Michael J. Manyak

Immunoscintigraphy with indium-111-capromab pendetide: evaluation before definitive therapy in patients with prostate cancer.

OBJECTIVESnNo standard noninvasive diagnostic test reliably differentiates patients with organ-confined prostate cancer from those with lymph node metastases. The ability of a radiolabeled monoclonal antibody, indium-111 (111ln)-capromab pendetide, to identify sites of metastatic disease in patients at moderate to high risk of nodal involvement was investigated.nnnMETHODSnThe study prospectively evaluated 160 patients with prostate cancer scheduled to undergo pelvic lymph node dissection (PLND) before or during definitive treatment. All were at relatively high risk of nodal involvement by virtue of significantly elevated baseline prostate-specific antigen (PSA) values, Gleason scores, and/or locally advanced clinical stages of disease. The histologic findings of the PLNDs were compared with the results of immunoscintigraphy, computed tomography, and magnetic resonance imaging.nnnRESULTSnAmong the 152 evaluable patientS studied with 111In-capromab pendetide before PLND, the sensitivity of immunoscintigraphy for lymph node detection was 62% and the specificity was 72%; the positive predictive value was 62% and the negative predictive value was 72%. In comparison, the sensitivity of computed tomography and magnetic resonance imaging was 4% and 15%, respectively, and the specificity was 100% for both procedures on the basis of a large number of negative interpretations. Logistic regression analysis revealed that immunoscintigraphy with 111In-capromab pendetide provided strong, independent evidence of the presence of lymph node metastases. Furthermore, the analysis indicated that certain combinations of PSA, Gleason score, and 111In-capromab pendetide were particularly effective at predicting the risk of nodal involvement.nnnCONCLUSIONSnImmunoscintigraphy with 111In-capromab pendetide outperformed standard diagnostic imaging techniques in the detection of prostate cancer lymph node metastases and provided independent prognostic information that complemented PSA, Gleason score, and clinical stage.

Oral bropirimine immunotherapy of bladder carcinoma in situ after prior intravesical bacille Calmette-Guérin

OBJECTIVESnBropirimine is an oral immunomodulator that has demonstrated anticancer activity in transitional cell carcinoma in situ (CIS) in both the bladder and upper urinary tract. Activity also has been documented in patients after prior therapy with bacille Calmette-Guérin (BCG). To more accurately estimate bropirimines efficacy in BCG-resistant bladder CIS, a Phase II trial was performed. A separate analysis was performed in additional patients intolerant of BCG toxicity.nnnMETHODSnPatients received bropirimine 3.0 g/day by mouth for 3 consecutive days, weekly, for up to 1 year. Bladder biopsies and cytologic examination were performed quarterly. Complete response (CR) required negative biopsy and cytology results.nnnRESULTSnTwenty-one of 86 patients entered were not evaluable. CR was seen in 21 (32%; 95th percentile confidence interval [CI], 21% to 44%) of 65 evaluable patients, including 14 (30%, CI 17% to 43%) of 47 BCG-resistant, and 7 (39%, CI 16% to 61%) of 18 BCG-intolerant patients. Overall, by intent-to-treat analysis, CR was thus seen in 21 (24%) of 86 subjects. Most BCG-resistant patients were failures to BCG without relapse, and had received 12 to 36 (median 12) BCG treatments; intolerant patients had received 4 to 11 treatments (median 6). Response duration ranged from 65 to 810 days, with median not yet reached (but greater than 12 months). Thirteen (15%) of 86 stopped bropirimine due to toxicity. Progression to invasive or metastatic disease during or immediately after therapy was documented in only 4 patients (6%), all nonresponders.nnnCONCLUSIONSnBropirimine may be an alternative to cystectomy for some patients with bladder CIS who have failed or have not tolerated BCG. Further evaluation to improve responses and durability is warranted.

Primary small noncleaved cell lymphoma of kidney

The kidney is the second most common site for metastasis of lymphoma though it remains asymptomatic and is not commonly detected with cross-sectional imaging studies. Primary renal lymphoma is a very rare lesion whose existence is controversial. The lymphoma reported here presented as a solitary renal mass without any other evidence of disease. Lymphoma should be included in the differential diagnosis for solitary renal masses even though the usual presentation is bilateral. Renal involvement with lymphoma requires a thorough search for extrarenal disease.

Long‐term safety and efficacy of dutasteride in the treatment of male patients with androgenetic alopecia

Androgenetic alopecia is an androgen‐induced pattern of progressive hair loss, which occurs in genetically predisposed people. This study aimed to determine long‐term safety, tolerability and efficacy of dutasteride 0.5 mg, an inhibitor of 5‐α‐reductase, in Japanese male patients with androgenetic alopecia. This was a multicenter, open‐label, prospective outpatient study (clinicaltrials.gov NCT01831791, GSK identifier ARI114264) in which patients took dutasteride 0.5 mg p.o. once daily for 52 weeks. Primary end‐points included adverse event assessment, incidence of drug‐related adverse event and premature discontinuations. Secondary end‐points included hair growth, hair restoration and global improvement in hair. A total of 120 patients were enrolled, of whom 110 completed 52 weeks of treatment. Nasopharyngitis, erectile dysfunction and decreased libido were the most frequently reported adverse events and most adverse events were mild. Drug‐related adverse events were reported with an incidence of 17%, none of which led to study withdrawal. Hair growth (mean target area hair count at week 52), hair restoration (mean target area hair width at week 52) and global appearance of hair (mean of the median score at week 52) improved from baseline during the study. As a potential future treatment option for male androgenetic alopecia, dutasteride 0.5 mg exhibited long‐term safety, tolerability and efficacy within this study population.

Nocturia improvement in the combination of Avodart® and tamsulosin (CombAT) study

PurposeThe purpose of the study was to assess the impact of dutasteride plus tamsulosin combination therapy, compared with dutasteride or tamsulosin monotherapy, on nocturia in men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia (LUTS/BPH) using data from the 4-year CombAT study.MethodsNocturia was assessed using Question 7 of the International Prostate Symptom Score questionnaire. Efficacy measures included as follows: mean change in nocturia at 3-month intervals up to 48xa0months; proportion of patients with improvement/worsening in nocturia; nocturnal voiding frequency at baseline and study end, overall and by baseline subgroups; and nocturnal voiding frequency <2 at study end in patients with a baseline score ≥2.ResultsIn total, 4,722 patients with a mean age of 66xa0years were included. Mean nocturia improvements were significantly superior (pxa0≤xa00.01) with combination therapy than with either monotherapy (adjusted mean change from baseline in IPSS Question 7 score at month 48: combination therapy −0.5, dutasteride −0.4, tamsulosin −0.3). Reduction in nocturia score with combination therapy was significantly (pxa0≤xa00.01) better than tamsulosin monotherapy across all baseline subgroups tested, except for men with previous 5ARI use. Among those with a baseline IPSS Q7 score ≥2, more patients with combination therapy had a score <2 at month 48 (34xa0%) compared with dutasteride (30xa0%, pxa0=xa00.018) or tamsulosin (26xa0%, pxa0<xa00.0001).ConclusionsCombination therapy provided greater improvements and less worsening of nocturia compared with both dutasteride and tamsulosin monotherapies. These analyses are the first to show greater improvement with a 5ARI/α-blocker combination versus either agent alone for the management of nocturia in patients with LUTS/BPH.

Impact of dutasteride on nocturia in men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia (LUTS/BPH): a pooled analysis of three phase III studies

PurposeTo assess the impact of dutasteride compared with placebo on nocturia in men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia, using pooled data from dutasteride phase III studies.MethodsNocturia was assessed using Question 7 of the International Prostate Symptom Score questionnaire. Efficacy measures included: mean change in nocturia at 24xa0months; proportion of patients with improvement/worsening in nocturia; nocturnal voiding frequency at baseline and study end, overall and by baseline subgroups; and nocturnal voiding frequency <2 at study end in patients with baseline score ≥2.ResultsIn total, 4,321 patients with a mean age of 66xa0years were evaluated. From month 12 onwards, mean nocturia improvements were significantly superior with dutasteride than with placebo (pxa0≤xa00.05). Reduction in nocturia was significantly better with dutasteride than with placebo across all baseline subgroups tested (pxa0≤xa00.05). Also at month 24, dutasteride therapy resulted in a greater proportion of subjects with nocturia improvement compared with placebo (pxa0≤xa00.05), with the largest treatment group differences in subjects with a baseline nocturia score of 2 or 3. Among patients with significant nocturia at baseline (score ≥2), significantly more subjects with dutasteride versus placebo had a score <2 at month 24 (26 vs. 19xa0%, pxa0<xa00.001).ConclusionsAfter 24xa0months of treatment, dutasteride treatment provided significantly greater improvements in nocturia, and less worsening, compared with placebo, primarily in subjects with two or three nocturia episodes per night. Studies specifically designed to assess nocturia are required to prospectively confirm these findings.

A prospective randomised placebo-controlled study of the impact of dutasteride/tamsulosin combination therapy on sexual function domains in sexually active men with lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH)

To prospectively assess the impact of the fixed‐dose combination (FDC) of the 5α‐reductase inhibitor (5ARI), dutasteride 0.5 mg and the α1‐adrenoceptor antagonist, tamsulosin 0.4 mg (DUT‐TAM FDC) therapy on sexual function domain scores in sexually active men with lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH), using the Mens Sexual Health Questionnaire (MSHQ).

The REDUCE Follow-Up Study: low rate of new prostate cancer diagnoses observed during a 2-year, observational, followup study of men who participated in the REDUCE trial.

PURPOSEnThe primary objective of the REDUCE (REduction by DUtasteride of prostate Cancer Events) Follow-Up Study was to collect data on the occurrence of newly diagnosed prostate cancers for 2 years beyond the 4-year REDUCE study.nnnMATERIALS AND METHODSnThe 4-year REDUCE study evaluated prostate cancer risk reduction in men taking dutasteride. This 2-year observational study followed men from REDUCE with a clinic visit shortly after study conclusion and with up to 2 annual telephone calls during which patient reported data were collected regarding prostate cancer events, chronic medication use, prostate specific antigen levels and serious adverse events. No study drug was provided and all biopsies during the 2-year followup were performed for cause. The primary objective was to collect data on the occurrence of new biopsy detectable prostate cancers. Secondary end points included assessment of Gleason score and serious adverse events.nnnRESULTSnA total of 2,751 men enrolled in the followup study with numbers similar to those of the REDUCE former treatment groups (placebo and dutasteride). Few new prostate cancers were detected during the 2-year followup period in either former treatment group. A greater number of cancers were detected in the former dutasteride group than in the former placebo group (14 vs 7 cases). No Gleason score 8-10 prostate cancers were detected in either former treatment group based on central pathology review. No new safety issues were identified during the study.nnnCONCLUSIONSnTwo years of followup of the REDUCE study cohort demonstrated a low rate of new prostate cancer diagnoses in the former placebo and dutasteride treated groups. No new Gleason 8-10 cancers were detected.

Impact of Formulation on the Pharmacokinetics of Dutasteride: Results from Two Phase I Studies

Background and ObjectivesDutasteride is currently marketed by GlaxoSmithKline (GSK), either as monotherapy or as a fixed-dose combination with tamsulosin. As part of the project to develop the fixed-dose combination product, alternative formulations of dutasteride were prepared by GSK, and their pharmacokinetic properties were investigated.MethodsTwo single-centre, open-label, active-comparator, randomised, three-period crossover studies were performed. The first study evaluated the relative bioavailability of dutasteride 0.5xa0mg soft gelatin capsule (marketed formulation, reference) versus a dutasteride 0.5xa0mg hard gelatin capsule and a dutasteride 0.5xa0mg tablet. The second assessed the relative bioavailability of dutasteride 0.5xa0mg from soft gelatin capsules containing 300 or 100xa0mg of mono- and diglycerides of caprylic acid/capric acid (MDC8, an emulsifying agent) versus the marketed formulation.ResultsIn the first study (nxa0=xa036), compared with the marketed soft gelatin capsule formulation, the bioavailability (least squares [LS] means ratio) of the tablet formulation was 76xa0% (90xa0% CI 0.68–0.84), and that of the hard gelatin capsule was 73xa0% (90xa0% CI 0.66–0.82). Peak exposures were also lower for the tablet (73xa0%; 90xa0% CI 0.66–0.81) and hard capsule (71xa0%; 90xa0% CI 0.64–0.79) relative to the marketed soft gelatin capsule. In the second study (nxa0=xa037), compared with the marketed soft gelatin formulation, the bioavailability (LS means ratio) of the 300xa0mg MDC8 capsule formulation was 95xa0% (90xa0% CI 0.88–1.03), and that of the 100xa0mg MDC8 capsule formulation was 93xa0% (90xa0% CI 0.86–1.00). Peak exposures were also lower for the 300xa0mg MDC8 (90xa0%; 90xa0% CI 0.81–0.99) and 100xa0mg MDC8 (87xa0%; 90xa0% CI 0.79–0.96) formulations.ConclusionsThe bioavailability of, and peak exposure to, dutasteride are influenced by the formulation of the administered medication. These studies demonstrate the importance of formulation for obtaining the optimal pharmacokinetic properties of dutasteride.

A randomised, double-blind study comparing the addition of bicalutamide with or without dutasteride to GnRH analogue therapy in men with non-metastatic castrate- resistant prostate cancer

BACKGROUNDnBicalutamide blocks androgen action and is frequently used in men with non-metastatic, castration-resistant prostate cancer (CRPC). By reducing intracellular dihydrotestosterone, dutasteride (dual 5-alpha reductase inhibitor) could increase the effectiveness of bicalutamide in this setting. The objective of the study is therefore to prospectively evaluate dutasteride plus bicalutamide in men with asymptomatic, non-metastatic CRPC with rising prostate-specific antigen (PSA).nnnMETHODSnProstate cancer patients with rising PSA whilst on first-line androgen deprivation therapy (ADT) were randomised (1:1) in a double-blind trial to receive bicalutamide 50mg plus placebo or bicalutamide 50mg plus dutasteride 3.5mg once daily for 18 months. Randomisation was stratified by centre; treatment assignments were generated using GlaxoSmithKlines RandAll System. Subjects who completed 18 months could participate in the 2-year extension. Central laboratory and study sites/monitors remained treatment-blinded. Primary end-point was time to disease progression (TDP) up to 42 months (defined as PSA progression from baseline or nadir, radiographic disease progression, death from prostate cancer or receipt of rescue medication).nnnFINDINGSnThere was no statistically significant difference in TDP in 127 men treated with bicalutamide/dutasteride (n=62) compared with bicalutamide/placebo (n=65) (hazard ratio (HR)=0.94 [95% confidence interval (CI) 0.61, 1.46]; p=0.79). The estimated median TDP was 425 days (95% CI 302, 858) in the bicalutamide/placebo group and 623 days (95% CI 369, 730) in the bicalutamide/dutasteride group. There was no statistically significant difference between the treatment groups for any secondary efficacy end-points, including time to treatment failure or PSA response. In the multivariate analysis, age, non-White race, higher baseline testosterone and lower baseline PSA were associated with longer TDP. Adverse events were comparable between treatment groups.nnnINTERPRETATIONnIn men with non-metastatic CRPC, adding dutasteride to bicalutamide did not significantly prolong TDP. Prospective data are provided concerning the common practice of using bicalutamide in this setting.