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Powles T.,Queen Mary, University of London | Eder J.P.,Yale Cancer Center | Fine G.D.,Genentech | Braiteh F.S.,Comprehensive Cancer Centers of Nevada | And 11 more authors.
Nature | Year: 2014

There have been no major advances for the treatment of metastatic urothelial bladder cancer (UBC) in the last 30 years. Chemotherapy is still the standard of care. Patient outcomes, especially for those in whom chemotherapy is not effective or is poorly tolerated, remain poor1,2.OnehallmarkofUBCis the presence of high rates ofsomatic mutations3-5. These alterations may enhance the ability of the host immune system to recognize tumour cells as foreign owing to an increasednumber of antigens6.However, these cancersmay also elude immune surveillance and eradication through the expression of programmed death-ligand 1 (PD-L1; also calledCD274 or B7-H1) in the tumour microenvironment7,8. Therefore, we examined the anti-PDL1 antibody MPDL3280A, a systemic cancer immunotherapy, for the treatment ofmetastaticUBC.MPDL3280Ais a high-affinity engineered human anti-PD-L1monoclonal immunoglobulin-G1 antibody that inhibits the interaction ofPD-L1 with PD-1 (PDCD1) and B7.1 (CD80)9. BecausePD-L1is expressed onactivatedTcells,MPDL3280A was engineered with amodification in the Fc domain that eliminates antibody-dependent cellular cytotoxicity at clinically relevant doses to prevent the depletion of T cells expressing PD-L1. Here we show that MPDL3280A has noteworthy activity in metastatic UBC. Responses were often rapid, with many occurring at the time of the first response assessment (6weeks) and nearly allwere ongoing at the data cutoff. This phase I expansion study, with an adaptive design that allowed for biomarker-positive enriched cohorts, demonstrated that tumours expressing PD-L1-positive tumour-infiltrating immunecells had particularly high response rates. Moreover, owing to the favourable toxicity profile, including a lack of renal toxicity, patients with UBC,who areoftenolder and have ahigher incidence of renalimpairment, may be better able to tolerateMPDL3280A versus chemotherapy. These results suggest thatMPDL3280A may have an important role in treating UBC - the drug received breakthrough designation status by theUSFood and DrugAdministration (FDA) in June 2014. ©2014 Macmillan Publishers Limited. All rights reserved.


Hutson T.E.,Baylor Sammons Cancer Center | Hutson T.E.,Us Oncology Research | Al-Shukri S.,Saint Petersburg State University | Stus V.P.,Municipal Institution Dnipropetrovsk Regional Clinical Hospital Na Ii Mechnikov | And 7 more authors.
The Lancet Oncology | Year: 2013

Background: In previous clinical trials of patients with metastatic renal-cell carcinoma, patients treated with axitinib as second-line therapy had longer median progression-free survival than those treated with sorafenib. We therefore undertook a phase 3 trial comparing axitinib with sorafenib in patients with treatment-naive metastatic renal-cell carcinoma. Methods: In this randomised, open-label, phase 3 trial, patients with treatment-naive, measurable, clear-cell metastatic renal-cell carcinoma from 13 countries were stratified by Eastern Cooperative Oncology Group performance status, and then randomly assigned (2:1) by a centralised registration system to receive axitinib 5 mg twice daily, or sorafenib 400 mg twice daily. The primary endpoint was progression-free survival, assessed by masked independent review committee in the intention-to-treat population. This ongoing trial is registered at ClinicalTrials.gov, NCT00920816. Findings: Between June 14, 2010, and April 21, 2011, we randomly assigned 192 patients to receive axitinib, and 96 patients to receive sorafenib. The cutoff date for this analysis was July 27, 2012, when 171 (59%) of 288 patients died or had disease progression, as assessed by the independent review committee. There was no significant difference in median progression-free survival between patients treated with axitinib or sorafenib (10·1 months [95% CI 7·2-12·1] vs 6·5 months [4·7-8·3], respectively; stratified hazard ratio 0·77, 95% CI 0·56-1·05). Any-grade adverse events that were more common (≥10% difference) with axitinib than with sorafenib were diarrhoea (94 [50%] of 189 patients vs 38 [40%] of 96 patients), hypertension (92 [49%] vs 28 [29%]), weight decrease (69 [37%] vs 23 [24%]), decreased appetite (54 [29%] vs 18 [19%]), dysphonia (44 [23%] vs ten [10%]), hypothyroidism (39 [21%] vs seven [7%]), and upper abdominal pain (31 [16%] vs six [6%]); those more common with sorafenib than with axitinib included palmar-plantar erythrodysaesthesia (PPE; 37 [39%] of 96 patients vs 50 [26%] of 189), rash (19 [20%] vs 18 [10%]), alopecia (18 [19%] vs eight [4%]), and erythema (18 [19%] vs five [3%]). The most common grade 3 or 4 adverse events in patients treated with axitinib included hypertension (26 [14%] of 189 patients), diarrhoea (17 [9%]), asthenia (16 [8%]), weight decrease (16 [8%]), and PPE (14 [7%]); common grade 3 or 4 adverse events in patients treated with sorafenib included PPE (15 [16%] of 96 patients), diarrhoea (five [5%]), and asthenia (five [5%]). Serious adverse events were reported in 64 (34%) of 189 patients receiving axitinib, and 24 (25%) of 96 patients receiving sorafenib. Interpretation: Axitinib did not significantly increase progression-free survival in patients with treatment-naive metastatic renal-cell carcinoma compared with those treated with sorafenib, but did demonstrate clinical activity and an acceptable safety profile. Funding: Pfizer Inc. © 2013 Elsevier Ltd.


Sweeney C.J.,Dana-Farber Cancer Institute | Sweeney C.J.,Harvard University | Carducci M.,Johns Hopkins University | Liu G.,University of Wisconsin - Milwaukee | And 13 more authors.
New England Journal of Medicine | Year: 2015

BACKGROUND Androgen-deprivation therapy (ADT) has been the backbone of treatment for metastatic prostate cancer since the 1940s. We assessed whether concomitant treatment with ADT plus docetaxel would result in longer overall survival than that with ADT alone. METHODS We assigned men with metastatic, hormone-sensitive prostate cancer to receive either ADT plus docetaxel (at a dose of 75 mg per square meter of body-surface area every 3 weeks for six cycles) or ADT alone. The primary objective was to test the hypothesis that the median overall survival would be 33.3% longer among patients receiving docetaxel added to ADT early during therapy than among patients receiving ADT alone. RESULTS A total of 790 patients (median age, 63 years) underwent randomization. After a median follow-up of 28.9 months, the median overall survival was 13.6 months longer with ADT plus docetaxel (combination therapy) than with ADT alone (57.6 months vs. 44.0 months; hazard ratio for death in the combination group, 0.61; 95% confidence interval [CI], 0.47 to 0.80; P<0.001). The median time to biochemical, symptomatic, or radiographic progression was 20.2 months in the combination group, as compared with 11.7 months in the ADT-alone group (hazard ratio, 0.61; 95% CI, 0.51 to 0.72; P<0.001). The rate of a prostate-specific antigen level of less than 0.2 ng per milliliter at 12 months was 27.7% in the combination group versus 16.8% in the ADT-alone group (P<0.001). In the combination group, the rate of grade 3 or 4 febrile neutropenia was 6.2%, the rate of grade 3 or 4 infection with neutropenia was 2.3%, and the rate of grade 3 sensory neuropathy and of grade 3 motor neuropathy was 0.5%. CONCLUSIONS Six cycles of docetaxel at the beginning of ADT for metastatic prostate cancer resulted in significantly longer overall survival than that with ADT alone. Copyright © 2015 Massachusetts Medical Society.


Finn R.S.,University of California at Los Angeles | Crown J.P.,Irish Cooperative Oncology Research Group | Lang I.,Orszagos Onkologiai Intezet | Boer K.,Szent Margit Korhaz | And 14 more authors.
The Lancet Oncology | Year: 2015

Background: Palbociclib (PD-0332991) is an oral, small-molecule inhibitor of cyclin-dependent kinases (CDKs) 4 and 6 with preclinical evidence of growth-inhibitory activity in oestrogen receptor-positive breast cancer cells and synergy with anti-oestrogens. We aimed to assess the safety and efficacy of palbociclib in combination with letrozole as first-line treatment of patients with advanced, oestrogen receptor-positive, HER2-negative breast cancer. Methods: In this open-label, randomised phase 2 study, postmenopausal women with advanced oestrogen receptor-positive and HER2-negative breast cancer who had not received any systemic treatment for their advanced disease were eligible to participate. Patients were enrolled in two separate cohorts that accrued sequentially: in cohort 1, patients were enrolled on the basis of their oestrogen receptor-positive and HER2-negative biomarker status alone, whereas in cohort 2 they were also required to have cancers with amplification of cyclin D1 (CCND1), loss of p16 (INK4A or CDKN2A), or both. In both cohorts, patients were randomly assigned 1:1 via an interactive web-based randomisation system, stratified by disease site and disease-free interval, to receive continuous oral letrozole 2·5 mg daily or continuous oral letrozole 2·5 mg daily plus oral palbociclib 125 mg, given once daily for 3 weeks followed by 1 week off over 28-day cycles. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population. Accrual to cohort 2 was stopped after an unplanned interim analysis of cohort 1 and the statistical analysis plan for the primary endpoint was amended to a combined analysis of cohorts 1 and 2 (instead of cohort 2 alone). The study is ongoing but closed to accrual; these are the results of the final analysis of progression-free survival. The study is registered with the ClinicalTrials.gov, number NCT00721409. Findings: Between Dec 22, 2009, and May 12, 2012, we randomly assigned 165 patients, 84 to palbociclib plus letrozole and 81 to letrozole alone. At the time of the final analysis for progression-free survival (median follow-up 29·6 months [95% CI 27·9-36·0] for the palbociclib plus letrozole group and 27·9 months [25·5-31·1] for the letrozole group), 41 progression-free survival events had occurred in the palbociclib plus letrozole group and 59 in the letrozole group. Median progression-free survival was 10·2 months (95% CI 5·7-12·6) for the letrozole group and 20·2 months (13·8-27·5) for the palbociclib plus letrozole group (HR 0·488, 95% CI 0·319-0·748; one-sided p=0·0004). In cohort 1 (n=66), median progression-free survival was 5·7 months (2·6-10·5) for the letrozole group and 26·1 months (11·2-not estimable) for the palbociclib plus letrozole group (HR 0·299, 0·156-0·572; one-sided p<0·0001); in cohort 2 (n=99), median progression-free survival was 11·1 months (7·1-16·4) for the letrozole group and 18·1 months (13·1-27·5) for the palbociclib plus letrozole group (HR 0·508, 0·303-0·853; one-sided p=0·0046). Grade 3-4 neutropenia was reported in 45 (54%) of 83 patients in the palbociclib plus letrozole group versus one (1%) of 77 patients in the letrozole group, leucopenia in 16 (19%) versus none, and fatigue in four (4%) versus one (1%). Serious adverse events that occurred in more than one patient in the palbociclib plus letrozole group were pulmonary embolism (three [4%] patients), back pain (two [2%]), and diarrhoea (two [2%]). No cases of febrile neutropenia or neutropenia-related infections were reported during the study. 11 (13%) patients in the palbociclib plus letrozole group and two (2%) in the letrozole group discontinued the study because of adverse events. Interpretation: The addition of palbociclib to letrozole in this phase 2 study significantly improved progression-free survival in women with advanced oestrogen receptor-positive and HER2-negative breast cancer. A phase 3 trial is currently underway. © 2015 Elsevier Ltd.


Hoskin P.,Mount Vernon Cancer Center | Sartor O.,Tulane Cancer Center | O'Sullivan J.M.,Queen's University of Belfast | Johannessen D.C.,University of Oslo | And 9 more authors.
The Lancet Oncology | Year: 2014

Background: Primary results from the phase 3 ALSYMPCA trial showed that radium-223 dichloride (radium-223), a targeted α-emitter, improved overall survival compared with placebo and was well tolerated in patients with castration-resistant prostate cancer and symptomatic bone metastases. We did a prespecified subgroup analysis from ALSYMPCA to assess the effect of previous docetaxel use on the efficacy and safety of radium-223. Methods: In the phase 3, randomised, double-blind ALSYMPCA trial, patients with symptomatic castration-resistant prostate cancer, at least two symptomatic bone metastases, no known visceral metastases, and who were receiving best standard of care were randomly assigned (2:1) via an interactive voice response system to receive six injections of radium-223 (50 kBq/kg intravenously) or matching placebo, with one injection given every 4 weeks. Patients had either received previous docetaxel treatment or were unsuitable for or declined docetaxel; previous docetaxel use (yes or no) was a trial stratification factor. We investigated the effect of previous docetaxel use on radium-223 treatment for the primary endpoint of overall survival, the main secondary efficacy endpoints, and safety. Efficacy analyses were done for the intention-to-treat population; safety analyses were done for the safety population. The trial has been completed and is registered with ClinicalTrials.gov, number NCT00699751. Findings: Randomisation took place between June 12, 2008, and Feb 1, 2011. 526 (57%) of 921 randomly assigned patients had received previous docetaxel treatment (352 in the radium-223 group and 174 in the placebo group) and 395 (43%) had not (262 in the radium-223 group and 133 in the placebo group). Radium-223 prolonged median overall survival compared with placebo, irrespective of previous docetaxel use (previous docetaxel use, hazard ratio [HR] 0·70, 95% CI 0·56-0·88; p=0·002; no previous docetaxel use, HR 0·69, 0·52-0·92; p=0·01). The benefit of radium-223 compared with placebo was seen in both docetaxel subgroups for most main secondary efficacy endpoints; risk for time to time to first symptomatic skeletal event was reduced with radium-223 versus placebo in patients with previous docetaxel use, but the difference was not significant in those with no previous docetaxel use. 322 (62%) of 518 patients previously treated with docetaxel had grade 3-4 adverse events, compared with 205 (54%) of 383 patients without docetaxel. Patients who had previously been treated with docetaxel had a higher incidence of grade 3-4 thrombocytopenia with radium-223 than with placebo (31 [9%] of 347 patients vs five [3%] of 171 patients), whereas the incidence was similar between treatment groups among patients with no previous docetaxel use (seven [3%] of 253 patients vs one [1%] of 130 patients). The incidences of grade 3-4 anaemia and neutropenia were similar between the radium-223 and placebo groups within both docetaxel subgroups. Interpretation: Radium-223 is effective and well tolerated in patients with castration-resistant prostate cancer and symptomatic bone metastases, irrespective of previous docetaxel use. Funding: Algeta ASA and Bayer HealthCare Pharmaceuticals. © 2014 Elsevier Ltd.


Galsky M.D.,Comprehensive Cancer Centers of Nevada | Galsky M.D.,Us Oncology Research | Vogelzang N.J.,Comprehensive Cancer Centers of Nevada | Vogelzang N.J.,Us Oncology Research
Annals of Oncology | Year: 2010

Background: Once castration resistance is documented and secondary hormone therapy is ineffective, standard treatment of metastatic prostate cancer is docetaxel, with bisphosphonates and radiopharmaceuticals administered to treat bone symptoms. To improve outcomes, numerous studies have evaluated docetaxel in combination with other agents. Here, results for docetaxel-based combination therapy in castration-resistant prostate cancer (CRPC) are reviewed. Materials and methods: Relevant studies were identified in databases of published literature, clinical trials, and conference abstracts using the search terms docetaxel and prostate, with additional searches carried out for identified agents. Results: Numerous classes of agents have been combined with docetaxel in phase II studies in CRPC, including tyrosine kinase inhibitors, antiangiogenic agents, bone-targeted agents, BCL-2 inhibitors, chemotherapies, immunologic agents, and vitamin D analogs. In several cases, promising rates of prostate-specific antigen response, tumor response, and survival have been reported. However, some combinations have caused increased toxicity. Phase III trials with docetaxel plus GVAX or DN-101 were terminated because of lower survival; phase III trials with docetaxel plus bevacizumab, aflibercept, dasatinib, zibotentan, atrasentan, or lenalidomide are ongoing. Conclusions: Docetaxel-based doublet therapy remains an active investigational strategy in CRPC. Further phase III data are awaited to determine whether survival can be extended compared with docetaxel alone. © The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.


Moyad M.A.,University of Michigan | Vogelzang N.J.,Comprehensive Cancer Centers of Nevada
Asian Journal of Andrology | Year: 2015

Cardiovascular disease (CVD) has been the number one cause of death in the U.S. for 114 of the last 115 years. Lifestyle factors that promote CVD also appear to increase prostate cancer risk and those that reduce CVD risk also appear to reduce the risk of prostate cancer.


Sonpavde G.,Baylor College of Medicine | Sternberg C.N.,San Camillo Forlanini Hospital | Rosenberg J.E.,Dana-Farber Cancer Institute | Hahn N.M.,Indiana University | And 2 more authors.
The Lancet Oncology | Year: 2010

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. © 2010 Elsevier Ltd.


Chao O.S.,Health Discovery | Goodman O.B.,Health Discovery | Goodman O.B.,Comprehensive Cancer Centers of Nevada
Molecular Cancer Research | Year: 2014

Tumors with BRCA germline mutations are defective in repairing DNA double-strand breaks (DSB) through homologous recombination (HR) pathways, making them sensitive to PARP inhibitors (PARPi). However, BRCA germline mutations are rare in prostate cancer limiting the ability to therapeutically target these pathways. This study investigates whether histone deacetylase (HDAC) inhibitors (HDACi), reported to modulate DSB repair pathways in sporadic cancers, can downregulate DSB repair pathways and sensitize prostate cancer cells to PARPi. Prostate cancer cells cotreated with theHDAC inhibitor, suberoylanilide hydroxamic acid (SAHA) and the PARPi, olaparib, demonstrated a synergistic decrease in cell viability compared with single-agent treatment (combination index < 0.9), whereas normal prostatic cells did not. Similarly, clonogenicity was significantly decreased after cotreatment. Flow cytometric cell-cycle analysis and Annexin-V staining revealed signi ficant apoptosis upon treatment with SAHA+olaparib. This coincided with increased DNA damage observed by immunofluorescence microscopy analysis of γ H2AX foci, a marker of DSBs. In addition, immunoblot analysis showed a significant and persistent increase in nuclear γH2AX levels. Both SAHA and olaparib downregulated the expression of HR-related proteins, BRCA1 and RAD51, whereas SAHA + olaparib had an additive effect on RAD51. Silencing RAD51 sensitized prostate cancer cells to SAHA and olaparib alone. Collectively, cotreatment with HDACi and PARPi downregulated HR-related protein expression and concomitantly increased DNA damage, resulting in prostate cancer cell death. ©2014 American Association for Cancer Research.


Donepudi S.,Comprehensive Cancer Centers of Nevada | Deconti R.C.,H. Lee Moffitt Cancer Center and Research Institute | Samlowski W.E.,Comprehensive Cancer Centers of Nevada
Seminars in Oncology | Year: 2012

Merkel cell carcinoma (MCC) is a highly aggressive skin malignancy. The growing incidence and recognition of this cancer in elderly or immunosuppressed individuals suggests that it is becoming an increasing clinical challenge. MCC recently has been demonstrated to have a probable viral pathogenesis related to a novel member of the polyomavirus (termed Merkel cell polyomavirus [MCV]). The molecular pathogenesis of viral carcinogenesis is currently being worked out in MCC. Current diagnostic and therapeutic strategies are discussed, with an eye toward the future development of molecularly targeted treatments. © 2012 Published by Elsevier Inc.

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