C.N. Sternberg

Open-Label Phase II Study Evaluating the Efficacy and Safety of Two Doses of Pertuzumab in Castrate Chemotherapy-Naive Patients With Hormone-Refractory Prostate Cancer

PURPOSE To determine the prostate-specific antigen (PSA) 50% decline rate within 24 weeks of starting treatment with single-agent pertuzumab in castrate patients with hormone-refractory prostate cancer (HRPC). PATIENTS AND METHODS Two independent Simons two-stage designs were used to evaluate two doses of pertuzumab administered intravenously once every 3 weeks. An interim analysis of the first 23 assessable patients in the first cohort treated at 420 mg (loading dose of 840 mg) allowed termination of additional enrollment if three patients had a 50% decline in PSA after all patients had completed at least three cycles of therapy or withdrew due to insufficient therapeutic response, death, or study-related toxicity before completing three cycles. A second cohort of patients treated at 1,050 mg could be enrolled with the same design, and if more than three patients had a 50% decline in PSA, 27 more patients would be treated at 1,050 mg. RESULTS Sixty-eight castrate, chemotherapy-naive men with HRPC were enrolled. A total of 35 patients were treated at 420 mg; no PSA declines 50% were observed at the interim analysis and recruitment was stopped. A total of 33 patients were then treated at 1,050 mg, and no PSA declines 50% were observed at the interim analysis. Pertuzumab was well tolerated. CONCLUSION Pertuzumab has no clinically significant single-agent activity in castrate patients with HRPC at either of the tested dose levels. This may reflect the continued presence of significant levels of intraprostatic androgen driving androgen receptor signaling.

Second-line systemic therapy and emerging drugs for metastatic transitional-cell carcinoma of the urothelium

Front-line platinum-based combination chemotherapy leads to high response rates but suboptimum overall survival for patients with advanced transitional-cell carcinoma of the urothelium. Bevacizumab is being assessed in combination with platinum-based first-line chemotherapy in a large phase 3 trial. Current second-line systemic therapies, including taxanes, yield disappointing outcomes. Vinflunine, a novel vinca alkaloid, showed some activity and was recently approved in Europe based on results of the first completed phase 3 trial in the second-line setting. Better understanding of molecular biology and the emergence of novel biological agents now offer the possibility of improved outcomes. Neoadjuvant therapy before cystectomy and consolidation therapy with biological agents after first-line therapy provide a framework for the development of new drugs. We propose that trials to approve new drugs target two separate populations; multicentre non-randomised phase 2 trials should include patients with chemotherapy-resistant disease progressing within 6 months of first-line therapy, and randomised trials might be appropriate for chemotherapy-sensitive disease progressing more than 6 months after first-line therapy. A multidisciplinary approach is necessary to make therapeutic advances. This review discusses current second-line therapy and emerging drugs for advanced transitional-cell carcinoma.

Pazopanib, a potent orally administered small-molecule multitargeted tyrosine kinase inhibitor for renal cell carcinoma

Background: The recent approvals of sunitinib, sorafenib and temsirolimus have revolutionized the management of renal cell carcinoma (RCC). Pazopanib (GW-786034) is a second-generation multitargeted tyrosine kinase inhibitor against VEGFR-1, 2 and 3, platelet-derived growth factor receptor (PDGFR)-α, PDGFR-β and c-kit. Objective: Data supporting the development of pazopanib for RCC are reviewed. Methods: Preclinical and clinical data available for pazopanib are presented. Results: Preclinical evaluation has revealed excellent anti-angiogenic and anti-tumor activity in several mouse models. A Phase II clinical trial of pazopanib in untreated or cytokine/bevacizumab pretreated RCC has demonstrated promising activity accompanied by a favorable toxicity profile. A placebo-controlled Phase III trial is ongoing in untreated or cytokine-treated patients with RCC. Ongoing trials are further evaluating pazopanib in a variety of other malignancies.

Effect of abiraterone acetate on fatigue in patients with metastatic castration-resistant prostate cancer after docetaxel chemotherapy

BACKGROUND Fatigue is a common, debilitating side-effect of prostate cancer and its treatment. Patient-reported fatigue was evaluated as part of COU-AA-301, a randomized, placebo-controlled, phase III trial of abiraterone acetate and prednisone versus placebo and prednisone in metastatic castration-resistant prostate cancer (mCRPC) patients after docetaxel chemotherapy. This is the first phase III study in advanced prostate cancer to evaluate fatigue outcomes using a validated fatigue-specific instrument. PATIENTS AND METHODS The Brief Fatigue Inventory (BFI) questionnaire was used to measure patient-reported fatigue intensity and fatigue interference with activities of daily life. All analyses were conducted using prespecified responder definitions of clinically meaningful changes. RESULTS A total of 797 patients were randomized to abiraterone acetate and prednisone, and 398 were randomized to placebo and prednisone. Compared with prednisone alone, in patients with clinically significant fatigue at baseline, abiraterone acetate and prednisone significantly increased the proportion of patients reporting improvement in fatigue intensity (58.1% versus 40.3%, P = 0.0001), improved fatigue interference (55.0% versus 38.0%, P = 0.0075), and accelerated improvement in fatigue intensity (median 59 days versus 194 days, P = 0.0155). CONCLUSIONS In patients with mCRPC progressing after docetaxel chemotherapy, abiraterone acetate and prednisone yielded clinically meaningful improvements in patient-reported fatigue compared with prednisone alone.

The medical management of prostate cancer: a multidisciplinary team approach

1 Department of Medical Oncology, San Camillo Forlanini Hospital, Rome, Italy, 2 Department of Medical Oncology, Medical University Vienna, Austria, 3 Dana-Farber Cancer Institute/Lank Center for Genitourinary Oncology, Boston, MA, USA, 4 Medical Oncology, Azienda Ospedaliera di Perugia, Perugia, Italy, Medical Oncology Service, University Hospital del Mar, Barcelona, Spain, 6 Department of Urology, Hacettepe University, Ankara, Turkey, 7 Department of Urology, University Clinics of Brussels, Brussels, Belgium, 8 Oregon Health and Science University Cancer Institute, Portland, OR, USA, 9 Medical Oncology Department, European Georges Pompidou Hospital, Paris, France, 10 Department of Urology and Andrology, Ludwig Boltzmann Institute for Urological Oncology, Danube Hospital, Vienna, Austria, 11 M. Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Klinika Nowotworow Ukladu Moczowego, Warszawa, Poland, 12 Department of Medical Oncology, Inselspital, Bern, Switzerland and 13 Mater Misericordiae Hospital and University College Dublin, Ireland

Phase II EORTC trial with 5-fluorouracil, cisplatin and interferon-α as second-line treatment of advanced transitional cell cancer of the urothelial tract

BACKGROUND Based on the favorable results of the combination 5-fluorouracil (5-FU), cisplatin and interferon-alpha as second-line treatment in advanced metastatic transitional-cell carcinoma of the urothelial tract a confirmatory study was executed in a multicenter setting. PATIENTS AND METHODS In this open label phase II study 43 patients failing adequate previous chemotherapy were treated with IFN-alpha2b 5 MU/m2 subcutaneously for 5 consecutive days starting on day 1 and 22 simultaneous with 5-FU 500 mg/m2 daily as a continuous infusion. In between the same dose of IFN-alpha2b was given 3 times weekly with CDDP 25 mg/m2 on days 1, 8, 15 and 22. This cycle was repeated every six weeks. RESULTS In 40 eligible patients 5 PR were seen (12.5%; 95% confidence interval (95% CI): 4.1%-26.8%). The major toxicity was hematological. Two toxic deaths were seen due to gastrointestinal hemorrhage. CONCLUSIONS In view of these results this combination can not be recommended as second line treatment for metastatic transitional-cell carcinoma of the urothelial tract.

Neoadjuvant systemic therapy for urological malignancies

Neoadjuvant cisplatin‐based combined chemotherapy is an established standard for muscle‐invasive bladder cancer and pathological complete remission is an excellent intermediate surrogate endpoint for survival. Phase III trials are ongoing to elucidate the role of neoadjuvant combined androgen deprivation and docetaxel‐based chemotherapy for localized high‐risk prostate cancer. Neoadjuvant therapy with biological agents targeting angiogenesis preceding cytoreductive nephrectomy for metastatic renal cell carcinoma is a novel approach, although ongoing randomized trials are validating this paradigm and attempting to establish the timing and necessity of cytoreductive nephrectomy. Neoadjuvant trials provide a window of opportunity to evaluate and screen novel agents for biological activity by using brief therapy preceding surgery and provide a rationale to further develop the most promising agents in larger trials. The neoadjuvant therapy approach followed by surgery is acceptable and feasible with a wide array of agents in urological cancers and provides a paradigm for evaluating the activity, mechanism of action and resistance to new treatments. Urological cancers are initially characterized by localized presentation in the vast majority of cases, coupled with a substantial risk of distant relapses following surgical resection. Therefore, the paradigm of neoadjuvant therapy preceding surgery may expedite the development of novel systemic agents and improve outcomes.

Lobaplatin in advanced urothelial tract tumors

Bladder cancer is the fifth most common cancer in men and the seventh in women. Combination regimens containing cisplatin have produced response rates in 50%70% of patients with complete responses in 20%-30% [1]. Lobaplatin (1,2-diamminomethylcyclobutane-platinum (II) lactate, D-19466) is a third generation platinum analogue. It is water soluble and stable and may not be cross-resistant with cisplatin [2, 3]. A favorable toxicity profile and similar efficacy to cisplatin stimulated a phase II study in patients with advanced urothelial tract tumors.

Treatment of metastatic urothelial cancer: opportunities for drug discovery and development

Conventional first‐line platinum‐based combination chemotherapy with gemcitabine/cisplatin and standard or dose‐dense methotrexate, vinblastine, doxorubicin and cisplatin yields high response rates but suboptimal long‐term outcomes for advanced urothelial cancer. Salvage therapy is an unmet need, with disappointing outcomes. The emergence of novel biological agents offers the promise of improved outcomes. Neoadjuvant therapy preceding cystectomy for muscle‐invasive bladder cancer provides an important paradigm and an interesting approach in developing novel agents. Patients who are not candidates for cisplatin require special attention. A multidisciplinary approach and collaboration among laboratory scientists, oncologists, urologists and radiation oncologists is necessary to make therapeutic advances. Recent and ongoing trials of novel chemotherapeutic and biological agents are reviewed.

Novel agents for muscle-invasive and advanced urothelial cancer.

Conventional front‐line platinum‐based combination chemotherapy yields high response rates but suboptimal long‐term outcomes for advanced urothelial cancer. Salvage therapy is an unmet need, with disappointing outcomes. The profusion of novel biological agents offers the promise of improved outcomes. Neoadjuvant therapy before cystectomy for muscle‐invasive bladder cancer provides an important paradigm and an interesting approach in developing novel agents. Patients who are not candidates for cisplatin require special attention. A multidisciplinary approach and collaboration among laboratory scientists, oncologists, urologists and radiation oncologists is necessary to make therapeutic advances. Recent and ongoing trials of novel chemotherapeutic and biologic agents are reviewed.