Japanese linguistic validation of the ureteral stent symptom questionnaire.

OBJECTIVE: We validated the Japanese version of the ureteral stent symptom questionnaire in patients with an indwelling ureteric stent. METHODS: The English version of the ureteral stent symptom questionnaire was translated into Japanese using a multistep process by three urologists and two independent translators. A total of 70 patients with indwelling ureteral stents completed the Japanese ureteral stent symptom questionnaire, as well as validated instruments, namely, the International Prostate Symptom Score or Overactive Bladder Symptom Score and the EuroQoL 5-dimension questionnaires. Patients completed questionnaires at 2 weeks after stent insertion and 4 weeks after stent removal. The second group included 87 healthy individuals who agreed to complete the questionnaires. The reliability of the Japanese version was evaluated for internal consistency using Cronbach's α test. Psychometric properties of the questionnaire were analyzed, and included convergent validity, sensitivity to change and discriminant validity. RESULTS: A total of 70 cases and 87 controls were suitable for the analysis. A comparison of patients with ureteric stents and healthy individuals was carried out, and the convergent validity determined by the correlation between other instruments and the corresponding ureteral stent symptoms questionnaire domains was satisfactory (P < 0.05). Internal consistencies (Cronbach's α coefficients 0.73-0.80) were satisfactory, except for the sexual matters domain. Test-retest reliability was good, except for the sexual matters domain (Spearman's coefficient 0.71-0.93). CONCLUSIONS: The Japanese version of the ureteral stent symptom questionnaire proved to be a reliable and robust instrument for the evaluation of ureteral stent-associated morbidity for both men and women.

Efficacy and safety of intravesical instillation of KRP-116D (50% dimethyl sulfoxide solution) for interstitial cystitis/bladder pain syndrome in Japanese patients: A multicenter, randomized, double-blind, placebo-controlled, clinical study.

OBJECTIVE: To evaluate the efficacy and safety of intravesical KRP-116D, 50% dimethyl sulfoxide solution compared with placebo, in interstitial cystitis/bladder pain syndrome patients. METHODS: Japanese interstitial cystitis/bladder pain syndrome patients with an O'Leary-Sant Interstitial Cystitis Symptom Index score of ≥9, who exhibited the bladder-centric phenotype of interstitial cystitis/bladder pain syndrome diagnosed by cystoscopy and bladder-derived pain, were enrolled. Patients were allocated to receive either KRP-116D (n = 49) or placebo (n = 47). The study drug was intravesically administered every 2 weeks for 12 weeks. RESULTS: For the primary endpoint, the change in the mean O'Leary-Sant Interstitial Cystitis Symptom Index score from baseline to week 12 was -5.2 in the KRP-116D group and -3.4 in the placebo group. The estimated difference between the KRP-116D and placebo groups was -1.8 (95% confidence interval -3.3, -0.3; P = 0.0188). Statistically significant improvements for KRP-116D were also observed in the secondary endpoints including O'Leary-Sant Interstitial Cystitis Problem Index score, micturition episodes/24 h, voided volume/micturition, maximum voided volume/micturition, numerical rating scale score for bladder pain, and global response assessment score. The adverse drug reactions were mild to moderate, and manageable. CONCLUSIONS: This first randomized, double-blind, placebo-controlled trial shows that KRP-116D improves symptoms, voiding parameters, and global response assessment, compared with placebo, and has a well-tolerated safety profile in interstitial cystitis/bladder pain syndrome patients with the bladder-centric phenotype.

A phase I study of enfortumab vedotin in Japanese patients with locally advanced or metastatic urothelial carcinoma.

Locally advanced or metastatic urothelial cancer is an aggressive form of cancer with high recurrence rates and low survival. Nectin-4 is a cell adhesion molecule commonly expressed in several tumors, including high expression in urothelial cancer. Enfortumab vedotin is an antibody-drug conjugate composed of an anti-Nectin-4 humanized monoclonal antibody linked to the microtubule disrupting agent, monomethyl auristatin E. In this phase I study (NCT03070990), Japanese patients with locally advanced/metastatic urothelial cancer treated with prior chemotherapy, or ineligible for cisplatin, were randomized 1:1 to receive 1.0 mg/kg (Arm A) or 1.25 mg/kg (Arm B) enfortumab vedotin on Days 1, 8, and 15 of each 28-day cycle. Assessing the pharmacokinetic and safety/tolerability profiles of enfortumab vedotin were primary objectives; investigator-assessed antitumor activity (RECIST v1.1) was a secondary objective. Seventeen patients (n = 9, Arm A; n = 8, Arm B) received treatment. Pharmacokinetic data suggest a dose-dependent increase in enfortumab vedotin maximum concentration and area under the concentration-time curve at Day 7. Enfortumab vedotin was well tolerated across both doses. Dysgeusia and alopecia (n = 9 each) were the most common treatment-related adverse events. Regardless of attribution, grade ≥ 3 adverse events occurring in ≥2 patients were anemia and hypertension (n = 2 each). One patient achieved a confirmed complete response (Arm A) and five achieved confirmed partial responses (n = 3, Arm A; n = 2, Arm B). Objective response and disease control rates were 35.3% and 76.5%, respectively. In Japanese patients with locally advanced/metastatic urothelial cancer, enfortumab vedotin is well tolerated with preliminary antitumor activity and a pharmacokinetic profile consistent with prior reports.

The resonance® metallic ureteral stent in the treatment of malignant ureteral obstruction: a prospective observational study.

BACKGROUND: To study the outcomes and experiences of using metallic stents in treating patients with malignant ureteral obstruction (MUO), we examined the effects of metallic ureteral stenting using the Cook Resonance® stent in the treatment of MUO. METHODS: All patients who had a Resonance metallic stent inserted between April 2015 and March 2018 at one of multiple facilities were prospectively observed with a 1-year follow-up. The primary outcome was the patency rate of the metallic ureteral stent. The secondary outcomes included the complications (e.g., infection and fever). RESULTS: Although stent insertion was attempted in 50 patients, the stent could not be inserted as a ureteral stent in three patients due to severe ureteral stricture, and one ureteral cancer patient was excluded from the analysis. The remaining 46 patients' median age was 67 years (range 28-85 years) (16 males, 30 females). Twenty-four patients died during the study; their median survival time was 226 days. The median follow-up period for the censored patients was 355 days (range 16-372 days), and just seven patients were still alive without Resonance failure > 1 year later. The women's IPSS scores tended to be lower than those of the men. Regarding the OABSS score, although the women's total score tended to be low, the difference between the men's and women's scores was nonsignificant. The bacteria detected from urine culture after stent insertion were more gram-positive than gram-negative. CONCLUSION: Metallic ureteric stenting using the Resonance stent is safe and effective for treating MUO. Subjective symptoms were relatively less in the female patients.

An open-label, phase 1 study of androgen receptor antagonist, apalutamide in Japanese patients with metastatic castration-resistant prostate cancer.

BACKGROUND: Apalutamide, a nonsteroidal potent androgen receptor antagonist, was safe and effective in patients with non-metastatic castration-resistant prostate cancer (nmCRPC) and metastatic-CRPC (mCRPC) in global studies. In this phase 1 study, safety, pharmacokinetics (PK), and efficacy of apalutamide were evaluated in Japanese patients with mCRPC. METHODS: In this open-label, multi-center study, patients received apalutamide 240 mg (once-daily, orally) for first 1 week (PK week) during which PK parameters were assessed. 1 week later (Cycle 1 Day1), after reassessing safety, continuous daily dosing (4 weeks/cycle; once-daily orally) was initiated. Endpoints evaluated were: safety, tolerability, PK and antitumour efficacy of apalutamide. Dose-limiting toxicities (DLTs) were evaluated during PK week and Cycle 1. RESULTS: All six patients received apalutamide. The most common treatment-emergent adverse events (TEAEs) were abdominal discomfort, nasopharyngitis, dysgeusia, rash, and hot flush [2/6 patients (33.3%) each]. No death or DLTs were reported. Grade 3 TEAEs were spinal-cord compression and renal disorder (1/6 patient each). In continuous daily dosing period, PK steady-state of apalutamide was reached approximately by week 4. A significant accumulation of apalutamide was observed (mean accumulation index 3.55), based on AUC0-24. Median (range) serum prostate-specific antigen level decreased from 54.42 (8.92-310.11) ng/mL at baseline to 11.70 (0.37-47.74) ng/mL at week 12 with ≥ 50% reduction in 4/6 (66.7%) patients and 90% reduction in 2/6 (33.3%) patients. CONCLUSION: Apalutamide had manageable safety profile, without any DLT or any new safety signals, and favourable efficacy in Japanese mCRPC patients. Thus, it was ascertained to be an adequate dosage regimen in Japanese mCRPC patients. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02162836.

Clinical evaluation of two consecutive UroVysion fluorescence in situ hybridization tests to detect intravesical recurrence of bladder cancer: a prospective blinded comparative study in Japan.

BACKGROUND: We evaluated the use of UroVysion fluorescence in situ hybridization tests to detect the intravesical recurrence of bladder cancer during follow-up after a transurethral resection of bladder tumor (TURBT). METHODS: In this prospective, blinded, comparative study, 486 patients treated by TURBT within the prior 2 years were registered at 12 centers. Urine cytology and UroVysion tests were performed once or twice at a central testing laboratory. For the patients with no suspicious findings of bladder cancer in the first analysis, the same examination set was repeated 3 months later as the second analysis. Totals of 468 and 399 patients were eligible for the first and second analyses, respectively. We determined the sensitivity and specificity of two consecutive UroVysion tests. RESULTS: Bladder cancers were identified in 44 patients at the first analysis. The UroVysion test had 50.0% (95% CI 35.2-64.8%) sensitivity and 72.4% (68.3-76.8%). Urine cytology had 4.5% (0.0-10.7%) sensitivity and 99.8% (99.3-100.0%) specificity. The concordant rate of the first and second UroVysion test results was 72% (kappa coefficient 0.157). Interestingly, the patients with two consecutive positive UroVysion test results had the highest cancer detection rate (14.8%), which is greater than those of the patients with a positive result in either (7.2%) or neither (1.2%) of the two tests at the 3-month follow-up. CONCLUSIONS: The UroVysion test provided higher sensitivity than urine cytology to detect bladder cancer during post-TURBT follow-up. Two consecutive UroVysion tests might be a better indicator to predict intravesical recurrence.

Role of lymph node dissection during radical nephroureterectomy for upper urinary tract urothelial cancer: multi-institutional large retrospective study JCOG1110A.

PURPOSE: To evaluate the impact of lymph node dissection (LND) on clinical outcome during radical nephroureterectomy (RNU) for patients with upper urinary tract urothelial cancer (UTUC). METHODS: We, the Urologic Oncology Study Group of the Japan Clinical Oncology Group (JCOG), retrospectively collected data from patients with non-metastatic UTUC who underwent RNU in 30 centers in 1995-2009. Ineligible patients and patients with previous and/or synchronous bladder cancer were excluded, and the remaining 2037 patients were analyzed. We compared overall and cancer-specific mortality between patients who underwent LND (LND group) and those without LND (no-LND group). RESULTS: Among 2037 patients, LND was performed in 1046 (51.4%) patients, and 223 (10.9%) patients had pathological node-positive (pN+) disease. All-cause mortality was observed in 503 patients (24.7%) during follow-up (median 45.8 months), including 363 patients (17.8%) who died of UTUC. Patients with pN+ disease showed significantly shorter overall survival (OS) compared with pN0 patients, and the estimated 5-year OS for pN+ patients was 30%. Older age, ≥cT3, and clinical node-positive disease were found as preoperative predictors for pN+ disease by multivariate analysis. In the comparison of OS and cancer-specific mortality between LND and no-LND groups, there was no significant improvement by LND in multivariate analysis. The median number of lymph nodes removed was six (IQR 3-11). There was no significant association between the number of lymph nodes removed and OS. CONCLUSIONS: The present study indicates that there is no therapeutic benefit of LND during RNU for UTUC, although pathologically positive LN status can predict poor prognosis.

Smoking effect on oncological outcome among men with prostate cancer after radical prostatectomy.

OBJECTIVE: To analyze the association between smoking and oncological outcome after radical prostatectomy in patients with prostate cancer. METHODS: This study included men who underwent radical prostatectomy between 2003 and 2013. The association of clinicopathological factors with smoking status and the prognostic significance of clinicopathological factors and smoking status on biochemical recurrence (BCR) were evaluated. RESULTS: Of the 1165 included patients, 226 (19.4%) were current smokers and 939 (80.6%) were nonsmokers. The median observation period was 39 months (interquartile range, 15-75 months). Current smokers were younger than nonsmokers and had higher PSA levels, higher biopsy and pathological Gleason scores, and more frequent lymph-node involvement than nonsmokers. Pathological Gleason score, extracapsular extension, seminal vesicle invasion, positive surgical margin, lymph-node involvement, and current smoking (hazard ratio [95% confidence interval]; 1.31 [1.00-1.72], P = 0.046) were identified as significant risk factors of BCR on univariate analysis. However, smoking status was not an independent predictive marker on multivariate analysis. CONCLUSIONS: Current smokers had adverse clinicopathological characteristics including high PSA level, high Gleason score, and lymph node involvement, suggesting that smoking promoted the progression of prostate cancer.

Co-introduction of a steroid with docetaxel chemotherapy for metastatic castration-resistant prostate cancer affects PSA flare.

OBJECTIVE: To investigate the potential relationship of steroid usage with prostate-specific antigen (PSA) flare as well as the prognostic impact of PSA flare, which is known to occur in 10-20% of patients with metastatic castration-resistant prostate cancer during docetaxel chemotherapy. PATIENTS AND METHODS: This study included 71 patients with metastatic castration-resistant prostate cancer treated by docetaxel chemotherapy with co-introduction of a steroid. PSA flare was defined as a transient PSA increase followed by a PSA decrease. RESULTS: PSA flare was recognized in 7.0-23.9% of patients according to the definition used. Intriguingly, men with steroid intake before the initiation of docetaxel chemotherapy experienced significantly fewer PSA flares. The progression-free survival rate in men with PSA flare was equivalent to that of PSA responders, but significantly better than men with PSA failure. CONCLUSIONS: Our results suggest that de novo steroid co-introduction with docetaxel chemotherapy induces the PSA flare phenomenon. This novel finding may account for the mechanism of PSA flare as well as being valuable for distinguishing PSA elevation attributable to PSA flare from that attributable to PSA failure.

Actions of cAMP on calcium sensitization in human detrusor smooth muscle contraction.

OBJECTIVES: To clarify the effect of cAMP on the Ca(2+) -sensitized smooth muscle contraction in human detrusor, as well as the role of novel exchange protein directly activated by cAMP (Epac) in cAMP-mediated relaxation. MATERIALS AND METHODS: All experimental protocols to record isometric tension force were performed using α-toxin-permeabilized human detrusor smooth muscle strips. The mechanisms of cAMP-mediated suppression of Ca(2+) sensitization activated by 10 µm carbachol (CCh) and 100 µm GTP were studied using a selective rho kinase (ROK) inhibitor, Y-27632, and a selective protein kinase C (PKC) inhibitor, GF-109203X. The relaxation mechanisms were further probed using a selective protein kinase A (PKA) activator, 6-Bnz-cAMP and a selective Epac activator, 8-pCPT-2'-O-Me-cAMP. RESULTS: We observed that CCh-induced Ca(2+) sensitization was inhibited by cAMP in a concentration-dependent manner. GF-109203X (10 µm) but not Y-27632 (10 µm) significantly enhanced the relaxation effect induced by cAMP (100 µm). 6-Bnz-cAMP (100 µm) predominantly decreased the tension force in comparison with 8-pCPT-2'-O-Me-cAMP (100 µm). CONCLUSIONS: We showed that cAMP predominantly inhibited the ROK pathway but not the PKC pathway. The PKA-dependent pathway is dominant, while Epac plays a minor role in human detrusor smooth muscle Ca(2+) sensitization.

Patient preferences for treatment of castration-resistant prostate cancer in Japan: a discrete-choice experiment.

BACKGROUND: Up to a fifth of patients diagnosed with prostate cancer (PC) will develop castration-resistant prostate cancer (CRPC), which has been associated with a poor prognosis. The aim of this study was to consider the patient perspective as part of the overall treatment decision-making process for CRPC, given that an alignment between patient preference and prescribing has been shown to benefit patient outcomes. This study examines preferences of patients with CRPC in Japan for treatment features associated with treatments like RA-223, abiraterone, and docetaxel and to examine the extent to which treatment preferences may vary between symptomatic and asymptomatic patients. METHODS: A two-phase research approach was implemented. In Phase 1, N = 8 patients with CRPC were recruited from a single hospital to complete a qualitative interview to provide feedback on the draft survey. In Phase 2, N = 134 patients with CRPC were recruited from five hospitals to complete a paper survey. The survey included 6 treatment choice questions, each asking patients to choose between two hypothetical treatments for their CRPC. Each treatment alternative was defined by the following attributes: length of overall survival (OS), time to a symptomatic skeletal event (SSE), method of administration, reduction in the risk of bone pain, treatment-associated risk of fatigue and lost work days. A hierarchical Bayesian logistic regression was used to estimate relative preference weights for each attribute level and mean relative importance. RESULTS: A total of N = 133 patients with CRPC completed the survey and were included in the final analysis. Patients had a mean age of 75.4 years (SD = 7.4) and had been diagnosed with PC a mean of 6.5 years prior (SD = 4.4). Over the attribute levels shown, fatigue (relative importance [RI] = 24.9 %, 95 % CI: 24.7 %, 25.1 %) was the most important attribute, followed by reduction in the risk of bone pain (RI = 23.2 %, 95 % CI: 23.0 %, 23.5 %), and OS (RI = 19.2 %, 95 % CI: 19.0 %, 19.4 %). Although symptomatic patients placed significantly more importance on delaying an SSE (p < .05), no other preference differences were observed. CONCLUSIONS: CRPC patients were more concerned about reduced quality of life from side effects of treatment rather than extension of survival, which may have implications for shared decision-making between patients and physicians.

A multicenter phase I/II study of enzalutamide in Japanese patients with castration-resistant prostate cancer.

BACKGROUND: The safety, tolerability, pharmacokinetics (PK) and anti-tumor activity of enzalutamide were investigated in patients with castration-resistant prostate cancer (CRPC) in Japan through a multicenter phase I/II study. METHODS: In phase I, patients with progressive metastatic CRPC received single, then multiple, ascending doses of enzalutamide 80, 160 or 240 mg/day. After assessment of tolerability at multiple doses of 160 mg/day for 4 weeks, post-docetaxel patients with CRPC and measurable disease were enrolled into phase II; receiving long-term administration of enzalutamide 160 mg/day. RESULTS: Nine and 38 patients were enrolled in phase I and II, respectively. During phase I, enzalutamide was well tolerated in each cohort; PK parameters were similar to those of non-Japanese populations in other studies. By week 12, overall response rate was 5.3 % and clinical benefit rate was 47.4 %. Prostate-specific antigen response rate (≥50 % reduction from baseline) was 28.9 %. Treatment-emergent adverse events reported in >20 % of patients in phase II were decreased weight, decreased appetite and constipation. No seizures were observed. CONCLUSION: Enzalutamide at 160 mg/day was well tolerated, with PK and safety profiles similar to the non-Japanese population. Anti-tumor activity was observed in post-docetaxel Japanese patients with metastatic CRPC. Apparent differences in anti-tumor activity compared with the AFFIRM study (a phase III trial in a diverse population of patients with CRPC post-docetaxel) may be attributed to differences in treatment history prior to starting enzalutamide. Particularly in Japan, the influence of sequence in hormone treatments, including combined androgen blockade therapy, should be considered. TRIAL REGISTRATION: ClinicalTrials.gov NCT01284920.

Should inclusion criteria for active surveillance for low-risk prostate cancer be more stringent? From an interim analysis of PRIAS-JAPAN.

PURPOSE: To define clinical and pathological factors predicting reclassification at the time of 1-year repeat biopsy (re-Bx) based on a Japanese cohort forming part of the Prostate Research International: Active Surveillance (PRIAS) study. PATIENTS AND METHODS: The inclusion criteria for the PRIAS study are as follows: clinical stage T1c/T2, PSA ≤ 10 ng/ml, PSA density (PSAD) < 0.2 ng/ml per milliliter, one or two positive biopsy cores, and Gleason score (GS) ≤ 6 at initial diagnostic biopsy. Baseline clinical characteristics and prostate-specific antigen doubling time (PSADT) at the time of re-Bx were analyzed via multivariate logistic regression with respect to reclassification and 'no cancer' status on the 1-year re-Bx. RESULTS: A total of 386 patients were enrolled in PRIAS-JAPAN by the end of 2013. Of these, 216 underwent re-Bx at 1 year. A total of 73 patients (33.8 %) were reclassified, whereas 74 (34.3 %) had no cancer. Older age, a higher PSAD, a higher positive core rate, and a shorter PSADT were significant predictors of reclassification. The positive core rate was the predictor common to reclassification, no cancer, and high GS, upon re-Bx. CONCLUSIONS: An interim analysis of a Japanese AS cohort participating in PRIAS revealed that the positive core rate was strongly associated with reclassification at the 1-year re-Bx. However, although amendment of the PRIAS inclusion criteria to incorporate a positive core might reduce any concern about underestimation, this would also reduce the number of patients undergoing AS.

Once-daily oxybutynin patch improves nocturia and sleep quality in Japanese patients with overactive bladder: Post-hoc analysis of a phase III randomized clinical trial.

OBJECTIVES: To investigate the efficacy of a once-daily oxybutynin patch for nocturia, and its influence on sleep quality in patients with overactive bladder. METHODS: We carried out post-hoc analysis of a phase III, randomized, double-blind, comparative study in which an oxybutynin patch was administered once daily for 12 weeks to Japanese patients with overactive bladder. Patients with a baseline mean of one or more episodes of nocturia per night (data from voiding diaries) were analyzed. The mean number of micturitions, mean voided volume per micturition, mean first voided volume at night, mean sleep duration, and hours of undisturbed sleep were compared between the once-daily oxybutynin patch group and the placebo group. All parameters were expressed as the least squares mean values. RESULTS: The analysis included 576 patients. The number of nocturia episodes decreased by 0.66 in the oxybutynin patch group versus 0.51 in the placebo group (P = 0.0249). Also, the voided volume per nocturnal micturition and the first voided volume at night showed a significant increase in the oxybutynin patch group compared with the placebo group (P = 0.0073 and P = 0.0005, respectively). The hours of undisturbed sleep showed significant prolongation by 76.14 min in the oxybutynin patch group versus 56.07 min in the placebo group (P = 0.0257). CONCLUSIONS: Oxybutynin patch treatment reduces the number of nocturia episodes and prolongs the hours of undisturbed sleep, thus improving sleep quality and sleep-related quality of life in patients with overactive bladder.

Non-inferiority of silodosin 4 mg once daily to twice daily for storage symptoms score evaluated by the International Prostate Symptom Score in Japanese patients with benign prostatic hyperplasia: a multicenter, randomized, parallel-group study.

OBJECTIVES: To compare the effect of treatment with silodosin 4 mg once daily versus that of silodosin 4 mg twice daily on storage symptoms in Japanese patients with benign prostatic hyperplasia. METHODS: A prospective, multicenter, 12-week, open-labeled study randomized a total of 268 men aged 50 years or older with benign prostatic hyperplasia and overactive bladder to silodosin 4 mg/day or 8 mg/day. Changes in the end-points of the average value of International Prostate Symptom Score, quality of life index in the International Prostate Symptom Score, Overactive Bladder Symptom Score and urodynamic parameters were evaluated. The change in the storage symptom subtotal score of the International Prostate Symptom Score was considered as the primary end-point. RESULTS: Silodosin 4 mg/day was not inferior to silodosin 8 mg/day in regard to the primary end-point. In contrast, the efficacy of treatment with silodosin 4 mg twice daily was greater than that of 4 mg once daily, based on both the quality of life index and the Overactive Bladder Symptom Score total score. There was a discrepancy between the scores evaluated using the International Prostate Symptom Score and Overactive Bladder Symptom Score questionnaires. CONCLUSIONS: Silodosin 4 mg once daily is not inferior to silodosin 4 mg twice daily in regard to storage symptoms score evaluated by the International Prostate Symptom Score. In contrast, silodosin 4 mg twice daily is more effective on storage symptoms evaluated by the Overactive Bladder Symptom Score than silodosin 4 mg once daily.

Phase-1 study of abiraterone acetate in chemotherapy-naïve Japanese patients with castration-resistant prostate cancer.

Persistent androgen synthesis under castration status in adrenal gland, testes and tumor cells is thought to be one of the major causes of development and progression of castration-resistant prostate cancer (CRPC). Abiraterone acetate (AA), the prodrug of abiraterone, which is an inhibitor of androgen synthesis enzymes, was evaluated for pharmacokinetics, pharmacodynamics, preliminary efficacy and safety in Japanese patients with CRPC in a phase-1, open-label and dose-escalation study. Chemotherapy-naïve Japanese CRPC patients (N = 27) received one of four AA daily doses (250 mg [n = 9], 500 mg [n = 6], 1000 [1 h premeal] mg [n = 6] and 1000 [2 h postmeal] mg [n = 6]) continuously through 28-day treatment cycles. In the first cycle, AA monotherapy was given on days 1-7 for pharmacokinetics, and AA plus prednisone (5 mg twice daily) from days 8 to 28. Of 27 patients, 9 continued treatment with AA until the data cut-off date (18 July 2013). Over the evaluated dose range, plasma abiraterone concentrations increased with dose, with median tmax 2-3 h. At each dose level, mean serum corticosterone concentrations increased, while testosterone and dehydroepiandrosterone sulfate concentrations rapidly decreased following a single AA dose and were further reduced to near the quantification limit on day 8 regardless of the dose. At least 3 patients from each dose-group experienced ≥50% prostate-specific antigen reduction, suggesting clinical benefit from AA in Japanese CRPC patients. AA was generally well-tolerated, and, therefore, the recommended AA dosage regimen in Japanese CRPC patients is 1000 mg oral dose under modified fasting conditions (at least 1 h premeal or 2 h postmeal). This study is registered at ClinicalTrials.gov: NCT01186484.

The oncological outcomes and risk stratification in docetaxel chemotherapy for castration-resistant prostate cancer.

OBJECTIVE: To clarify the risk factors and develop a refined risk-stratification model to help in the appropriate selection of docetaxel chemotherapy in patients with castration-resistant prostate cancer. METHODS: This study included 97 Japanese patients with castration-resistant prostate cancer who were treated with 70-75 mg/m(2) docetaxel and 10 mg prednisone every 3 or 4 weeks from 2008 to 2013. The oncological outcomes and prognostic significance of clinicopathological factors were analyzed, and significant prognostic factors were used to develop a risk-stratification model. RESULTS: Prostate-specific antigen decline was observed in 75 patients (77.3%), including 43 (44.3%) who achieved a prostate-specific antigen decline of ≥ 50%. The median progression-free survival and overall survival were 5.1 and 20.8 months, respectively. Univariate analysis identified performance status, alkaline phosphatase value, visceral metastasis, duration from diagnosis, duration from initiation of hormone treatment and prior treatment with estramustine as significant predictors of overall survival. Among these, alkaline phosphatase value, visceral metastasis and duration from initiation of hormone treatment were independent prognostic factors in multivariate analysis. Furthermore, risk classification according to the number of independent risk factors present effectively stratified survival among docetaxel-treated castration-resistant prostate cancer patients. CONCLUSIONS: Oncologic outcomes in Japanese patients with castration-resistant prostate cancer receiving docetaxel chemotherapy were comparable to or slightly better than those in Western populations, and the risk-stratification model developed in this study may help to predict prognosis and contribute to the selection of suitable therapy after castration resistance.

The efficacy and safety of degarelix, a GnRH antagonist: a 12-month, multicentre, randomized, maintenance dose-finding phase II study in Japanese patients with prostate cancer.

OBJECTIVE: To assess the efficacy and safety of degarelix, a new gonadotropin-releasing hormone antagonist, for achieving and maintaining serum testosterone suppression (≤0.5 ng/ml) during the 12-month treatment of Japanese patients with prostate cancer. METHODS: This Phase II study was conducted as a multicentre, randomized, parallel-group, open-label study. A total of 273 patients with adenocarcinoma of the prostate (any stage) were treated. Degarelix was administered subcutaneously at an initial dose of 240 mg followed by monthly maintenance doses of either 80 or 160 mg for a total of 12 doses. The treatment continued for 12 months. RESULTS: Dose regimens of 240/80 and 240/160 mg maintained castrate levels of testosterone in 94.5 and 95.2% of the patients, respectively. After 3 days, 99.3 and 98.5% of the patients, respectively, reached these levels without a testosterone surge. Prostate-specific antigen levels decreased rapidly following degarelix administration and remained low throughout the study. Best overall response rates according to RECIST were 71.4 (20/28) and 72.7% (16/22), respectively. Eighteen patients (6.6%) withdrew from the study due to adverse events. The most common adverse events were injection site reactions; other adverse events included hot flush, nasopharyngitis, weight increase and pyrexia. CONCLUSIONS: Both monthly degarelix dosing regimens were found to be effective in testosterone suppression without a testosterone surge, prostate-specific antigen reductions and anti-tumour effect in Japanese patients with prostate cancer, as was shown in the overseas Phase III study. Degarelix was also well tolerated.

Maintenance therapy with bacillus Calmette-Guérin Connaught strain clearly prolongs recurrence-free survival following transurethral resection of bladder tumour for non-muscle-invasive bladder cancer.

OBJECTIVE: • To confirm the recurrence-preventing efficacy and safety of 18-month bacillus Calmette-Guérin (BCG) maintenance therapy for non-muscle-invasive bladder cancer. PATIENTS AND METHODS: • The enrolled patients had been diagnosed with recurrent or multiple non-muscle-invasive bladder cancer (stage Ta or T1) after complete transurethral resection of bladder tumours (TURBT). • The patients were randomized into three treatment groups: a maintenance group (BCG, 81 mg, intravesically instilled once weekly for 6 weeks as induction therapy, followed by three once-weekly instillations at 3, 6, 12 and 18 months after initiation of the induction therapy), a non-maintenance group (BCG, 81 mg, intravesically instilled once weekly for 6 weeks) and an epirubicin group (epirubicin, 40 mg, intravesically instilled nine times). The primary endpoint was recurrence-free survival (RFS). RESULTS: • Efficacy analysis was performed for 115 of the full-analysis-set population of 116 eligible patients, including 41 maintenance group patients, 42 non-maintenance group patients and 32 epirubicin group patients. • At the 2-year median point of the overall actual follow-up period, the final cumulative RFS rates in the maintenance, non-maintenance and epirubicin groups were 84.6%, 65.4% and 27.7%, respectively. • The RFS following TURBT was significantly prolonged in the maintenance group compared with the non-maintenance group (generalized Wilcoxon test, P= 0.0190). CONCLUSION: • BCG maintenance therapy significantly prolonged the post-TURBT RFS compared with BCG induction therapy alone or epirubicin intravesical therapy.