Norman Zinner

Natural history of rising serum prostate-specific antigen in men with castrate nonmetastatic prostate cancer

PURPOSE To describe the natural history of nonmetastatic prostate cancer and rising prostate-specific antigen (PSA) despite androgen deprivation therapy. PATIENTS AND METHODS The 201 patients in this report were the placebo control group from an aborted randomized controlled trial to evaluate the effects of zoledronic acid on time to first bone metastasis in men with prostate cancer, no bone metastases, and rising PSA despite androgen deprivation therapy. Relationships between baseline covariates and clinical outcomes were assessed by Cox proportional hazard analyses. Covariates in the model were baseline PSA, Gleason sum, history of bilateral orchiectomies, regional lymph node metastases at diagnosis, prior prostatectomy, time from androgen deprivation therapy to random assignment, time from diagnosis to random assignment, and PSA velocity. RESULTS At 2 years, 33% of patients had developed bone metastases. Median bone metastasis-free survival was 30 months. Median time to first bone metastases and overall survival were not reached. Baseline PSA level greater than 10 ng/mL (relative risk, 3.18; 95% CI, 1.74 to 5.80; P < .001) and PSA velocity (4.34 for each 0.01 increase in PSA velocity; 95% CI, 2.30 to 8.21; P < .001) independently predicted shorter time to first bone metastasis. Baseline PSA and PSA velocity also independently predicted overall survival and metastasis-free survival. Other covariates did not consistently predict clinical outcomes. CONCLUSION Men with nonmetastatic prostate cancer and rising PSA despite androgen deprivation therapy have a relatively indolent natural history. Baseline PSA and PSA velocity independently predict time to first bone metastasis and survival.

Prospective Randomized Controlled Trial of Extended-Release Oxybutynin Chloride and Tolterodine Tartrate in the Treatment of Overactive Bladder: Results of the OBJECT Study

OBJECTIVE To compare the efficacy and tolerability of extended-release oxybutynin chloride and tolterodine tartrate at 12 weeks in participants with overactive bladder. SUBJECTS AND METHODS The OBJECT (Overactive Bladder: Judging Effective Control and Treatment) study was a prospective, randomized, double-blind, parallel-group study conducted between March and October 2000 at 37 US study sites. Participants who had between 7 and 50 episodes of urge incontinence per week and 10 or more voids in 24 hours received extended-release oxybutynin, 10 mg/d, or tolterodine, 2 mg twice daily. The outcome measures were the number of episodes of urge incontinence, total incontinence, and micturition frequency at 12 weeks adjusted for baseline. RESULTS A total of 315 women and 63 men were randomized and treated, and 332 participants (276 women, 56 men) completed the study. At the end of the study, extended-release oxybutynin was significantly more effective than tolterodine in each of the main outcome measures: weekly urge incontinence (P=.03), total incontinence (P=.02), and micturition frequency episodes (P=.02) adjusted for baseline. Both drugs improved symptoms of overactive bladder significantly from baseline to the end of the study as assessed by the 3 main outcome measures (P<.001). Dry mouth, the most common adverse event, was reported by 28.1% and 33.2% of participants taking extended-release oxybutynin and tolterodine, respectively (P=.32). Rates of central nervous system and other adverse events were low and similar in both groups. CONCLUSIONS Extended-release oxybutynin was more effective than tolterodine as measured by end-of-study urge incontinence, total incontinence, and micturition frequency episodes. Both groups had similar rates of dry mouth and other adverse events.

Comparative efficacy and safety of transdermal oxybutynin and oral tolterodine versus placebo in previously treated patients with urge and mixed urinary incontinence

OBJECTIVES To compare the efficacy and safety of an oxybutynin transdermal delivery system (OXY-TDS) and oral, long-acting tolterodine (TOL-LA) with placebo in previously treated patients with urge or mixed urinary incontinence. METHODS After withdrawal of their current antimuscarinic therapy, 361 adult patients were randomized to 12 weeks of double-blind, double-dummy treatment with twice weekly OXY-TDS 3.9 mg/day, daily TOL-LA 4 mg, or placebo. Evaluations included change from baseline in patient urinary diary symptoms, incontinence-specific quality of life, and safety. RESULTS OXY-TDS 3.9 mg/day and TOL-LA 4 mg/day significantly reduced the number of daily incontinence episodes (median change -3 OXY-TDS and -3 TOL-LA versus -2 placebo; P <0.05), increased the average void volume (median change 24 and 29 mL versus 5.5 mL, P <0.01), and improved quality of life (incontinence impact questionnaire [IIQ] total score, P <0.05; Urogenital Distress Inventory Irritative Symptom subscale, P <0.05) compared with placebo. The most common adverse event for OXY-TDS was localized application site pruritus (14% versus 4% placebo) accompanied by a low incidence of systemic side effects (eg, dry mouth 4.1%). Anticholinergic adverse events occurred with greatest frequency during TOL-LA treatment (dry mouth 7.3% versus 1.7% placebo, P <0.05). CONCLUSIONS OXY-TDS and TOL-LA are effective and comparable treatments for patients with urge and mixed incontinence. OXY-TDS improves systemic safety with regard to anticholinergic side effects. Local skin irritation occurs in some OXY-TDS patients.

A phase 3, multicenter, open-label, randomized study of abarelix versus leuprolide acetate in men with prostate cancer.

OBJECTIVES To evaluate the levels of testosterone and other hormones in men with prostate cancer treated with abarelix versus leuprolide acetate. METHODS Patients (n = 269) were randomized to receive open-label abarelix 100 mg or leuprolide acetate 7.5 mg by intramuscular injection. The results of the first 84 days of the study are reported. The primary efficacy endpoints included avoidance of testosterone surge, castration on day 8, and achievement and maintenance of castration from days 29 through 85. The secondary endpoints included castration on days 2, 4, and 15; a reduction in prostate-specific antigen level; and measurements of other hormones. Patients were monitored for clinical adverse events and laboratory abnormalities. RESULTS No men in the abarelix group and 82% of men in the leuprolide acetate group experienced a testosterone surge (P <0.001). Abarelix caused rapid medical castration: 24% of men 1 day after treatment and 78% after 7 days compared with 0% of men treated with leuprolide acetate on either day. A comparable percentage of men achieved and maintained castration between days 29 and 85 in each group. Prostate-specific antigen had a statistically significant decrease for the first month in patients treated with abarelix. Dihydrotestosterone, luteinizing hormone, prostate-specific antigen, and follicle-stimulating hormone showed similar rapid reductions without an initial increase. The overall occurrence of adverse events was similar across the treatment groups, and most were sequelae of comorbid disorders. CONCLUSIONS Treatment with abarelix produced a higher percentage of patients who avoided a testosterone surge and had a more rapid time to testosterone suppression with a higher rate of medical castration 1 day after treatment and greater reductions in testosterone, luteinizing hormone, follicle-stimulating hormone, and dihydrotestosterone during the first 2 weeks of treatment compared with leuprolide acetate. The achievement and maintenance of castration was comparable between the two groups.

The gonadotropin-releasing hormone antagonist abarelix depot versus luteinizing hormone releasing hormone agonists leuprolide or goserelin: initial results of endocrinological and biochemical efficacies in patients with prostate cancer.

PURPOSE We contrasted the endocrinological and biochemical efficacies of abarelix depot, a pure gonadotropin-releasing hormone antagonist, with a prospective concurrent control cohort receiving luteinizing hormone releasing hormone (LH-RH) agonists with or without antiandrogen for treatment of patients with prostate cancer receiving initial hormonal therapy. MATERIALS AND METHODS In this phase 2 open label study 242 patients with prostate cancer requiring initial hormonal treatment received abarelix depot (209) or LH-RH agonists (33) with or without antiandrogen. A total of 100 mg. abarelix depot was delivered intramuscularly every 28 days with an additional injection on day 15. LH-RH agonists with or without antiandrogen were administered according to the depot formulation used. Endocrine efficacy was measured by the absence of testosterone surge and rapidity of castration onset. The rate of prostate specific antigen decrease was assessed. RESULTS No patient treated with abarelix depot had testosterone surge during week 1 compared with 82% of those treated with LH-RH agonists. The concomitant administration of antiandrogen had no effect. During the first week of drug administration, in 75% of patients treated with abarelix depot and in 0% of those treated with LH-RH agonist medical castration was achieved. Prostate specific antigen decrease was faster, with no flare or surge in patients treated with abarelix depot. Abarelix depot was well tolerated. CONCLUSIONS Abarelix depot represents a new class of hormonal therapy, gonadotropin releasing hormone antagonists, that has rapid medical castration and avoids the testosterone surge characteristic of LH-RH agonists.

Mixed urinary incontinence symptoms: urodynamic findings, incontinence severity, and treatment response

OBJECTIVE To investigate the relationship between the symptom of mixed urinary incontinence and incontinence severity, urodynamic findings, and treatment response. METHODS This is a secondary analysis of data from 553 women randomized into a double-blind, placebo-controlled study evaluating duloxetine (serotonin–norepi-nephrine reuptake inhibitor) for the treatment of predominant stress urinary incontinence. Assessment variables included incontinent episode frequency, the Incontinence Quality of Life Questionnaire (I-QOL), and the Patient Global Impression of Severity Scale (PGI-S). Urge symptoms were identified with three urge I-QOL questions not included in corrected I-QOL calculations. RESULTS At baseline, 171 women (31%) had mixed urinary incontinence. They had more severe baseline urinary incontinence than did those with stress urinary incontinence (mean incontinent episode frequency 14.3 versus 10.5; PGI-S normal or mild 26.5% versus 70.4%; mean corrected I-QOL 59.1 versus 79.9; all Ps < .001). Baseline urodynamics were performed on a subset of 86 women. Subjects with both urodynamic stress incontinence and detrusor overactivity had less severe incontinence compared with subjects with only urodynamic stress incontinence. Both mixed urinary incontinence and stress urinary incontinence groups had significant decreases in median incontinent episode frequency at a 40 mg per day (62% and 58%, respectively) and 80 mg per day (63% and 65%) duloxetine dose compared with placebo (33% and 44%; all Ps < .05). Response was not dependent on the type of symptoms (interaction P = .47). CONCLUSION For women presenting with predominant stress urinary incontinence symptoms, the major determinant of concurrent urge symptoms was incontinence severity and not the pathophysiologic condition(s) causing the incontinence; duloxetine demonstrated equal efficacy for women with mixed urinary incontinence and pure stress urinary incontinence.

Trospium 60 mg Once Daily (QD) for Overactive Bladder Syndrome: Results from a Placebo-Controlled Interventional Study

OBJECTIVES A once-daily (QD) formulation of trospium chloride has been developed for the management of overactive bladder syndrome (OAB). This randomized controlled trial evaluated the efficacy and tolerability of this new extended-release formulation, trospium chloride 60 mg QD. METHODS Adults with OAB with urinary urgency, frequency, and urgency urinary incontinence (UUI) were eligible for inclusion. Subjects received trospium 60 mg QD or placebo for 12 weeks. Change in the mean number of toilet voids per day and UUI episodes per day were the primary outcome variables. Changes in urgency severity were also assessed and adverse events (AEs) were recorded. RESULTS Overall, 564 subjects participated in the study (trospium QD 280; placebo 284). Trospium QD demonstrated significant improvement in both primary outcome variables. The mean number of toilet voids per day was reduced from approximately 13 at baseline to 10.3 for trospium QD versus 11.1 for placebo (P <0.001) at week 12, whereas the number of UUI episodes per day was reduced from approximately 4 at baseline to 1.7 at week 12 with trospium QD versus 2.4 for placebo (P <0.001). Trospium QD also reduced urgency severity (P <0.001) and increased voided volume (P <0.01) compared with placebo. Benefits over placebo were apparent within the first week of treatment. Trospium QD was well tolerated; the most frequent AEs being dry mouth (trospium QD 12.9%; placebo 4.6%) and constipation (7.5% versus 1.8%, respectively). Central nervous system side effects were rarely observed and were comparable between groups. CONCLUSIONS Trospium QD represents a convenient, effective, and well-tolerated treatment option for OAB.

Oxybutynin transdermal system improves the quality of life in adults with overactive bladder: a multicentre, community-based, randomized study

To assess health‐related quality‐of‐life (HRQoL) and safety with the oxybutynin transdermal system (OXY‐TDS) (Oxytrol®, Watson Pharma, Corona, CA, USA) in the Multicentre Assessment of Transdermal Therapy in Overactive Bladder With Oxybutynin (MATRIX) study, as HRQoL measurements are increasingly important in evaluating pharmacotherapy for overactive bladder (OAB).

Long-term sustained improvement in symptoms of benign prostatic hyperplasia with the dual 5α-reductase inhibitor dutasteride : results of 4-year studies

To report additional analyses of efficacy over the initial 2 years and during a 2‐year open‐label extension of the three pivotal phase 3 studies in which dutasteride, a dual inhibitor of type 1 and 2 5α‐reductase, was shown to be effective and well tolerated.

Darifenacin treatment for overactive bladder in patients who expressed dissatisfaction with prior extended-release antimuscarinic therapy

Introduction and objective:  Patient perception of overactive bladder (OAB) treatment outcomes can be a useful indicator of benefit and may help drive persistence on treatment, which is known to be poor in OAB. It remains unclear whether OAB patients dissatisfied with one antimuscarinic can achieve satisfaction with another and supporting data are limited. This study investigated patient‐reported outcomes and clinical parameters during darifenacin treatment in OAB patients who expressed dissatisfaction with prior extended‐release (ER) oxybutynin or tolterodine therapy (administered for ≥ 1 week within the past year).