Borealis-1: a randomized, first-line, placebo-controlled, phase II study evaluating apatorsen and chemotherapy for patients with advanced urothelial cancer.

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 1000 mg 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 600 mg 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 apatorsen-treatment 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.

A prognostic index model for predicting overall survival in patients with metastatic castration-resistant prostate cancer treated with abiraterone acetate after docetaxel.

BACKGROUND: Few prognostic models for overall survival (OS) are available for patients with metastatic castration-resistant prostate cancer (mCRPC) treated with recently approved agents. We developed a prognostic index model using readily available clinical and laboratory factors from a phase III trial of abiraterone acetate (hereafter abiraterone) in combination with prednisone in post-docetaxel mCRPC. PATIENTS AND METHODS: Baseline data were available from 762 patients treated with abiraterone-prednisone. Factors were assessed for association with OS through a univariate Cox model and used in a multivariate Cox model with a stepwise procedure to identify those of significance. Data were validated using an independent, external, population-based cohort. RESULTS: Six risk factors individually associated with poor prognosis were included in the final model: lactate dehydrogenase > upper limit of normal (ULN) [hazard ratio (HR) = 2.31], Eastern Cooperative Oncology Group performance status of 2 (HR = 2.19), presence of liver metastases (HR = 2.00), albumin ≤4 g/dl (HR = 1.54), alkaline phosphatase > ULN (HR = 1.38) and time from start of initial androgen-deprivation therapy to start of treatment ≤36 months (HR = 1.30). Patients were categorized into good (n = 369, 46%), intermediate (n = 321, 40%) and poor (n = 107, 13%) prognosis groups based on the number of risk factors and relative HRs. The C-index was 0.70 ± 0.014. The model was validated by the external dataset (n = 286). CONCLUSION: This analysis identified six factors used to model survival in mCRPC and categorized patients into three distinct risk groups. Prognostic stratification with this model could assist clinical practice decisions for follow-up and monitoring, and may aid in clinical trial design. TRIAL REGISTRATION NUMBERS: NCT00638690.

A phase II study of the HDAC inhibitor SB939 in patients with castration resistant prostate cancer: NCIC clinical trials group study IND195.

BACKGROUND: SB939 is a potent oral inhibitor of class 1, 2, and 4 histone deacetylases (HDACs). These three HDAC classes are highly expressed in castration resistant prostate cancer (CRPC) and associated with poor clinical outcomes. We designed a phase II study of SB939 in men with metastatic CRPC. METHODS: Patients received SB939 60 mg on alternate days three times per week for 3 weeks on a 4-week cycle. Primary endpoints were PSA response rate (RR) and progression-free survival (PFS). Secondary endpoints included objective response rate and duration; overall survival; circulating tumor cell (CTC) enumeration and safety. Exploratory correlative studies of the TMPRSS2-ERG fusion and PTEN biomarkers were also performed. RESULTS: Thirty-two patients were enrolled of whom 88 % had received no prior chemotherapy. The median number of SB939 cycles administered was three (range 1-8). Adverse events were generally grade 1-2, with five pts experiencing one or more grade three event. One patient died due to myocardial infarction. A confirmed PSA response was noted in two pts (6 %), lasting 3.0 and 21.6 months. In patients with measurable disease there were no objective responses. Six patients had stable disease lasting 1.7 to 8.0 months. CTC response (from ≥5 at baseline to <5 at 6 or 12 weeks) occurred in 9/14 evaluable patients (64 %). CONCLUSION: Although SB939 was tolerable at the dose/schedule given, and showed declines in CTC in the majority of evaluable patients, it did not show sufficient activity based on PSA RR to warrant further study as a single agent in unselected patients with CRPC.

A phase 2 study of patupilone in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel: Canadian Urologic Oncology Group study P07a.

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.

Second-line systemic therapies for metastatic urothelial carcinoma: a population-based cohort analysis.

Introduction: Patients with urothelial carcinoma (uc) have a poor prognosis after progression on first-line cisplatin-based chemotherapy. Real-world data about second-line cytotoxic therapies are limited. We sought to characterize patients with metastatic uc who receive more than 1 line of systemic therapy and to describe their treatments and outcomes. Methods: Using BC Cancer's pharmacy database, we identified patients with documented metastatic uc who had received more than 1 line of systemic therapy. A retrospective chart review was then performed to collect clinicopathologic, treatment, and outcomes data. Results: The 51 included patients, of whom 42 were men (82%), had a median age of 65 years (range: 38-81 years). Sites of metastasis included lymph nodes (n = 30), bone (n = 7), lung (n = 9), and peritoneum (n = 2). Second-line chemotherapy regimens included gemcitabine-cisplatin [gc (n = 14)], paclitaxel (n = 24), docetaxel (n = 12), and an oral topoisomerase i inhibitor (n = 1). Median time to progression (ttp) and overall survival (os) were 2.0 and 6.83 months respectively. Compared with patients who received a different agent, patients who had experienced a prior response to first-line gc and who were re-challenged with second-line gc had a better median ttp (11.0 months vs. 6.0 months, p = 0.02) and survived longer (4.0 months vs. 1.0 months, p = 0.02). No differences in os between non-gc regimens were evident. Conclusions: In patients with metastatic uc, overall outcomes remain poor, but compared with patients receiving other agents, the subgroup of patients re-challenged with second-line gc demonstrated improved ttp. Conventional chemotherapy regimens provide only modest benefits in the second-line setting and have largely been replaced with immunotherapy.

Palliative radiotherapy improves pain and reduces functional interference in patients with painful bone metastases: a quality assurance study.

AIMS: To characterise the effect of palliative radiotherapy treatment outcomes as evaluated by the Brief Pain Inventory within a radiotherapy clinic, as a quality assurance initiative. MATERIALS AND METHODS: Tumour and treatment parameters of patients with painful bone metastases treated through a dedicated bone pain radiotherapy clinic have been prospectively recorded since 2002. One hundred and nine ambulatory patients provided pre- and post-treatment pain assessments at 4-6 weeks after palliative radiotherapy. The self-administered Brief Pain Inventory questionnaire was completed by patients during their visits. Changes in pain and seven-item functional interference scores were analysed. RESULTS: Most of the patients had prostate (n=42) or breast (n=42) cancer. The mean Karnofsky performance score was 70 before palliative radiation therapy. Sixty-eight per cent of patients were treated with a single fraction (6-8 Gy) and 25% received 20 Gy/five fractions. The overall response (reduction in worst pain by > or = 2/10) was 72%. Sixty-one per cent of patients had stable or reduced consumption of opioid analgesics. A significant reduction for all seven functional interference items was seen after treatment, the greatest improvement being general activity (-2.4/10). There was significant correlation between pain reduction and improvement in functional interference. CONCLUSION: This quality assurance initiative showed that palliative radiotherapy reduced both pain and its interference on function among ambulatory patients with symptomatic bone metastases. The reduction in pain was correlated with reductions in functional interference. Clinical trials of palliative radiotherapy should provide data that allow an evaluation of various domains of chronic pain.

The future of systemic therapies for localised prostate cancer.

In the last decade, many systemic therapies have become available to improve survival in the setting of castration-resistant prostate cancer. Once effective treatments for advanced and incurable disease have been established, these agents are generally explored in the adjuvant and neoadjuvant settings to evaluate their role in increasing the chance of cure for localised disease. Clinical trials evaluating new therapies in high-risk prostate cancer can broadly be divided into two categories. Phase III (and some phase II) trials generally evaluate treatments that have already been shown to provide clinical benefit in the advanced disease setting; whereas smaller phase I (and some phase II) trials often serve as proof-of-principle assessments in the development of novel agents. The goal of this review is to provide an overview of present and ongoing clinical trials of both of these categories, evaluating the promise of systemic therapies in the setting of high-risk localised prostate cancer. We undertook a search of Ovid Medline, Embase and clinicaltrials.gov for prospective clinical studies assessing systemic therapy for early stage prostate cancer, either before or after definitive local treatment (surgery or radiation) from 2000 onwards. This resulted in 53 studies, of which 29 were deemed worthy of this overview and are presented herein, broadly divided by mechanism of action. Clearly, the arena evaluating the future of systemic therapies for localised prostate cancer will be a very active one.