For those in whom ejaculatory dysfunction is likely to be problematic, silodosin will not have clinical utility. On the other hand, in the scenario where ejaculatory dysfunction is of no concern, silodosin will likely provide greater efficacy and tolerability. Therefore, in some scenarios, the unique -subtype selectivity of silodosin will translate into clinical benefit. RIU: What is the best way to treat BPH: monotherapy or combination therapy? Dr. Lepor: If the goal is to improve LUTS, -blockers are the superior medical treatment independent of prostate volume. Men with small prostates do not achieve any LUTS therapeutic benefit with 5ARIs. In larger prostates, 5ARIs will have some benefit in alleviating LUTS. Therefore, if the goal is relief of LUTS, it is best to offer an -blocker and add additional medications if warranted based on LUTS severity. The Medical Therapy of Prostate Symptoms (MTOPS) study demonstrated that the combination of an -blocker and a 5ARI is the most effective way to retard progression of BPH. Medical therapy exerted its greatest effect on preventing LUTS progression. -Blockers and 5ARIs were most effective at preventing LUTS progression in men with small and large prostates, respectively. Medical therapy also exhibited an effect on preventing progression to acute urinary retention (AUR). The benefit was observed primarily in the groups of men with larger prostates treated with 5ARIs, but needs to be put in perspective. In the combination-treated group, a total of 42 men had to be treated in order to prevent a single episode of AUR. The risk and clinical benefit were both greatest in the subset of men with the largest prostates. RIU: Are PDE-5 inhibitors effective for the treatment of BPH? Dr. Lepor: There is increasing epidemiological data that BPH and erectile dysfunction are causally related because these disorders co-exist in the aging male population. This, coupled with the fact that the prostate has an abundance of PDE-5, provides the rationale for using this class of drugs in BPH. There are now several randomized, placebo-controlled studies that have shown PDE-5 inhibitors significantly improve LUTS relative to placebo. The magnitude of LUTS improvement relative to placebo is comparable to -blockers. Interestingly, LUTS were improved without any observed increase in Qmax. This provides further evidence disassociating improvements in BOO and LUTS. VOL. 11 NO. 4 2009 REVIEWS IN UROLOGY 183 3. RIU0477_12-14.qxd 12/14/09 5:35 PM Page 184 Advances in the Medical Treatment of BPH continued The primary limitation of PDE-5 inhibitors is their cost and side effects. A daily PDE-5 inhibitor is ideal for the man with BPH and erectile dysfunction who seeks treatment for both conditions. RIU: Is it safe and effective to treat BPH with an anticholinergic agent? Dr. Lepor: The use of anticholinergic agents has long been considered a contraindication for men with BPH. This contraindication was not based on medical evidence. In a recent study, 879 men with both overactive bladder (OAB) and BPH were randomized to placebo, tolterodine extended release (ER) (anticholinergic agent), tamsulosin, or a combination of tolterodine and tamsulosin. The change in total International Prostate Symptom Score (IPSS) was significantly greater in the tamsulosin and combination groups relative to placebo, and there was no significant difference between IPSS between placebo and tolterodine ER. The global assessment of improvement was significant in the combination arm and almost significant in the tamsulosin arm relative to placebo. The additional advantage of adding an anticholinergic to tamsulosin is modest, at best. There was no significant increase in AUR events. However, a 12-week course of an anticholinergic agent in BPH is inadequate because in the MTOPS trial, the risk of AUR progresses with time throughout the 7-year follow-up. RIU: Are gonadotropin-releasing hormone (GnRH) antagonists safe and effective for BPH? Dr. Lepor: GnRH agonists have been shown to reduce the volume of BPH with some modest clinical benefits related to improvements in LUTS and BOO. The primary disadvantage of GnRH agonists is the incidence and severity of short-term, immediate, and long-term adverse events. The initial rationale for GnRH antagonists for the treatment of BPH was the opportunity to titrate lowering serum testosterone to a level that might reduce prostate volume without causing adverse events. The ability to titrate the lowering of testosterone was not achievable with the agonists, which exhibited an “all or no effect” on testosterone suppression. 184 VOL. 11 NO. 4 2009 REVIEWS IN UROLOGY A large, phase II, randomized, placebo-controlled study in men with BPH conducted in Eastern Europe strongly supported the safety and effectiveness of cetrorelix acetate for treating LUTS secondary to BPH. The clinical effect of cetrorelix was dose dependent. The optimal dosing regimen was 90 mg of cetrorelix administered on days 1 and 14. The improvement in IPSS and peak flow rate over placebo observed throughout the duration of the 26-week study exceeded the efficacy previously reported with blockers. At the effective doses, cetrorelix did not appear to cause vasomotor or sexual side effects. At the effective doses, cetrorelix lowered testosterone levels only transiently to levels that were far above castrate levels. Despite the fact that testosterone levels had returned to baseline within a few weeks, the effectiveness was maintained for the 26 weeks of the study. These studies strongly suggested that the mechanism of effectiveness is not due to testosterone lowering. Because LHRH receptors are present in the prostate, it was hypothesized that inhibition of these receptors may have a therapeutic effect on inflammation or prostate growth. Due to the compelling evidence of efficacy in the phase II study, Aeterna Zentaris (Warren, NJ) embarked on 2 pivotal, phase III, 1-year studies in the United States and Europe. In the US study, 637 men were randomized to receive placebo or cetrorelix on weeks 0, 2, 26, and 28. The cumulative dose on weeks 0 and 2 was 78 mg and on weeks 26 and 28 was 78 mg or 52 mg. The results of the phase III studies were recently announced to the financial community. Unfortunately, there were no statistically significant benefits of cetrorelix over placebo for the primary outcome measure, which was improvement in IPSS. In addition, the drug also did not have a significant effect over placebo on peak flow rate or prostate volume. It is very difficult to reconcile the lack of efficacy based on the very favorable phase II studies, which not only demonstrated significant efficacy over placebo but also dose dependency of this efficacy. We will await further analysis of the US study and the results of the European study, which should be available in November 2009, before the fate of cetrorelix and other GNRH antagonists for BPH is resolved.