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Background: Five-year survival of patients with inoperable, advanced urothelial carcinoma treated with the first-line chemotherapy is 5%-15%. We assessed whether the Hsp27 inhibitor apatorsen combined with gemcitabine plus cisplatin (GC) could improve overall survival (OS) in these patients. Patients and methods: This placebo-controlled, double-blind, phase II trial randomized 183 untreated urothelial carcinoma patients (North America and Europe) to receive GC plus either placebo (N=62), 600 mg apatorsen (N=60), or 1000mg apatorsen (N=61). In the experimental arm, treatment included loading doses of apatorsen followed by up to six cycles of apatorsen plus GC. Patients receiving at least four cycles could continue apatorsen monotherapy as maintenance until progression or unacceptable toxicity. The primary end point was OS. Results: OS was not significantly improved in the single or combined 600- or 1000-mg apatorsen arms versus placebo [hazard ratio (HR), 0.86 and 0.90, respectively]. Exploratory study of specific statistical modeling showed a trend for improved survival in patients with baseline poor prognostic features treated with 600mg apatorsen compared with placebo (HR=0.72). Landmark analysis of serum Hsp27 (sHsp27) levels showed a trend toward survival benefit for poor-prognosis patients in 600- and 1000- mg apatorsen arms who achieved lower area under the curve sHsp27 levels, compared with the placebo arm (HR=0.45 and 0.62, respectively). Higher baseline circulating tumor cells (⩾5 cells/7.5 ml) was observed in patients with poor prognosis in correlation with poor survival. Treatment-emergent adverse events were manageable and more common in both apatorsentreatment arms. Conclusions: Even though apatorsen combined with standard chemotherapy did not demonstrate a survival benefit in the overall study population, patients with poor prognostic features might benefit from this combination. Serum Hsp27 levels may act as a biomarker to predict treatment outcome. Further exploration of apatorsen in poor-risk patients is warranted. [ABSTRACT FROM AUTHOR]

Abiraterone is a new hormonal drug for metastatic castration resistant prostate cancer. In a retrospective analysis, neutrophil/lymphocyte ratio (NLR) ≤ 5 and restricted metastatic spread to either bones or lymph nodes were associated with PSA response to abiraterone. These two variables were combined to a score that was associated with PSA response and OS, in both a training and a validation cohort.Background Abiraterone acetate (abiraterone) prolongs overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC). This study's objective was to retrospectively identify factors associated with prostate-specific antigen (PSA) response to abiraterone and validate them in an independent cohort. We hypothesized that the neutrophil/lymphocyte ratio (NLR), thought to be an indirect manifestation of tumor-promoting inflammation, may be associated with response to abiraterone. Patients and methods All patients receiving abiraterone at the Princess Margaret (PM) Cancer Centre up to March 2013 were reviewed. The primary end point was confirmed PSA response defined as PSA decline ≥50% below baseline maintained for ≥3 weeks. Potential factors associated with PSA response were analyzed using univariate and multivariable analyses to generate a score, which was then evaluated in an independent cohort from Royal Marsden (RM) NHS foundation. Results A confirmed PSA response was observed in 44 out of 108 assessable patients (41%, 95% confidence interval 31%–50%). In univariate analysis, lower pre-abiraterone baseline levels of lactate dehydrogenase, an NLR ≤ 5 and restricted metastatic spread to either bone or lymph nodes were each associated with PSA response. In multivariable analysis, only low NLR and restricted metastatic spread remained statistically significant. A score derived as the sum of these two categorical variables was associated with response to abiraterone (P = 0.007). Logistic regression analysis on an independent validation cohort of 245 patients verified that this score was associated with response to abiraterone (P = 0.003). It was also associated with OS in an exploratory analysis. Conclusions A composite score of baseline NLR and extent of metastatic spread is associated with PSA response to abiraterone and OS. Our data may help understand the role of systemic inflammation in mCRPC and warrant further research. [ABSTRACT FROM PUBLISHER]

Background Multiple factors can influence outcomes of patients receiving identical interventions in clinical trials and in routine practice. Here, we compare outcomes of men with metastatic castrate-resistant prostate cancer (mCRPC) treated with docetaxel and prednisone in routine practice and in clinical trials. Patients and methods We reviewed patients with mCRPC treated with docetaxel at Princess Margaret Cancer Centre. Primary outcomes were overall survival and PSA response rate. Secondary outcomes were reasons for discontinuation and febrile neutropenia. Outcomes were compared for men treated in routine practice and in clinical trials, and with data from the TAX 327 study. Results From 2001 to 2011, 438 men were treated, of whom 357 received 3-weekly docetaxel as first-line chemotherapy: 314 in routine practice and 43 in clinical trials. Trial patients were younger and had better performance status. Median survival was 13.6 months [95% confidence interval (95% CI) 12.1–15.1 months] in routine practice and 20.4 months (95% CI 17.4–23.4 months, P = 0.007) within clinical trials, compared with 19.3 months (95% CI 17.6–21.3 months, P < 0.001) in the TAX 327 study. PSA response rates were 45%, 54%, and 53%, respectively (P = NS). Reasons for treatment discontinuation were similar although trial patients received more cycles (median: 6 versus 8 versus 9.5, P < 0.001). Rates of febrile neutropenia were 9.6, 0, and 3% (P < 0.001) while rates of death within 30 days of last dose were 4%, 0%, and 3%, respectively (P = NS). Conclusions Survival of patients with mCRPC treated with docetaxel in routine practice is shorter than for men included in trials and is associated with more toxicity. [ABSTRACT FROM PUBLISHER]

Background: The purpose of this study was to determine the clinical activity of patupilone in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel.Patients and methods: Eligible patients had progressive disease within 6 months of receiving docetaxel. Patupilone was administered 10 mg/m2 i.v. every 3 weeks. The primary end point was the proportion of patients with a confirmed ≥50% prostate-specific antigen (PSA) decline.Results: Eighty-three patients were enrolled. At baseline, the median time to progression after prior docetaxel was 1.4 months (range 0–5.7). Gastrointestinal serious adverse events occurred in four of the six initial patients leading to a reduction of the starting dose of patupilone to 8 mg/m2 for subsequent patients. Grade 3–4 toxicity at this dose included diarrhea (22%), fatigue (21%), and anorexia (10%). One patient experienced grade 3–4 hematologic toxicity. A PSA decline of ≥50% occurred in 47% of patients. A partial measurable disease response occurred in 24% of assessable patients. A patient-reported pain response was observed in 59% of assessable patients. Median time to PSA progression was 6.1 months [95% confidence interval (CI) 4.7–8.0] and median overall survival was 11.3 months (95% CI 9.8–15.4).Conclusions: Patupilone at 8 mg/m2 was tolerable, had antitumor activity, and was associated with symptomatic improvement in patients previously treated with docetaxel. [ABSTRACT FROM AUTHOR]