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Background: Patients with metastatic castration-resistant prostate cancer have few treatment options after novel hormonal therapy (eg, abiraterone or enzalutamide). We aimed to evaluate cabozantinib, a tyrosine kinase inhibitor with immunomodulatory properties, in combination with the PD-L1 inhibitor atezolizumab in metastatic castration-resistant prostate cancer., Methods: COSMIC-021 is an ongoing, multicentre, open-label, phase 1b study with a dose-escalation stage followed by tumour-specific expansion stages. Expansion cohort 6 in metastatic castration-resistant prostate cancer was enrolled at 42 cancer research centres in France, Italy, the Netherlands, Spain, and the USA. Eligible patients were aged 18 years or older and had metastatic castration-resistant prostate cancer with radiographic soft tissue progression following treatment with either enzalutamide or abiraterone, or both; measurable soft tissue disease per Response Evaluation Criteria In Solid Tumours (RECIST) version 1.1; and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received oral cabozantinib 40 mg per day and intravenous atezolizumab 1200 mg once every 3 weeks. Study treatment continued until progressive disease or unacceptable toxicity. All enrolled patients were assessed for efficacy and safety. The primary endpoint was objective response rate per RECIST version 1.1 as assessed by the investigator. This study is registered with ClinicalTrials.gov, NCT03170960., Findings: Between April 24, 2018, and Aug 31, 2020, 132 patients were enrolled and received at least one dose of study treatment. At data cutoff (Feb 19, 2021), median duration of follow-up was 15·2 months (IQR 9·6-21·7). Objective response rate was 23% (95% CI 17-32; 31 of 132 patients), with three (2%) confirmed complete responses and 28 (21%) confirmed partial responses. 72 (55%) of 132 patients had grade 3-4 treatment-related adverse events, with the most common being pulmonary embolism (11 [8%] patients), diarrhoea (nine [7%]), fatigue (nine [7%]), and hypertension (nine [7%]). There was one grade 5 treatment-related adverse event (dehydration). 74 (56%) of 132 patients had serious adverse events of any causality. 28 (21%) of 132 patients had treatment-related adverse events leading to discontinuation of either study drug., Interpretation: Cabozantinib plus atezolizumab showed promising antitumour activity in patients with metastatic castration-resistant prostate cancer after novel hormonal therapy with an acceptable safety profile, supporting further evaluation of this combination., Funding: Exelixis., Competing Interests: Declaration of interests NA has acted in a consulting or advisory role for Astellas, AstraZeneca, Aveo, Bayer, Bristol-Myers Squibb (BMS), Calithera, Clovis, Eisai, Eli Lilly, EMD Serono, Exelixis, Foundation Medicine, Genentech, Gilead, Jenssen, Merck, MEI Pharma, Nektar, Novartis, Pfizer, Pharmacyclics, and Seattle Genetics; and received research funding to his institution from AstraZeneca, Bavarian Nordic, Bayer, BMS, Calithera, Celldex, Clovis, Eisai, Eli Lilly, EMD Serono, Exelixis, Genentech, GlaxoSmithKline, Immunomedics, Jenssen, Medivation, Merck, Nektar, New Link Genetics, Novartis, Pfizer, Prometheus, Rexahn, Roche, Sanofi, Seattle Genetics, Takeda, and Tracon. BM has received grants to his institution from BMS, Calithera, Exelixis, Pfizer, and Seattle Genetics; and personal fees from Astellas, Bayer, BMS, Calithera, Dendreon, EMD Serono, Eisai, Exelixis, Nektar, Pfizer, and Seattle Genetics. BLM has acted in a consulting or advisor role for AbbVie, Astellas, AVEO Oncology, Bayer Oncology, BMS, Clovis, Exelixis, Janssen, Merck, Peloton Therapeutics, Pfizer, and Tempus and has received grants to his institution from Bayer Oncology, BMS, Clovis, Exelixis, Genentech, and Peloton Therapeutics. TBD has acted in a consulting or advisory role for AbbVie, AstraZeneca, Bayer, Exelixis, Janssen, Pfizer, and Seattle Genetics. RRM has received personal fees from Exelixis; has acted in a consulting or advisory role for AstraZeneca, Aveo, Bayer, BMS, Calithera, Caris, Dendreon, Janssen, Merck, Myovant, Novartis, Pfizer, Sanofi, Sorrento Therapeutics, Tempus, and Vividion; and has received research funding from Bayer and Tempus. LP has received financing of scientific research from Pfizer, Exelixis, and Merck. RD has acted in a consulting or advisory role for Astellas, AstraZeneca, Aveo, Bayer, BMS, Exelixis, EMD Serono, Gilead, Hengrui, Hinova, Janssen, Merck, Myovant, Pfizer, Propella, Sanofi Genzyme, Seattle Genetics, and Tavanta. YL has received grants from Celsius, Janssen, and Roche and personal fees from Astellas, AstraZeneca, BMS, Gilead, Janssen, Merck KGaA, MSD, Roche, Pfizer, Sanofi, and Seattle Genetics. UV has received grants from BMS, Exelixis, Merck; and personal fees from AAA, Aveo, Bayer, BMS, Exelixis, Merck, Pfizer, and Sanofi. DC, AP, and MS are employees of Exelixis. TKC has received institutional and personal paid and unpaid support for research, advisory boards, consultancy, and honoraria from AstraZeneca, Aravive, Aveo, Bayer, BMS, Calithera, Circle Pharma, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, IQVA, Infinity, Ipsen, Jansen, Kanaph, Lilly, Merck, Nikang, Nuscan, Novartis, Pfizer, Roche, Sanofi Aventis, Surface Oncology, Takeda, Tempest, Up-To-Date, and CME events (Peerview, OncLive, MJH, and others); has institutional patents filed on molecular mutations and immunotherapy response and ctDNA; has equity in Tempest, Pionyr, Osel, and NuscanDx; and has acted on committees for NCCN, GU Steering Committee, and ASCO/ESMO. SP has acted in a consulting or advisory role for F Hoffman LaRoche and received research funding to his institution from Eisai, Exelixis, Genentech, Roche, and Pfizer. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Purpose: COSMIC-021 is evaluating cabozantinib plus atezolizumab in patients with solid tumors. We report results from patients with advanced clear cell (cc) and non-clear cell (ncc) renal cell carcinoma (RCC)., Methods: This phase Ib study (NCT03170960) enrolled patients age ≥ 18 years with advanced RCC. A dose-escalation stage was followed by expansion cohorts. For cohort expansion, prior systemic therapy was not permitted for ccRCC but allowed for nccRCC. Patients received oral cabozantinib 40 mg once a day (ccRCC and nccRCC) or 60 mg once a day (ccRCC only) plus atezolizumab (1,200 mg intravenously, once every 3 weeks). The primary end point was investigator-assessed objective response rate (ORR) per RECIST v1.1; the secondary end point was safety., Results: A total of 102 patients were enrolled. Median follow-up was 25.8, 15.3, and 13.3 months for the 40-mg ccRCC, 60-mg ccRCC, and nccRCC groups, respectively. ORR was 53% (80% CI, 41 to 65) in the 40-mg ccRCC group (n = 34) and 58% (80% CI, 46 to 70) in the 60-mg ccRCC group (n = 36), 3% and 11%, respectively, with complete response; median progression-free survival (exploratory end point) was 19.5 and 15.1 months, respectively. In nccRCC (n = 32), ORR was 31% (80% CI, 20 to 44), all partial responses; median progression-free survival was 9.5 months. Grade 3 or 4 treatment-related adverse events (TRAEs) were reported by 71% of patients in the 40-mg ccRCC group, 67% in the 60-mg ccRCC group, and 38% in the nccRCC group; TRAEs leading to discontinuation of both agents occurred in 15%, 6%, and 3% of patients, respectively. There were no grade 5 TRAEs., Conclusion: The novel combination of cabozantinib plus atezolizumab demonstrated encouraging clinical activity and acceptable tolerability in patients with advanced ccRCC and nccRCC. Disease control was observed across dose levels and histologic subtypes., Competing Interests: Sumanta K. PalConsulting or Advisory Role: F. Hoffmann LaRocheResearch Funding: Eisai, Genentech, Roche, Exelixis, PfizerTravel, Accommodations, Expenses: Genentech, Seattle Genetics Bradley McGregorConsulting or Advisory Role: Bayer, Seattle Genetics/Astellas, Exelixis, AstraZeneca, Astellas Pharma, Genentech/Roche, Nextar, Janssen Oncology, Pfizer, EMD Serono, Eisai, Dendreon, Bristol Myers SquibbResearch Funding: Bristol Myers Squibb, Exelixis, Calithera Biosciences, Seattle Genetics/Astellas Cristina SuárezConsulting or Advisory Role: Bristol Myers Squibb, Ipsen, Sanofi, Pfizer, EUSA Pharma, Astellas Pharma, Novartis, Merck Sharp & Dohme, EisaiSpeakers' Bureau: Bristol Myers Squibb, Ipsen, Pfizer, Roche/Genentech, AstraZeneca, Merck Sharp & DohmeResearch Funding: Astellas Pharma, Roche/Genentech, Exelixis, AstraZeneca, Bristol Myers Squibb, Pfizer, Novartis, Janssen Oncology, Calithera Biosciences, AB Science, Arog, AVEO, Bayer, SFJ Pharmaceuticals Group, Blueprint Medicines, Clovis Oncology, Boehringer Ingelheim, Cougar Biotechnology, Deciphera, GlaxoSmithKline, Incyte, Karyopharm Therapeutics, MedImmune, Nanobiotix, Millennium, Puma Biotechnology, TevaTravel, Accommodations, Expenses: Bristol Myers Squibb, Roche, Ipsen Che-Kai TsaoConsulting or Advisory Role: Eisai, Clovis Oncology, MerckResearch Funding: Exelixis William KellyHonoraria: Janssen Oncology, BayerConsulting or Advisory Role: Merck Sharp & DohmeResearch Funding: Sanofi, Novartis, Janssen Oncology, Bayer, Exelixis, Seattle Genetics, Endocyte, Amgen, BioClin Therapeutics, Sarah Cannon Research Institute, RocheTravel, Accommodations, Expenses: Janssen Oncology, Merck Sharp & Dohme Ulka VaishampayanConsulting or Advisory Role: Pfizer, Exelixis, Bayer, Bristol Myers Squibb/Medarex, Merck Serono, Advanced Accelerator Applications, Alkermes, Helsinn TherapeuticsSpeakers' Bureau: Pfizer, Bayer, ExelixisResearch Funding: Astellas Pharma, Exelixis, Bristol Myers Squibb, Merck KGaA Lance PagliaroResearch Funding: Pfizer, Genentech/Roche, Exelixis, Merck Sharp & DohmeTravel, Accommodations, Expenses: Merck Benjamin L. MaughanConsulting or Advisory Role: Janssen Oncology, Exelixis, Tempus, Bristol Myers Squibb, Astellas Medivation, Bayer, AVEO, Clovis Oncology, Merck, Peloton TherapeuticsResearch Funding: Clovis Oncology, Bristol Myers Squibb, Bavarian Nordic, ExelixisTravel, Accommodations, Expenses: Exelixis Yohann LoriotHonoraria: Sanofi, PfizerConsulting or Advisory Role: Janssen, Astellas Pharma, Roche, AstraZeneca, MSD Oncology, Seattle Genetics, Bristol Myers Squibb, Immunomedics, Taiho PharmaceuticalResearch Funding: Sanofi, Janssen Oncology, MSD Oncology, AstraZeneca, Clovis Oncology, Exelixis, Boehringer Ingelheim, Incyte, Pfizer, Oncogenex, Medivation, CureVac, NektarTravel, Accommodations, Expenses: Astellas Pharma, Janssen Oncology, Roche, MSD Oncology, AstraZeneca, Seattle Genetics Daniel CastellanoConsulting or Advisory Role: Janssen Oncology, Roche/Genentech, Astellas Pharma, AstraZeneca, Pfizer, Novartis, Ipsen, Bristol Myers Squibb, MSD Oncology, Bayer, Lilly, Sanofi, Pierre Fabre, Boehringer IngelheimResearch Funding: Janssen OncologyTravel, Accommodations, Expenses: Pfizer, Roche, Bristol Myers Squibb, AstraZeneca Spain Sandy SrinivasConsulting or Advisory Role: Eisai, Bayer, Bristol Myers Squibb, Merck, Exelixis, AstraZeneca, Seattle GeneticsResearch Funding: Bristol Myers Squibb, Genentech, Merck, Exelixis, Eisai, Bayer, AstraZeneca, Seattle Genetics/AstellasOther Relationship: Pfizer Rana R. McKayConsulting or Advisory Role: Janssen, Novartis, Tempus, Exelixis, Pfizer, Bristol Myers Squibb, Astellas Medivation, Dendreon, Bayer, Sanofi, Merck, Vividion Therapeutics, Calithera Biosciences, AstraZenecaResearch Funding: Pfizer, Bayer, Tempus Robert DreicerConsulting or Advisory Role: Astellas Pharma, Pfizer, Eisai, Merck, EMD Serono, Propella Therapeutics, Myovant Sciences, Bayer, Tavanta Therapeutics, Veru, Infinity Pharmaceuticals, Pfizer/AstellasResearch Funding: Seattle Genetics, Bristol Myers Squibb, Exelixis, Novartis Thomas HutsonEmployment: Texas OncologyHonoraria: Pfizer, Astellas Pharma, Bristol Myers Squibb, Exelixis, Eisai, Novartis, Johnson & Johnson, Bayer/OnyxConsulting or Advisory Role: Bayer/Onyx, Pfizer, Novartis, Astellas Pharma, Johnson & Johnson, Bristol Myers Squibb, Eisai, ExelixisSpeakers' Bureau: Pfizer, Johnson & Johnson, Eisai, Exelixis, Astellas Pharma, Bristol Myers SquibbResearch Funding: Pfizer, Johnson & Johnson, Exelixis, Eisai, Bristol Myers Squibb Sarita DubeyEmployment: Genentech/RocheStock and Other Ownership Interests: Genentech/Roche Scott WernekeEmployment: ExelixisStock and Other Ownership Interests: Exelixis Ashok PanneerselvamEmployment: ExelixisStock and Other Ownership Interests: Exelixis Dominic CurranEmployment: Exelixis, Syneos Health (I)Stock and Other Ownership Interests: ExelixisTravel, Accommodations, Expenses: Exelixis Christian ScheffoldEmployment: ExelixisStock and Other Ownership Interests: ExelixisPatents, Royalties, Other Intellectual Property: Patent Toni K. ChoueiriEmployment: Dana Farber Cancer HospitalLeadership: Dana Farber Cancer Hospital, NCCN, KidneyCan, ASCOStock and Other Ownership Interests: Pionyr, Tempest TherapeuticsHonoraria: NCCN, UpToDate, Michael J. Hennessy Associates, ASCO, Harborside Press, Analysis Group, AstraZeneca, Alexion Pharmaceuticals, Sanofi/Aventis, Bayer, Bristol Myers Squibb, Genentech/Roche, GlaxoSmithKline, Merck, Novartis, Peloton Therapeutics, Pfizer, Corvus Pharmaceuticals, Ipsen, Foundation Medicine, Eisai, PlatformQ Health, Clinical Care Options, Navinata Health, Kidney Cancer Association, Exelixis, Prometheus, Lpath, The New England Journal of Medicine, Lancet Oncology, Cerulean Pharma, Alligent, EMD Serono, HERON, Lilly, Janssen Oncology, IQvia, Aveo, NCI GU Steering CommitteeConsulting or Advisory Role: Pfizer, Bayer, Novartis, GlaxoSmithKline, Merck, Bristol Myers Squibb, Roche/Genentech, Eisai, Foundation Medicine, Cerulean Pharma, AstraZeneca, Exelixis, Prometheus, Alligent, Ipsen, Corvus Pharmaceuticals, Lpath, Alexion Pharmaceuticals, Sanofi/Aventis, Peloton Therapeutics, UpToDate, NCCN, Michael J. Hennessy Associates, Analysis Group, Kidney Cancer Association, Clinical Care Options, PlatformQ Health, Navinata Health, Harborside Press, ASCO, The New England Journal of Medicine, Lancet Oncology, EMD Serono, HERON, Lilly, ESMO, NiKang Therapeutics, Kanaph Therapeutics, Infinity Pharmaceuticals, AraviveResearch Funding: Pfizer, Novartis, Merck, Exelixis, TRACON Pharma, GlaxoSmithKline, Bristol Myers Squibb, AstraZeneca, Peloton Therapeutics, Roche/Genentech, Celldex, Agensys, Eisai, Takeda, Prometheus, Ipsen, Corvus Pharmaceuticals, Cerulean Pharma, Seattle Genetics/Astellas, Bayer, Foundation Medicine, Roche, Calithera Biosciences, Analysis Group, NCI, Gateway for Cancer Research, Congressionally Directed Medical Research Programs (DOD)Patents, Royalties, Other Intellectual Property: International Patent Application No. PCT/US2018/058430, titled Biomarkers of Clinical Response and Benefit to Immune Checkpoint Inhibitor Therapy, International Patent Application No. PCT/US2018/12209, titled PBRM1 Biomarkers Predictive of Anti-Immune Checkpoint ResponseTravel, Accommodations, Expenses: Pfizer, Bayer, Novartis, GlaxoSmithKline, Merck, Bristol Myers Squibb, Roche/Genentech, Eisai, Foundation Medicine, Cerulean Pharma, AstraZeneca, Exelixis, Prometheus, Alligent, Ipsen, Corvus Pharmaceuticals, Lpath, Alexion Pharmaceuticals, Sanofi/Aventis, UpToDate, Peloton Therapeutics, NCCN, Michael J. Hennessy Associates, Analysis Group, Kidney Cancer Association, Clinical Care Options, PlatformQ Health, Harborside Press, Navinata Health, The New England Journal of Medicine, Lancet Oncology, EMD Serono, HERON, Lilly, ESMOOther Relationship: Medical writing and editorial assistance support may have been funded by Communications companies funded by pharmaceutical companies such as ClinicalThinking, Health Interactions, Envision Pharma Group, Fishawack Group of Companies, Parexel Neeraj AgarwalConsulting or Advisory Role: Pfizer, Medivation/Astellas, Bristol Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Pharmacyclics, Foundation Medicine, Astellas Pharma, Exelixis, Merck, Novartis, Eisai, Seattle Genetics, EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech, Gilead SciencesResearch Funding: Bayer, Bristol Myers Squibb, Takeda, Pfizer, Exelixis, Amgen, AstraZeneca, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck, Lilly, Nektar, ORIC Pharmaceuticals, CRISPR Therapeutics, ArvinasNo other potential conflicts of interest were reported.

Purpose: The combination of gemcitabine and cisplatin (GC) is a standard therapy for metastatic urothelial carcinoma. Based on data that angiogenesis plays a role in urothelial carcinoma growth and progression, a randomized placebo-controlled trial was performed with the primary objective of testing whether patients treated with GC and bevacizumab (GCB) have superior overall survival (OS) than patients treated with GC and placebo (GCP)., Patients and Methods: Between July 2009 and December 2014, 506 patients with metastatic urothelial carcinoma without prior chemotherapy for metastatic disease and no neoadjuvant or adjuvant chemotherapy within 12 months were randomly assigned to receive either GCB or GCP. The primary end point was OS, with secondary end points of progression-free survival, objective response, and toxicity., Results: With a median follow-up of 76.3 months among alive patients, the median OS was 14.5 months for patients treated with GCB and 14.3 months for patients treated with GCP (hazard ratio for death = 0.87; 95% CI, 0.72 to 1.05; two-sided stratified log-rank P = .14). The median progression-free survival was 8.0 months for GCB and 6.7 months for GCP (hazard ratio = 0.77; 95% CI, 0.63 to 0.95; P = .016). The proportion of patients with grade 3 or greater adverse events did not differ significantly between both arms, although increased bevacizumab-related toxicities such as hypertension and proteinuria occurred in the bevacizumab-treated arm., Conclusion: The addition of bevacizumab to GC did not result in improved OS. The observed median OS of about 14 months is consistent with prior phase III trials of cisplatin-based chemotherapy., Competing Interests: Jonathan E. RosenbergStock and Other Ownership Interests: IlluminaHonoraria: UpToDate, Medscape, Peerview, Research To Practice, Intellisphere, Clinical Care Options, ClinicalMind, Physicans' Education ResourceConsulting or Advisory Role: Lilly, Merck, Roche/Genentech, AstraZeneca/MedImmune, Bristol Myers Squibb, Seattle Genetics, Bayer, BioClin Therapeutics, QED Therapeutics, Adicet Bio, Fortress Biotech, Pharmacyclics, Western Oncolytics, GlaxoSmithKline, Janssen Oncology, Astellas Pharma, Boehringer Ingelheim, Pfizer/EMD Serono, Mirati Therapeutics, ImmunomedicsResearch Funding: Genentech/Roche, Seattle Genetics, Bayer, AstraZeneca, QED Therapeutics, Astellas PharmaPatents, Royalties, Other Intellectual Property: Predictor of platinum sensitivity Karla A. BallmanConsulting or Advisory Role: ARIAD, Medtronic, Takeda, AgenusPatents, Royalties, Other Intellectual Property: Prostate cancer signature patentExpert Testimony: Janssen Oncology, Lilly, Sanofi Susan HalabiEmployment: ASCO Amir MortazaviHonoraria: Motive Medical IntelligenceConsulting or Advisory Role: Seattle Genetics, Debiopharm Group, PfizerResearch Funding: Acerta Pharma, Genentech/Roche, Merck, Novartis, Seattle Genetics, Mirati Therapeutics, Bristol Myers Squibb, Roche, Astellas Pharma, Debiopharm Group Christopher SweeneyStock and Other Ownership Interests: LeuchemixConsulting or Advisory Role: Sanofi, Janssen Biotech, Astellas Pharma, Bayer, Genentech/Roche, AstraZeneca, Pfizer, Amgen, LillyResearch Funding: Janssen Biotech, Astellas Pharma, Sanofi, Bayer, Dendreon, PfizerPatents, Royalties, Other Intellectual Property: Leuchemix, Parthenolide, Dimethylaminoparthenolide. Exelixis: Abiraterone plus cabozantinib combination Walter M. StadlerConsulting or Advisory Role: CVS Caremark, Sotio, AstraZeneca, Eisai, Bayer, Pfizer, Merck, Treadwell TherapeuticsResearch Funding: Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Exelixis, Novartis, Genentech/Roche, GlaxoSmithKline, Medivation, Pfizer, Merck, Millennium, Janssen, Johnson & Johnson, AstraZeneca, AbbVie, X4 Pharma, Calithera Biosciences, Clovis Oncology, Eisai, Seattle Genetics, Tesaro, Corvus Pharmaceuticals, Astellas MedivationExpert Testimony: TevaOther Relationship: UpToDate, American Cancer Society Benjamin A. TeplyConsulting or Advisory Role: Janssen, AstraZenecaResearch Funding: AstraZeneca, Inovio Pharmaceuticals, Bristol Myers SquibbPatents, Royalties, Other Intellectual Property: Receive royalties from patents related to health/medicine, held by MIT Joel PicusConsulting or Advisory Role: Novo Nordisk, PfizerResearch Funding: BioClin Therapeutics, Mirati Therapeutics, Rexahn Pharmaceuticals, Seattle Genetics, TRACON Pharma, eFFECTOR Therapeutics Scott T. TagawaConsulting or Advisory Role: Medivation, Astellas Pharma, Dendreon, Janssen, Bayer, Genentech, Endocyte, Immunomedics, Karyopharm Therapeutics, AbbVie, Tolmar, QED Therapeutics, Amgen, Sanofi, Pfizer, Clovis Oncology, Novartis, Genomic Health, POINT Biopharma, Blue Earth Diagnostics, Seattle Genetics, AIkido Pharma, 4D PharmaResearch Funding: Lilly, Sanofi, Janssen, Astellas Pharma, Progenics, Millennium, Amgen, Bristol Myers Squibb, Dendreon, Rexahn Pharmaceuticals, Bayer, Genentech, Newlink Genetics, Inovio Pharmaceuticals, AstraZeneca, Immunomedics, Novartis, AVEO, Boehringer Ingelheim, Merck, Stem CentRx, Karyopharm Therapeutics, AbbVie, Medivation, Endocyte, Exelixis, Clovis Oncology, POINT BiopharmaTravel, Accommodations, Expenses: Sanofi, Immunomedics, AmgenUncompensated Relationships: Telix Pharmaceuticals, ATLAB Pharma, Phosplatin Therapeutics Sreedhar KatragaddaConsulting or Advisory Role: Curio ScienceTravel, Accommodations, Expenses: Xcenda Daniel VaenaHonoraria: HMPConsulting or Advisory Role: Bristol Myers Squibb, Bayer, Genomic Health, Natera, Seattle Genetics, Exelixis, EMD Serono, Immunomedics, Bristol Myers Squibb/Celgene, EisaiResearch Funding: Bristol Myers Squibb, Novartis, AstraZeneca, Peloton Therapeutics, BioClin Therapeutics, Aeglea Biotherapeutics, Nektar, Calithera Biosciences, Tizona Therapeutics Inc, Compugen, TG Therapeutics, Merck, OBI Pharma, Incyte, Seattle Genetics, Roche/Genentech, Blueprint Medicines Christopher HoimesHonoraria: Seattle GeneticsConsulting or Advisory Role: Bristol Myers Squibb, Eisai, Prometheus, Seattle Genetics, Genentech/Roche, Merck Sharp & Dohme, 2bPreciseSpeakers' Bureau: Bristol Myers Squibb, Genentech/Roche, Astellas Pharma, Seattle Genetics, EisaiResearch Funding: Merck Sharp & DohmeUncompensated Relationships: 2bPrecise Elizabeth R. PlimackConsulting or Advisory Role: Bristol Myers Squibb, Genentech/Roche, Janssen, Merck, Flatiron Health, Seattle Genetics, Pfizer, AstraZeneca, Infinity Pharmaceuticals, MEI PharmaResearch Funding: Bristol Myers Squibb, AstraZeneca, Pfizer, Merck Sharp & Dohme, Astellas Pharma, Genentech/RochePatents, Royalties, Other Intellectual Property: US patent no.: 14/588,503, Filed January 2, 2015Open Payments Link: https://openpaymentsdata.cms.gov/physician/66377 Thomas W. FlaigLeadership: Aurora OncologyStock and Other Ownership Interests: Aurora OncologyConsulting or Advisory Role: Seattle Genetics, Janssen OncologyResearch Funding: Novartis, Bavarian Nordic, Dendreon, GTx, Janssen Oncology, Medivation, Sanofi, Pfizer, Bristol Myers Squibb, Roche/Genentech, Exelixis, Aragon Pharmaceuticals, Sotio, Tokai Pharmaceuticals, AstraZeneca/MedImmune, Lilly, Astellas Pharma, Agensys, Seattle Genetics, La Roche-Posay, Merck, SeagenPatents, Royalties, Other Intellectual Property: The University of Colorado has filed two patents related in which I am an inventor. These are related to early-stage bladder cancer treatment and detection. Neither is commercialized or licensed at this time Robert DreicerConsulting or Advisory Role: Astellas Pharma, Pfizer, Eisai, Merck, EMD Serono, Propella Therapeutics, Myovant Sciences, Bayer, Tavanta Therapeutics, Veru, Infinity Pharmaceuticals, Pfizer/AstellasResearch Funding: Seattle Genetics, Bristol Myers Squibb, Exelixis, Novartis Dean BajorinConsulting or Advisory Role: Merck, Dragonfly Therapeutics, Fidia Farmaceutici SpA, Bristol Myers Squibb FoundationResearch Funding: Novartis, Merck, Bristol Myers Squibb, AstraZeneca, Astellas Pharma, Seattle Genetics/AstellasTravel, Accommodations, Expenses: Merck Olwen HahnLeadership: Via OncologyStock and Other Ownership Interests: Teleflex MedicalHonoraria: Cardinal HealthConsulting or Advisory Role: PfizerTravel, Accommodations, Expenses: Cardinal Health Eric J. SmallStock and Other Ownership Interests: Fortis, Harpoon TherapeuticsHonoraria: Janssen, Johnson & JohnsonConsulting or Advisory Role: Fortis, Janssen Oncology, Beigene, Tolero Pharmaceuticals, Teon Therapeutics, Ultragenyx PharmaceuticalsResearch Funding: JanssenTravel, Accommodations, Expenses: JanssenOpen Payments Link: https://openpaymentsdata.cms.gov/physician/660367/summary Michael J. MorrisConsulting or Advisory Role: Bayer, Endocyte, Advanced Accelerator Applications, ORIC Pharmaceuticals, Johnson & Johnson, Curium Pharma, AthenexResearch Funding: Bayer, Sanofi, Endocyte, Progenics, Corcept Therapeutics, Roche/Genentech, JanssenTravel, Accommodations, Expenses: Endocyte, FujifilmNo other potential conflicts of interest were reported.

Background: ECOG3805 is a randomized trial of testosterone suppression with or without docetaxel for metastatic hormone-sensitive prostate cancer (mHSPC). Deeper prostate-specific antigen (PSA) suppression is prognostic for outcome. However, the concordance of PSA rise and radiographic progression has not been examined previously in mHSPC, whereas this has been reported in metastatic castration-resistant prostate cancer., Objective: To determine the patterns of progression by PSA and radiographic parameters in patients in ECOG3805., Design, Setting, and Participants: We conducted a retrospective analysis of all patients in ECOG3805. Patients were classified according to the PSA level at progression (whether PSA level was below 2.0 ng/mL or not) and the type of progression event in the study (either PSA progression as defined by the study with or without clinical progression, or clinical progression alone). Baseline demographics, clinical outcomes, and patterns of progression were compared between the groups., Results and Limitations: One in eight patients had clinical progression below a PSA level of 2 ng/mL, and approximately 25% developed clinical progression in the absence of confirmed PSA progression. Overall survival from randomization was shorter in patients with clinical progression without confirmed PSA progression than in patients with PSA progression alone as the first progression. Patient demographics at study entry were not predictive of the pattern of progression. Study limitations include its retrospective and post hoc nature., Conclusions: Clinical progression prior to PSA rise or at low PSA levels is a relatively frequent phenomenon in mHSPC and is associated with poorer overall survival. Further biological and clinical studies of these patients are warranted., Patient Summary: Reliance on prostate-specific antigen (PSA) alone is an inadequate strategy to monitor patients undergoing treatment for metastatic hormone-sensitive prostate cancer. Prostate cancer can get worse on scans even with low PSA and/or no or small changes in PSA. Imaging should be added to PSA testing to monitor patients with metastatic prostate cancer., (Copyright © 2020 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Purpose: A prognostic model for overall survival of post-platinum patients with metastatic urothelial carcinoma receiving PD-1/PD-L1 inhibitors is necessary as existing models were constructed in the chemotherapy setting., Materials and Methods: Patient level data were used from phase I/II trials evaluating PD-L1 inhibitors following platinum based chemotherapy for metastatic urothelial carcinoma. The derivation data set consisted of 2 phase I/II trials evaluating atezolizumab (405). Two phase I/II trials that evaluated avelumab (242) and durvalumab (198) comprised the validation data sets. Cox regression analyses evaluated the association of candidate prognostic factors with overall survival. Stepwise selection was used to select an optimal model using the derivation data set. Discrimination and calibration were assessed in the avelumab and durvalumab data sets., Results: The 5 prognostic factors identified in the optimal model using the atezolizumab derivation data set were ECOG-PS (1 vs 0, HR 1.80, 95% CI 1.36-2.36), liver metastasis (HR 1.55, 95% CI 1.20-2.00), platelet count (HR 2.22; 95% CI 1.54-3.18), neutrophil-to-lymphocyte ratio (HR 1.94, 95% CI 1.57-2.40) and lactate dehydrogenase (HR 1.60, 95% CI 1.28-1.99). There was robust discrimination of survival between low, intermediate and high risk groups. The c-statistic was 0.692 in the derivation and 0.671 and 0.773 in the avelumab and durvalumab validation data sets, respectively. A web based interactive tool was developed to calculate the expected survival probabilities based on risk factors., Conclusions: A validated 5-factor model has satisfactory prognostic performance for survival across 3 PD-L1 inhibitors to treat metastatic urothelial carcinoma after platinum therapy and may assist in stratification, interpreting and designing trials incorporating PD-1/PD-L1 inhibitors in the post-platinum setting.

Introduction: The addition of the androgen-signaling inhibitors (ASI) apalutamide, enzalutamide and abiraterone acetate or docetaxel to standard androgen deprivation therapy (ADT) has been demonstrated to improve overall survival in men with hormone-sensitive metastatic prostate cancer (HSMPC)., Areas Covered: The majority of men presenting with metastatic prostate cancer will now benefit from the addition of either a novel ASI or docetaxel to standard ADT. In the absence of comparative studies of these agents, clinicians are left with assessing the individual studies and attempting to individualize therapy., Expert Opinion: ADT with either docetaxel or androgen-signaling inhibitors (ASI) have changed the treatment landscape of HSMPC with clinically meaningful improvement in overall survival compared to ADT alone. Among the factors to consider in the selection of the optimal agent include the volume of disease, performance status and comorbidities, toxicity profile cost and drug availability, and further resistance or sequencing options.

Background Mammalian target of rapamycin (mTOR) pathway and angiogenesis through vascular endothelial growth factor (VEGF) have been shown to play important roles in prostate cancer progression. Preclinical data in prostate cancer has suggested the potential additive effect dual inhibition of VEGF and mTOR pathways. In this phase I/II trial we assessed the safety and efficacy of bevacizumab in combination with temsirolimus for the treatment of men with metastatic castration-resistant prostate cancer (mCRPC). Methods In the phase I portion, eligible patients received temsirolimus (20 mg or 25 mg IV weekly) in combination with a fixed dose of IV bevacizumab (10 mg/kg every 2 weeks). The primary endpoint for the phase II portion was objective response measured by either PSA or RECIST criteria. Exploratory endpoints included changes in circulating tumor cells (CTC) and their correlation with PSA response to treatment. Results Twenty-one patients, median age 64 (53-82), with pre-treatment PSA of 205.3 (11.1-1801.0), previously treated with a median of 2 (0-5) lines of therapy for mCRPC received the combination of temsirolimus weekly at 20 mg (n = 4) or 25 mg (n = 17) with bevacizumab 10 mg/kg every 2 weeks (n = 21). Median time to progression was 2.6 months (95% CI, 1.2-3.9) and the median best PSA change from baseline to 12 weeks was a 32% increase (-40-632%) which met the predefined futility rule and led to early termination of the study. Nine patients (43%) had ≥ grade 3 toxicity that included fatigue (24%), anorexia (10%), nausea/vomiting (5%) and lymphopenia (5%). In exploratory analysis, a decrease in CTC levels was observed in 9 out of 11 patients. No association between PSA levels and CTC levels was detected. Conclusions The combination of temsirolimus and bevacizumab showed limited clinical activity in mCRPC patients previously treated with chemotherapy and was associated with significant adverse events (AEs). Transient decrease in CTC levels was independent from PSA response. NCT01083368.

Background: Docetaxel (D) at the time of starting androgen deprivation therapy (ADT) for metastatic castrate naive prostate cancer shows a clear survival benefit for patients with high-volume (HV) disease. It is unclear whether patients with low-volume (LV) disease benefit from early D., Objective: To define the overall survival (OS) of aggregate data of patient subgroups from the CHAARTED and GETUG-AFU15 studies, defined by metastatic burden (HV and LV) and time of metastasis occurrence (at diagnosis or after prior local treatment [PRLT])., Design, Setting, and Participants: Data were accessed from two independent phase III trials of ADT alone or ADT+D-GETUG-AFU15 (N=385) and CHAARTED (N=790), with median follow-ups for survivors of 83.2 and 48.2 mo, respectively. The definition of HV and LV disease was harmonized., Outcome Measurements and Statistical Analysis: The primary end point was OS., Results and Limitations: Meta-analysis results of the aggregate data showed significant heterogeneity in ADT+D versus ADT effect sizes between HV and LV subgroups (p=0.017), and failed to detect heterogeneity in ADT+D versus ADT effect sizes between upfront and PRLT subgroups (p=0.4). Adding D in patients with HV disease has a consistent effect in improving median OS (HV-ADT: 34.4 and 35.1 mo, HV-ADT+D: 51.2 and 39.8 mo in CHAARTED and GETUG-AFU15, respectively; pooled average hazard ratio or HR (95% confidence interval [CI]) 0.68 ([95% CI 0.56; 0.82], p<0.001). Patients with LV disease showed much longer OS, without evidence that D improved OS (LV-ADT: not reached [NR] and 83.4; LV-ADT+D: 63.5 and NR in CHAARTED and GETUG-AFU15, respectively; pooled HR (95% CI) 1.03 (95% CI 0.77; 1.38). Aggregate data showed no evidence of heterogeneity of early D in LV and HV subgroups irrespective of whether patients had PRLT or not. Post hoc subgroup analysis was based on aggregated data from two independent phase III randomized trials., Conclusions: There was no apparent survival benefit in the CHAARTED and GETUG-AFU15 studies with D for LV. Across both studies, early D showed consistent effect and improved OS in HV patients., Patient Summary: Patients with a higher burden of metastatic prostate cancer starting androgen deprivation therapy (ADT) have a poorer prognosis and are more likely to benefit from early docetaxel. Low-volume patients have longer overall survival with ADT alone, and the toxicity of docetaxel may outweigh its benefits., (Copyright © 2018 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Purpose Docetaxel added to androgen-deprivation therapy (ADT) significantly increases the longevity of some patients with metastatic hormone-sensitive prostate cancer. Herein, we present the outcomes of the CHAARTED (Chemohormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer) trial with more mature follow-up and focus on tumor volume. Patients and Methods In this phase III study, 790 patients with metastatic hormone-sensitive prostate cancer were equally randomly assigned to receive either ADT in combination with docetaxel 75 mg/m 2 for up to six cycles or ADT alone. The primary end point of the study was overall survival (OS). Additional analyses of the prospectively defined low- and high-volume disease subgroups were performed. High-volume disease was defined as presence of visceral metastases and/or ≥ four bone metastases with at least one outside of the vertebral column and pelvis. Results At a median follow-up of 53.7 months, the median OS was 57.6 months for the chemohormonal therapy arm versus 47.2 months for ADT alone (hazard ratio [HR], 0.72; 95% CI, 0.59 to 0.89; P = .0018). For patients with high-volume disease (n = 513), the median OS was 51.2 months with chemohormonal therapy versus 34.4 months with ADT alone (HR, 0.63; 95% CI, 0.50 to 0.79; P < .001). For those with low-volume disease (n = 277), no OS benefit was observed (HR, 1.04; 95% CI, 0.70 to 1.55; P = .86). Conclusion The clinical benefit from chemohormonal therapy in prolonging OS was confirmed for patients with high-volume disease; however, for patients with low-volume disease, no OS benefit was discerned.

Background: This multicenter, randomized, open-label, active-controlled study evaluated therapeutic equivalence, steady-state pharmacokinetics, and safety of a novel abiraterone acetate fine particle formulation (AAFP) 500mg plus methylprednisolone vs. the originator AA (OAA) 1000mg plus prednisone in men with metastatic castrate-resistant prostate cancer (mCRPC). The primary endpoint was a comparison of average of serum testosterone levels on treatment days 9 and 10 between groups., Methods: Men with progressive mCRPC, receiving gonadotropin-releasing hormone agonist or antagonist therapy, and with a serum testosterone level of <50ng/dl were randomized 1:1 to either AAFP 500mg daily plus 4mg methylprednisolone orally twice daily (BID), or OAA 1000mg daily plus 5mg prednisone BID for 84 days. Serum testosterone, serum prostate-specific antigen (PSA), steady-state (trough) abiraterone pharmacokinetics, and safety were evaluated., Results: Fifty-three patients were enrolled (n = 24, AAFP; n = 29, OAA). Mean age was 75.1 years and 54.7% had Gleason>7. Over 90% of patients in each group achieved absolute testosterone levels of ≤1ng/dl during the study. The averaged absolute testosterone levels ≤0.1ng/dl were achieved in 25% of AAFP-treated patients and 17% of OAA-treated patients. A PSA-50 response was observed in>65% of patients in both groups on days 28, 56, and 84 (P = NS, all timepoints). Days 9 and 10 averaged rounded-up least squares (LS) mean (SE) serum testosterone levels were comparable (1.05ng/dl [0.04], AAFP; 1.02ng/dl [0.03], OAA; P = 0.4703 for LS mean difference). The geometric mean ratio between groups was 1.021 (90% CI: 0.965-1.081); the 90% CI fell within 80.0% to 125.0% equivalence limits. The LS mean differences in abiraterone trough plasma concentrations were not statistically significant at any visit. Adverse event frequency was comparable between arms (75.0%, AAFP; 82.8%, OAA). Musculoskeletal events were more common among OAA-treated patients (37.9% vs. 12.5%)., Conclusion: Therapeutic equivalence between AAFP 500mg daily and OAA 1000mg daily based on serum testosterone levels was confirmed in mCRPC patients. Both agents led to similar PSA-50 response rates. Abiraterone trough levels were similar between treatments. No new safety concerns were observed., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose We evaluated the relationship between prostate-specific antigen (PSA) and overall survival in the context of a prospectively randomized clinical trial comparing androgen-deprivation therapy (ADT) plus docetaxel with ADT alone for initial metastatic hormone-sensitive prostate cancer. Methods We performed a landmark survival analysis at 7 months using the E3805 Chemohormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer (CHAARTED) database ( ClinicalTrials.gov identifier: NCT00309985). Inclusion required at least 7 months of follow-up and PSA levels at 7 months from ADT initiation. We used the prognostic classifiers identified in a previously reported trial (Southwest Oncology Group 9346) of PSA ≤ 0.2, > 0.2 to 4, and > 4 ng/mL. Results Seven hundred nineteen of 790 patients were eligible for this subanalysis; 358 were treated with ADT plus docetaxel, and 361 were treated with ADT alone. Median follow-up time was 23.1 months. On multivariable analysis, achieving a 7-month PSA ≤ 0.2 ng/mL was more likely with docetaxel, low-volume disease, prior local therapy, and lower baseline PSAs (all P ≤ .01). Across all patients, median overall survival was significantly longer if 7-month PSA reached ≤ 0.2 ng/mL compared with > 4 ng/mL (median survival, 60.4 v 22.2 months, respectively; P < .001). On multivariable analysis, 7-month PSA ≤ 0.2 and low volume disease were prognostic of longer overall survival (all P < 0.01). The addition of docetaxel increased the likelihood of achieving a PSA ≤ 0.2 ng/mL at 7 months (45.3% v 28.8% of patients on ADT alone). Patients on ADT alone who achieved a 7-month PSA ≤ 0.2 ng/mL had the best survival and were more likely to have low-volume disease (56.7%). Conclusion PSA ≤ 0.2 ng/mL at 7 months is prognostic for longer overall survival with ADT for metastatic hormone-sensitive prostate cancer irrespective of docetaxel administration. Adding docetaxel increased the likelihood of a lower PSA and improved survival.

Purpose: Orteronel (TAK-700) is an investigational, nonsteroidal, reversible, selective 17,20-lyase inhibitor. This study examined orteronel in patients with metastatic castration-resistant prostate cancer that progressed after docetaxel therapy., Patients and Methods: In our study, 1,099 men were randomly assigned in a 2:1 schedule to receive orteronel 400 mg plus prednisone 5 mg twice daily or placebo plus prednisone 5 mg twice daily, stratified by region (Europe, North America [NA], and non-Europe/NA) and Brief Pain Inventory-Short Form worst pain score. Primary end point was overall survival (OS). Key secondary end points (radiographic progression-free survival [rPFS], ≥ 50% decrease of prostate-specific antigen [PSA50], and pain response at 12 weeks) were to undergo statistical testing only if the primary end point analysis was significant., Results: The study was unblinded after crossing a prespecified OS futility boundary. The median OS was 17.0 months versus 15.2 months with orteronel-prednisone versus placebo-prednisone (hazard ratio [HR], 0.886; 95% CI, 0.739 to 1.062; P = .190). Improved rPFS was observed with orteronel-prednisone (median, 8.3 v 5.7 months; HR, 0.760; 95% CI, 0.653 to 0.885; P < .001). Orteronel-prednisone showed advantages over placebo-prednisone in PSA50 rate (25% v 10%, P < .001) and time to PSA progression (median, 5.5 v 2.9 months, P < .001) but not pain response rate (12% v 9%; P = .128). Adverse events (all grades) were generally more frequent with orteronel-prednisone, including nausea (42% v 26%), vomiting (36% v 17%), fatigue (29% v 23%), and increased amylase (14% v 2%)., Conclusion: Our study did not meet the primary end point of OS. Longer rPFS and a higher PSA50 rate with orteronel-prednisone indicate antitumor activity., (© 2015 by American Society of Clinical Oncology.)

Background: Orteronel is an investigational, partially selective inhibitor of CYP 17,20-lyase in the androgen signalling pathway, a validated therapeutic target for metastatic castration-resistant prostate cancer. We assessed orteronel in chemotherapy-naive patients with metastatic castration-resistant prostate cancer., Methods: In this phase 3, double-blind, placebo-controlled trial, we recruited patients with progressive metastatic castration-resistant prostate cancer and no previous chemotherapy from 324 study centres (ie, hospitals or large urologic or group outpatient offices) in 43 countries. Eligible patients were randomly assigned in a 1:1 ratio to receive either 400 mg orteronel plus 5 mg prednisone twice daily or placebo plus 5 mg prednisone twice daily. Randomisation was done centrally with an interactive voice response system and patients were stratified by region (Europe, North America, and not Europe or North America) and the presence or absence of radiographic disease progression at baseline. The two primary endpoints were radiographic progression-free survival and overall survival, determined in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01193244., Findings: From Oct 31, 2010, to June 29, 2012, 2353 patients were assessed for eligibility. Of those, 1560 were randomly assigned to receive either orteronel plus prednisone (n=781) or placebo plus prednisone (n=779). The clinical cutoff date for the final analysis was Jan 15, 2014 (with 611 deaths). Median follow-up for radiographic progression-free survival was 8·4 months (IQR 3·7-16·6). Median radiographic progression-free survival was 13·8 months (95% CI 13·1-14·9) with orteronel plus prednisone and 8·7 months (8·3-10·9) with placebo plus prednisone (hazard ratio [HR] 0·71, 95% CI 0·63-0·80; p<0·0001). After a median follow-up of 20·7 months (IQR 14·2-25·4), median overall survival was 31·4 months (95% CI 28·6-not estimable) with orteronel plus prednisone and 29·5 months (27·0-not estimable) with placebo plus prednisone (HR 0·92, 95% CI 0·79-1·08; p=0·31). The most common grade 3 or worse adverse events were increased lipase (137 [17%] of 784 patients in the orteronel plus prednisone group vs 14 [2%] of 770 patients in the placebo plus prednisone group), increased amylase (77 [10%] vs nine [1%]), fatigue (50 [6%] vs 14 [2%]), and pulmonary embolism (40 [5%] vs 27 [4%]). Serious adverse events were reported in 358 [46%] patients receiving orteronel plus prednisone and in 292 [38%] patients receiving placebo plus prednisone., Interpretation: In chemotherapy-naive patients with metastatic castration-resistant prostate cancer, radiographic progression-free survival was prolonged with orteronel plus prednisone versus placebo plus prednisone. However, no improvement was noted in the other primary endpoint, overall survival. Orteronel plus prednisone was associated with increased toxic effects compared with placebo plus prednisone. On the basis of these and other data, orteronel is not undergoing further development in metastatic castration-resistant prostate cancer., Funding: Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Purpose: Enzastaurin is an oral serine/threonine kinase inhibitor that inhibits the beta isoform of protein kinase C and which may have therapeutic activity in prostate cancer. We explored the efficacy of docetaxel/prednisone with or without enzastaurin in patients with castration-resistant metastatic prostate cancer., Methods: A nonrandomized safety cohort consisting of 14 patients was followed by a double-blind randomized Phase II trial. Patients received standard doses of docetaxel (75 mg/m(2)) with prednisone 10 mg daily with or without 500 mg/day of enzastaurin., Results: There was no difference in the objective response rate between the enzastaurin and placebo arms (placebo: 7 [15.2 %]; enzastaurin: 6 [15.0 %]; P = 1.00). The median PFS was 229 days for patients in the enzastaurin arm versus 213 days for the placebo arm (P = 0.524). The 1-year overall survival rates were almost identical, with 76.7 % and 75.1 % in the enzastaurin and placebo arms, respectively. Therapy was well tolerated although the combination of enzastaurin and docetaxel was more myelosuppressive than with docetaxel alone., Conclusions: The clinical activity of docetaxel/prednisone plus enzastaurin cannot be distinguished from docetaxel/prednisone alone, given the limitations of a randomized Phase II design. Although the toxicity profile was favorable for the enzastaurin-containing regimen, there is no compelling rationale to move this combination forward for the treatment of castration-resistant metastatic prostate cancer.

Context: We present a summary of the Second International Consultation on Bladder Cancer recommendations on chemotherapy for the treatment of bladder cancer using an evidence-based strategy., Objective: To review the data regarding chemotherapy in patients with clinically localized and metastatic bladder cancer with a focus on its use for patients in the neoadjuvant and adjuvant settings., Evidence Acquisition: Medline databases were searched for original articles published prior to April 1, 2012, using the following search terms: bladder cancer, urothelial cancer, metastatic, advanced, neoadjuvant, and adjuvant therapy. Proceedings of major conferences from the last 5 yr also were searched. Novel and promising drugs currently in clinical trials were included., Evidence Synthesis: The major findings are addressed in an evidence-based manner. Prospective trials and important cohort data were analyzed., Conclusions: Cisplatin-based combination chemotherapy for advanced and metastatic bladder cancer is an established standard, improving overall survival. In the advanced setting, cisplatin-ineligible patients may benefit from gemcitabine and carboplatin. Meta-analyses undertaken for neoadjuvant cisplatin-based combination chemotherapy show a 5% benefit in overall survival. Pathologic complete remission may be an intermediate surrogate for survival, but requires further validation. Use of neoadjuvant chemotherapy is low, and is attributable to patient and physician choice because of limited benefit, advanced age, and comorbidities including renal and/or cardiac dysfunction. Sufficient data to support adjuvant chemotherapy are lacking., (Copyright © 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Purpose: We evaluated the safety and efficacy of intetumumab in combination with docetaxel in patients with castrate-resistant metastatic prostate cancer. Patients and methods In this phase 1, open-label, multicenter, nonrandomized study, 75 mg/m² docetaxel was administered on Day 1 of each of nine 21-day treatment cycles and intetumumab 5 or 10 mg/kg was administered on Days 1, 8, and 15 of Cycles 2 and 3 and on Day 1 of all subsequent cycles. The primary endpoint was the incidence of dose-limiting toxicities (DLTs) during Cycles 2 and 3. Secondary endpoints included serum prostate-specific antigen (PSA) response and objective response based on Response Evaluation Criteria in Solid Tumors (RECIST)., Results: Ten patients were treated (5 mg/kg n = 3, 10 mg/kg n = 7). No DLTs occurred. Most treatment-emergent adverse events (TEAEs) occurred in the 10-mg/kg intetumumab group. Common TEAEs were neutropenia (10 mg/kg n = 6) and nausea (5 mg/kg n = 1, 10 mg/kg n = 5). Four 10-mg/kg-treated patients reported serious TEAEs; of these, only febrile neutropenia was considered probably intetumumab-related. In the 10-mg/kg group, four patients had a serum PSA response (two of whom responded within 3 months of treatment), one patient demonstrated partial tumor response for 11 weeks, and none had progressive disease at Cycle 9. No PSA or tumor response was observed in the 5-mg/kg group., Conclusions: Intetumumab was generally safe and well tolerated in combination with docetaxel, with a higher incidence of TEAEs in the 10 mg/kg dose cohort. The efficacy of 10 mg/kg intetumumab in combination with docetaxel appears to warrant further study.

Background: Docetaxel is the standard of care for patients with metastatic, castrate-resistant prostate cancer (CRPC). Gemcitabine is a nucleoside analogue with broad antitumor activity. In a phase 2 study of combined docetaxel and gemcitabine, the authors assessed its safety and activity in patients with chemotherapy-naive, metastatic CRPC., Methods: Eligible patients had untreated, metastatic CRPC with radiologic and/or biochemical evidence of progression after antiandrogen withdrawal with castrate testosterone levels, an Eastern Cooperative Oncology performance status (ECOG PS) of 0 to 2, and adequate organ function; no previous chemotherapy was permitted. Patients received gemcitabine (800 mg/m²) Days 1 and 8 and docetaxel (75 mg/m²) on Day 8 every 21 days for a maximum of 6 cycles. Response was evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) for measurable disease. A prostate-specific antigen (PSA) response was defined as a decline ≥ 50% in baseline PSA level., Results: Thirty-five patients with chemotherapy-naive, metastatic CRPC were enrolled. The median age was 67 years, and 60% of patients had an ECOG PS of 0. PSA responses were observed in 49% of patients. Among the patients who had measurable disease (n = 25), 3 patients (12%) had a confirmed, RECIST-defined partial response (PR); 4 patients (16%) had an unconfirmed PR; and 15 patients (60%) achieved stable disease. The most common adverse events included grade 1 and 2 fatigue (69%), alopecia (80%), and nausea/vomiting (54%). No treatment-related deaths were noted, but an unusually high incidence of grade 3 and 4 neutropenia was observed., Conclusions: The efficacy of combined gemcitabine and docetaxel in metastatic CRPC was similar to that observed with single-agent docetaxel. In contrast to single-agent docetaxel, the combination was moderately toxic and had an impact primarily on bone marrow reserve., (Copyright © 2010 American Cancer Society.)

Objective: Low-dose interleukin-2 (IL-2) is a historical treatment for metastatic renal cell carcinoma (mRCC). Increased vascular endothelial growth factor (VEGF) levels inhibit dendritic cell (DC) differentiation and augment production of immunosuppressive regulatory T (Treg) cells. Bevacizumab is an antibody that binds to VEGF, has activity in mRCC and may augment the anti-tumour immune effects of IL-2. To determine the clinical and immunomodulatory effects of this combination, a prospective, phase II trial of bevacizumab plus low-dose IL-2 was conducted., Patients and Methods: Patients with untreated mRCC received bevacizumab (10 mg/kg i.v. every 2 weeks) and IL-2 (125,000 units/kg/day subcutaneously from Monday to Friday for 6 consecutive weeks followed by a 2-week rest period). Endpoints included progression-free survival, Response Evaluation Criteria in Solid Tumors-defined objective response rate, immunomodulatory effects and safety., Results: Between January 2005 and September 2007, twenty-six patients with untreated mRCC were enrolled. The median progression-free survival was 9.6 months (95% CI, 4.1-16.9 months) The objective response rate was 15% and an additional 38% of patients had tumour burden reduction of <30%. Grade 3 constitutional adverse events (fatigue, fever/chills) and neutropenia were observed in 42% and 12% of patients, respectively. Peripheral blood CD1c(+) myeloid and CD303(+) plasmacytoid DC increased during treatment as did IL-8 levels and CD4(+) CD25(+) FoxP3(+) Treg cells. No changes in T helper type 1/2-associated cytokines were observed., Conclusion: Bevacizumab plus low-dose IL-2 has modest clinical activity in mRCC. Toxicity was largely IL-2 related without enhancement of bevacizumab-related toxicity. Biological data indicate inhibition of VEGF levels and increase of immunosuppressive Treg cells without an effect on DC activation., (© 2010 THE AUTHORS. JOURNAL COMPILATION © 2010 BJU INTERNATIONAL.)

Purpose: Metastasectomy is often incorporated in overall treatment in patients with metastatic renal cell carcinoma. While this approach was studied in the immunotherapy era, only a few cases have been described in the targeted therapy era. Thus, we evaluated the role of metastasectomy in patients with metastatic renal cell carcinoma who received prior targeted therapy., Materials and Methods: We retrospectively evaluated the records of patients who underwent consolidative metastasectomy after targeted therapy at 3 institutions from 2004 to 2009. All patients received at least 1 cycle of targeted therapy before surgical resection of all visible disease., Results: We identified 22 patients. Metastasectomy sites included the retroperitoneum in 12 patients, lung in 6, adrenal gland in 2, bowel in 2, and mediastinum, bone, brain and inferior venal caval thrombus in 1 each. A total of 6 postoperative complications were observed in 4 patients within 12 weeks after surgery, which resolved with appropriate management. Postoperatively 9 patients received at least 1 targeted therapy. In 11 patients recurrence developed a median of 42 weeks after metastasectomy and another 11 experienced no recurrence at a median of 43 weeks. At a median followup of 109 weeks 21 patients were alive and 1 died of renal cell carcinoma 105 weeks after metastasectomy., Conclusions: In a cohort of select patients with a limited tumor burden after treatment with targeted agents consolidative metastasectomy is feasible with acceptable morbidity. Significant time off targeted therapy and long-term tumor-free status are possible with this approach., (Copyright © 2011 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Objective: To determine if the fractional percentage of tumour volume (FPTV) removed with debulking nephrectomy was associated with progression-free survival (PFS) after subsequent targeted therapy, as a debulking nephrectomy is the standard of care in metastatic renal cell carcinoma (mRCC), but there are few data., Patients and Methods: The Cleveland Clinic Taussig Cancer Institute Urologic Oncology database was retrospectively reviewed from 2005 to 2008 to identify patients with mRCC who had undergone debulking nephrectomy followed by vascular endothelial growth factor (VEGF)-targeted therapy, defined as sunitinib-, sorafenib- or bevacizumab-based therapy. FPTV was calculated as the largest diameter of the primary tumour divided by the total tumour burden (as per the Response Evaluation Criteria in Solid Tumors, RECIST) through investigator re-review of imaging. PFS was defined from the start date of systemic therapy to disease progression per RECIST criteria., Results: Forty-six patients were identified (80% men, median age 61 years, all clear cell histology and 67% with an Eastern Cooperative Oncology Group performance status of 0). Patients received treatment with bevacizumab ± interleukin-2 (18), sunitinib (14), sorafenib (11) or sunitinib + bevacizumab (three). The median diameter of the primary tumour was 10.0 cm. The median (range) FPTV removed was 95 (80-99)%. In univariable analysis, the FPTV removed (P = 0.002) and normal haemoglobin level (P = 0.04) were associated with improved PFS. In multivariable analysis, the FPTV removed (P < 0.001), male gender (P = 0.001) and corrected calcium (P = 0.05) were independent predictors of PFS., Conclusion: A greater percentage of tumour burden removed at debulking nephrectomy is significantly associated with improved PFS on subsequent VEGF-targeted systemic therapy., (© 2010 THE AUTHORS. JOURNAL COMPILATION © 2010 BJU INTERNATIONAL.)

Background: The prevalence of chronic kidney disease (CKD) in patients with upper tract urothelial carcinoma (UTUC) is poorly defined, both before and after nephrouretectomy. Although multimodal treatment paradigms for UTUC are under-developed, this has important implications on patients' ability to receive cisplatin-based combination chemotherapy (CBCC)., Methods: Estimated glomerular filtration rate (eGFR) was calculated using the Modification of Diet in Renal Disease formula in 336 patients with UTUC, who were treated at the Cleveland Clinic by nephroureterectomy since 1992. An eGFR cutoff of 60 mL/min/1.73 m(2) was used to determine the presence of CKD and eligibility for CBCC., Results: Median age was 72 years and median preoperative eGFR was 59 mL/min/1.73m(2). Before nephroureterectomy, only 48% of patients were eligible to receive CBCC and this decreased to 22% postoperatively (P < .001). In the 144 patients with pT2-pT4 and/or pN1-pN3 disease who are suitable to receive CBCC, these proportions were 40% and 24%, respectively (P = .009). Although 50 patients overall received some form of perioperative chemotherapy, only 3 and 11 patients received neoadjuvant and adjuvant CBCC, respectively., Conclusions: CKD is prevalent in the UTUC population and a minority of patients has an optimal eGFR to receive neoadjuvant CBCC. Nephrouretectomy may eliminate CBCC as a therapeutic option in 49% of high-risk patients if it is deferred to the adjuvant setting. Multimodal treatment strategies for UTUC should focus on neoadjuvant chemotherapy, as few patients are eligible for adjuvant CBCC because of the substantial decline in eGFR caused by nephroureterectomy.

Purpose: This randomized phase II study evaluated ASA404 (vadimezan; 5,6-dimethylxanthenone-4-acetic acid) in combination with docetaxel in castration-refractory metastatic prostate cancer (CRMPC)., Experimental Design: Seventy-four patients with histopathologically confirmed CRMPC previously untreated with chemotherapy were randomized to receive either

Purpose: Bevacizumab is an antibody against vascular endothelial growth factor; sunitinib is an inhibitor of vascular endothelial growth factor and related receptors. The safety and maximum tolerated dose of sunitinib plus bevacizumab was assessed in this phase I trial., Experimental Design: Patients with advanced solid tumors were treated on a 3+3 trial design. Patients received sunitinib daily (starting dose level, 25 mg) for 4 weeks on followed by 2 weeks off and bevacizumab (starting dose level, 5 mg/kg) on days 1, 15, and 29 of a 42-day cycle. Dose-limiting toxicities during the first 6-week cycle were used to determine the maximum tolerated dose., Results: Thirty-eight patients were enrolled. Patients received a median of 3 cycles of treatment (range, 1-17(+)). There was one dose-limiting toxicity (grade 4 hypertension) at 37.5 mg sunitinib and 5 mg/kg bevacizumab. Grade 3 or greater toxicity was observed in 87% of patients including hypertension (47%), fatigue (24%), thrombocytopenia (18%), proteinuria (13%), and hand-foot syndrome (13%). Dose modifications and delays were common at higher dose levels. No clinical or laboratory evidence of microangiopathic hemolytic anemia was observed. Seven patients had a confirmed Response Evaluation Criteria in Solid Tumors-defined partial response (18%; 95% confidence interval, 8-34%). Nineteen of the 32 patients with a postbaseline scan (59%) had at least some reduction in overall tumor burden (median, 32%; range, 3-73%)., Conclusions: The combination of sunitinib and bevacizumab in patients with advanced solid tumors is feasible, albeit with toxicity at higher dose levels and requiring dose modification with continued therapy. Antitumor activity was observed across multiple solid tumors.

Background: The postcystectomy survival benefit associated with the combination of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) neoadjuvant chemotherapy (NC) for muscle-invasive bladder cancer has been most evident in patients who achieve a pathologic complete response. The outcome of NC and open radical cystectomy (RC) was evaluated in a contemporary cohort of patients in a tertiary referral setting., Methods: From January 2006 to November 2007, 117 patients underwent open RC at Cleveland Clinic for muscle-invasive bladder cancer, 29 (25%) of whom received NC. Patient information was obtained from a prospective database., Results: Clinical stage at the time of diagnosis in the NC cohort was T2 in 23 (79%) and T3-4a in 6 (21%) patients. A total of 20 (69%) patients received the combination of gemcitabine and cisplatin (GC), 4 (14%) received MVAC, and 5 (17%) received other regimens. The median interval from the time of diagnosis of muscle-invasive bladder cancer to RC was 208 days (interquartile range, 149 days -327 days) in the NC cohort. Overall, only 2 patients (7%; 95% confidence interval [95% CI], 0 patients-17 patients) achieved a pathologic complete response, 18 (62%; 95% CI, 43 patients-81 patients) had nonorgan-confined residual cancer, and the overall median progression-free survival was 10.5 months (95% CI, 7 months -14 months)., Conclusions: Few RC patients in these investigators' recent experience achieved a pathologic complete response with NC, and most experienced rapid disease progression. These poor outcomes may be related to the use of non-MVAC-based regimens or excessive delay in performing RC. In the absence of supportive data for GC in the neoadjuvant setting, MVAC remained the preferred regimen. Excessive delays in performing RC may negate the benefit of NC., ((c) 2009 American Cancer Society.)

Background: Renal cell carcinoma (RCC) is recognized as a neoplasm resistant to chemotherapy. In vitro experiments demonstrated that suramin, at noncytotoxic doses, enhanced the activity of chemotherapy including 5-fluorouracil (5-FU) in xenograft models., Patients and Methods: A phase I/II trial of noncytotoxic suramin in combination with weekly 5-FU in patients with metastatic RCC was conducted. The treatment consisted of intravenous (i.v.) suramin followed by a 500 mg/m2 i.v. bolus of 5-FU given 4.5 hours after starting suramin. In the phase I portion, a cohort of 6 patients received a suramin dose calculated to achieve a plasma level of 10-50 micromol/L. Therapy was administered once weekly for 6 doses, followed by 2 weeks off. This was followed by a phase II portion in which the primary goal was to determine the objective response rate., Results: Twenty-three patients were enrolled in the study: 6 in the phase I portion and 17 in phase II. Seventy-eight percent of patients were men, the mean age was 58.8 years, 96% had previous nephrectomy, and 70% had received previous systemic therapy. Histologic subtype was clear cell in 91%. Dose-limiting toxicity was observed in 1 of 6 patients (grade 3 hypersensitivity related to suramin infusion). The suramin dosing nomogram used in phase I and II portions of the trial yielded the desired plasma level of 10-50 micromol/L from 4.5 hours to 48 hours after infusion in 94 of 115 treatments. No objective responses were noted, and the median time to treatment failure was 2.5 months. The major toxicities (all grades) were fatigue (83%), nausea/vomiting (78%), diarrhea (61%), and chills (61%)., Conclusion: Suramin levels expected to reverse fibroblast growth factor-induced resistance can be achieved with the dosing regimen used in this study. The toxicity observed with suramin and 5-FU was acceptable. The combination does not have clinical activity in patients with metastatic RCC.

Purpose: Pegylated interferon alpha-2b (PEG-Intron) is a conjugate of polyethylene glycol (PEG) and interferon alpha-2b, has a prolonged half-life, and an increased area under the curve (AUC) for interferon alpha-2b. The combination of PEG-Intron with recombinant interleukin-2 (rIL-2) was investigated in a phase 1 trial. To determine the maximal tolerable dose (MTD) and preliminary efficacy of concurrent subcutaneous (SC) administration of PEG-Intron and rIL-2 in patients with metastatic renal cell carcinoma (RCC)., Methods: Cohorts of 3-6 patients received escalating doses of PEG-Intron (I-1.5, II- 1.5, III-3.0, IV-3.0, V-4.5 microg/kg SC) given weekly in combination with rIL-2 administered three times weekly (TIW) for 6 weeks. rIL-2 dose levels were escalated in weeks 1 and 4 (I-10.0, II-15.0, III-15.0, IV-20.0, V-20.0 MIU/m(2) SC), and 5.0 MIU/m(2) SC TIW was administered during weeks 2, 3, 5 and 6., Results: Thirty-four patients (24 men; 10 women) were accrued at dose levels I (n = 4), II (n = 4), III (n = 6), IV (n = 14), and V (n = 6) between October 2000 and October 2002. All but one patient had prior nephrectomy (n = 33) and all but one patient (97%) had received no prior systemic therapy. Patients received a median of four cycles of treatment (range 1-9). Dose limiting toxicity occurred at dose level V and included grade 4 neutropenia and hypoxemia. A partial response was found in 5 pts (15%). Median progression-free and overall survival were 9.0 (95% C.I. 5.6-13.1 months) and 31.9 months (95% C.I. 17.2-61.9 months), respectively., Conclusion: The combination of PEG-Interferon and SC rIL-2 can be administered with acceptable toxicity.

Background: There is a need to identify active new regimens in patients with advanced urothelial cancer. Pemetrexed and gemcitabine are active agents in advanced urothelial cancer. A phase 2 trial of the combination of these 2 agents was performed in patients with advanced urothelial cancer who were previously untreated for metastatic disease., Methods: Forty-six patients with advanced urothelial carcinoma received pemetrexed disodium 500 mg/m2 and gemcitabine 1000 mg/m2 intravenously on Day 1, with gemcitabine repeated on Day 8. Cycles were repeated every 3 weeks for a maximum of 6 cycles., Results: Two patients attained a complete response, and 12 patients attained a partial response for an overall response rate of 31.8% (90% confidence interval, 20.4%-45.2%). The median time to disease progression was 5.8 months, and the median overall survival was 13.4 months. Thirty-three patients (75%) experienced grade>or=3 neutropenia, and 5 patients (11%) had febrile neutropenia. There were 2 therapy-related deaths., Conclusions: The combination of pemetrexed and gemcitabine had moderate antitumor activity in previously untreated patients with advanced urothelial cancer at the expense of significant myelosuppression., (Copyright (c) 2008 American Cancer Society.)

Purpose: Granulocyte macrophage colony-stimulating factor (GM-CSF) and thalidomide are active agents in prostate cancer. This study assessed the biological effects and safety of GM-CSF and thalidomide in patients with localized prostate cancer before radical prostatectomy., Experimental Design: Locally advanced prostate cancer patients undergoing radical prostatectomy were recruited for this study. Treatment consisted of two 28-day cycles of GM-CSF (250 microg, s.c., thrice weekly) and thalidomide (200 mg, orally, daily) on days 1 to 28 of each cycle. Radical prostatectomy occurred within 7 to 10 days after completion of therapy. Pretreatment and posttreatment specimens were used to assess the expression of CD3, CD68, Ki-67, S100, PTEN, and CD31. Peripheral blood was examined for dendritic cells, regulatory T cells, and cytokines., Results: Twenty-eight patients were enrolled. No pathologic responses (P0) were observed and no unexpected toxicities or surgical complications occurred. Eighty-one percent of patients had a prostate-specific antigen decline (mean +/- SD decrease was 21.1 +/- 15.4%; median, 18.0%). With a median follow-up of 32 months, five patients have experienced progression. Radical prostatectomy tumor tissue specimens showed significant CD3 and S100 overexpression when compared with pretreatment biopsies. No significant changes in tumor macrophage infiltration were observed. Increased number of serum dendritic cell, as well as high serum levels of interleukin-8, basic fibroblast growth factor, and vascular endothelial growth factor, was also observed., Conclusions: Neoadjuvant GM-CSF and thalidomide was safe and feasible and did not affect the perioperative morbidity of radical prostatectomy. Although no pathologic complete responses were observed, significant posttreatment tumor T-cell and dendritic cell infiltration was noted. No significant changes in serum cytokines, dendritic cells, or regulatory T cells were induced.

Purpose: To compare the safety and activity of DN-101, a new high-dose oral formulation of calcitriol designed for cancer therapy, and docetaxel with placebo and docetaxel., Patients and Methods: Patients with progressive metastatic androgen-independent prostate cancer and adequate organ function received weekly docetaxel 36 mg/m2 intravenously for 3 weeks of a 4-week cycle combined with either 45 microg DN-101 or placebo taken orally 1 day before docetaxel. The primary end point was prostate-specific antigen (PSA) response within 6 months of enrollment, defined as a 50% reduction confirmed at least 4 weeks later., Results: Two hundred fifty patients were randomly assigned. Baseline characteristics were similar in both arms. Within 6 months, PSA responses were seen in 58% in DN-101 patients and 49% in placebo patients (P = .16). Overall, PSA response rates were 63% (DN-101) and 52% (placebo), P = .07. Patients in the DN-101 group had a hazard ratio for death of 0.67 (P = .04) in a multivariate analysis that included baseline hemoglobin and performance status. Median survival has not been reached for the DN-101 arm and is estimated to be 24.5 months using the hazard ratio, compared with 16.4 months for placebo. Grade 3/4 adverse events occurred in 58% of DN-101 patients and in 70% of placebo-treated patients (P = .07). Most common grade 3/4 toxicities for DN-101 versus placebo were neutropenia (10% v 8%), fatigue (8% v 16%), infection (8% v 13%), and hyperglycemia (6% v 12%)., Conclusion: This study suggests that DN-101 treatment was associated with improved survival, but this will require confirmation because survival was not a primary end point. The addition of weekly DN-101 did not increase the toxicity of weekly docetaxel.

Purpose: To determine the dose-limiting toxicities and maximum tolerated dose, and evaluate the antitumor activity of bortezomib/docetaxel combination therapy in androgen-independent prostate cancer., Experimental Design: Two bortezomib doses (1.3 and 1.6 mg/m(2)/dose) in combination with four docetaxel doses (25-40 mg/m(2)/dose) were evaluated. Both drugs were administered weekly for 2 out of 3 weeks. Antitumor activity was evaluated using prostate-specific antigen (PSA) levels and Response Evaluation Criteria in Solid Tumors guidelines., Results: Eighty-three patients received at least one dose of study drug. No dose-limiting toxicities were observed despite escalation to the highest dose level. PSA response (>or=50% decline in PSA levels from the baseline) occurred in 19 (28%) of 67 evaluable patients and was maintained for >or=4 weeks in 14 patients (21%). According to Response Evaluation Criteria in Solid Tumors guidelines, 11% achieved a partial response, and an additional 67% had stable disease. The degree of proteasome inhibition was similar to that reported with single-agent bortezomib. Treatment was well tolerated; fatigue was the most common drug-related adverse event, whereas diarrhea was the most common drug-related grade 3/4 adverse event. No clinically significant febrile neutropenia or neuropathy occurred., Conclusions: The maximum tolerated dose of this 21-day regimen has not been reached. The highest dose level (1.6 mg/m(2) bortezomib plus 40 mg/m(2) docetaxel) was feasible and tolerable; bortezomib plus docetaxel showed antitumor activity. Activity and tolerability results were consistent with previous studies of bortezomib alone or in combination with docetaxel. Further investigations are warranted to determine activity and optimize bortezomib/docetaxel therapy in androgen-independent prostate cancers.

Background: Capecitabine is an orally administered fluoropyrimidine that is converted to 5-fluorouracil by thymidine phosphorylase. In view of the recognized synergism of fluoropyrimidines with interferon-alpha (IFNalpha), a Phase II study to characterize the toxicity and efficacy of the combination of capecitabine and rHuIFNalpha-2a for the treatment of patients with renal cell carcinoma (RCC) was conducted., Patients and Methods: Eligible patients had metastatic RCC, measurable disease, and no prior systemic therapy. A total of 32 patients were entered into the study. Histologic subtypes included clear cell (n = 28) and nonclear cell (n = 2). Histology was unknown for 2 patients. The first 14 patients were treated with capecitabine 1,000 mg/m(2) twice daily on days 1-14 and 22-36, combined with IFNalpha-2a 3.0 MU/m(2) subcutaneously 3 times weekly. Because of toxicity requiring dose reductions during the first cycle, the capecitabine dose was reduced to 825 mg/m(2) twice daily on days 1-14 and 22-36 in the subsequent 18 patients., Results: Responses were seen in 4 of 32 patients (12%) (95% confidence interval 4% to 29%), with 1 complete response and 3 partial responses. There were 3 responses that occurred at the higher capecitabine starting dose level. Median response duration was 12 months (range 4.6-15.0). There were 12 patients (38%) who had stable disease for at least 2 cycles (duration 2.9 to 33.6+ months). One-year survival was 63%. Toxicity was moderate to severe and required dose reductions in 88% of patients. There were 23 patients who had grade > or =3 toxicity., Conclusion: The combination of capecitabine and IFNalpha-2a has limited activity in metastatic RCC and is associated with moderate-to-severe toxicity.

Despite improvements in surgical techniques and outcomes, 5-year survival rates for patients with muscle-invasive bladder cancer remain suboptimal. Almost 50% of patients will eventually progress and develop systemic disease. Although various single agents have shown activity in patients with advanced or metastatic disease, randomized trials have demonstrated the utility of cisplatin-based combinations regimens. Despite relatively high objective response rates, the impact on survival in patients with advanced disease has been quite limited. Surgical resection in selected patients achieving significant objective response to cytotoxic therapy can contribute to long-term survival rates. The role of salvage therapy in advanced disease remains undefined. Evaluation of several active compounds has yielded unimpressive results with low objective response rates and overlapping CIs. Recognition that the maximum benefit from conventional cytotoxics has been achieved has led to the recent initiation of a number of clinical trials evaluating targeted agents in the management of advanced urothelial cancer.

Objectives: To perform a Phase II trial of docetaxel administered on a weekly schedule for 6 weeks before radical prostatectomy (RP) in patients with locally advanced prostate cancer., Methods: Treatment consisted of six doses of docetaxel 40 mg/m(2) intravenously administered weekly for 6 weeks followed by RP. Eligibility criteria included clinical Stage T2b, prostate-specific antigen (PSA) level 15 ng/mL or greater or Gleason sum 8 or greater, and no evidence of metastatic disease. The primary endpoint was feasibility and drug-related and surgical-related toxicities. Secondary endpoints included pre-RP PSA level, local response, pathologic outcomes, and time to PSA failure., Results: Twenty-nine patients were entered; 80% completed all 6 weeks of therapy and 97% underwent RP. The median PSA level was 12 ng/mL (range 2.5 to 43.3), the median Gleason sum was 8 (range 6 to 9), and all had Stage T2b or greater disease. A statistically significant reduction in the prechemotherapy versus postchemotherapy mean PSA level was observed (12.00 +/- 1.86 ng/mL versus 8.42 +/- 1.63 ng/mL, P <0.03), with 79% of patients experiencing some reduction and 24% a more than 50% reduction in PSA level in response to docetaxel alone. No unexpected toxicities and no intraoperative complications occurred. Pathologic analysis demonstrated residual carcinoma in all cases. Three patients (11%) had organ-confined disease, and 26 (93%) had achieved an undetectable PSA postoperatively. At a median follow-up of 23 months (range 1.5 to 36), 20 patients were disease free with no additional therapy., Conclusions: This trial establishes the baseline effect of short-course high-dose docetaxel alone on locally advanced prostate cancer. Additional study of this paradigm with other agents alone and in combination with docetaxel seems warranted.

Background: The regimens of carboplatin plus paclitaxel (CP) and methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC) were compared in patients with advanced urothelial carcinoma., Methods: Patients with metastatic urothelial carcinoma were randomized to receive either CP (paclitaxel at a dose of 225 mg/m(2) and carboplatin [targeted area under the concentration-time curve (AUC) of 6] given every 21 days) or the standard M-VAC dosage., Results: Eighty-five patients were randomized to the respective treatment regimens (41 to CP and 44 to M-VAC). Response rates and overall survival were similar for both treatment arms. Patients treated with CP had an overall response rate of 28.2% (95% binomial confidence interval, 15.0-44.9%) compared with an overall response rate of 35.9% for the M-VAC arm (95% binomial confidence interval, 21.2-52.8%) (P = 0.63, Fisher exact test). The median progression-free survival among patients who were treated with M-VAC was 8.7 months and was 5.2 months for patients receiving CP (P = 0.24, log-rank test). At a median follow-up of 32.5 months, the median survival for patients treated with M-VAC was 15.4 months versus 13.8 months for patients treated with CP (P = 0.65, log-rank test). Patients treated with M-VAC were found to have more severe worst-degree toxicities compared with patients treated with CP (P = 0.0001). There were no significant differences with regard to quality of life as assessed by the Functional Assessment of Cancer Therapy-Bladder (FACT-BL) instrument (P = 0.33)., Conclusions: Interpretation of the results of this study must be made with caution because the study failed to reach its accrual goal. Patients treated with CP had a median survival of 13.8 months compared with 15.4 months for patients treated with M-VAC. Patients treated with CP appeared in general to better tolerate their treatment; however, there were no significant differences noted with regard to measured quality of life parameters., (Copyright 2004 American Cancer Society.)

Background: Gemcitabine and docetaxel are active agents in advanced urothelial carcinoma. A Phase II trial of this combination was performed to determine the activity and toxicity of these agents in a multiinstitutional setting in patients previously treated with one prior chemotherapy regimen., Methods: Twenty-nine eligible patients with advanced urothelial carcinoma were treated with docetaxel at a dose of 40 mg/m(2) over 1 hour followed by gemcitabine, 800 mg/m(2), over 30 minutes, both intravenously (i.v.) on Days 1 and 8. Cycles were repeated every 21 days until disease progression or a maximum of 6 cycles., Results: Five patients obtained an objective response for an overall response rate of 17% (90% confidence interval, 7-33%). One patient achieved a complete clinical response. The median overall survival of the group was 7.7 months. Toxicity was moderate with granulocytopenia, anorexia, and fatigue being the most commonly noted side effects., Conclusions: Gemcitabine and docetaxel is an active second-line combination in patients with advanced urothelial carcinoma. Responses in visceral, lymph node, and soft tissues sites were observed. Granulocytopenia without fever, fatigue, and anorexia was common. Thromboembolic symptoms were reported and are of concern. The combination of gemcitabine and docetaxel has the potential to palliate a subset of previously treated patients with an adequate performance status., (Copyright 2003 American Cancer Society.)

Advanced transitional cell carcinoma of the urothelium is an aggressive malignancy characterized by a median survival period of less than 1 year. Although this disease is moderately chemotherapy-sensitive, to the authors' knowledge the impact of therapy reported to date on survival has been minimal. The authors presented an overview of the results from a series of clinical trials conducted over a 25-year period under the auspices of the Eastern Cooperative Oncology Group. They reviewed a series of antineoplastic agents identified by these studies with activity in advanced urothelial cancer and discussed current and future investigational goals and directions., (Copyright 2003 American Cancer Society)

Purpose: Combined biological therapy with 13-cis-retinoic acid (13-cRA) and interferon alpha-2a (IFN alpha-2a) was reported to be highly effective in squamous cell carcinoma of the cervix and skin. Squamous cell carcinoma of the penis is rare in the United States, accounting for less than 1/2% of all male malignancies. Because of the association of infection with human papillomavirus with both carcinomas of the cervix and penis and their shared squamous cell histology, we carried out a phase II study of 13-cRA and IFN alpha-2a in carcinoma of the penis., Materials and Methods: Eighteen ambulatory patients with surgically unresectable, recurrent, and/or metastatic squamous cell carcinoma of the penis were treated with IFN alpha-2a, 3MU/day administered subcutaneously and 13-cRA, 1 mg/kg orally daily for at least eight weeks, unless intolerable toxicity occurred., Results: One patient was ineligible; one patient withdrew prior to treatment. Among the 16 eligible, treated patients, there was one complete response. Fourteen patients had progressive disease as their only treatment effect. Two patients were unevaluable for tumor response because they had no follow-up tumor measurements. No unexpected treatment-related toxicities were found on study. The only common form of grade 3 toxicity was hypertriglyceridemia found in eight of the 17 patients (47%). No toxicities above grade 3 were observed., Conclusion: In contrast to its benefit in squamous cell carcinomas of the cervix and skin, the combination of 13-cRA and IFN alpha-2a has low efficacy in advanced carcinoma of the penis.

Background: Chemotherapy options for the patients with advanced urothelial carcinoma and renal dysfunction are limited. The authors performed a Phase II trial of paclitaxel plus carboplatin in patients with advanced carcinoma of the urothelium and renal dysfunction., Methods: Forty-two patients were accrued; 37 eligible patients were treated. Patients received paclitaxel 225 mg/m(2) over three hours followed by carboplatin targeted area under the concentration-time curve = 6 mg/mL. minute every three weeks for up to six cycles., Results: The median number of cycles received was four (range, one to six). The objective response rate was 24.3% (95% confidence interval, 11.9-41.7%). The median progression free survival was 3 months and the median overall survival was 7.1 months. The number of poor prognostic risk factors (Eastern Cooperative Oncology Group performance status > 1 or lung, liver, or bone metastases) significantly predicted for survival. The most common > or = 1 Grade 3 toxicities included granulocytopenia (60%) and neurotoxicity (35%)., Conclusions: Paclitaxel/carboplatin is a chemotherapy option for patients with advanced urothelial carcinoma and renal dysfunction. Future trials in chemotherapy development for this patient population are warranted., (Copyright 2002 American Cancer Society.)

ObjectiveTo bridge gaps in translational science and develop the concepts for 2 novel biomarker-driven clinical trials: one in the presurgical setting and the other in the setting of bladder preservation with chemoradiation.Methods and materialsThe National Cancer Institute sponsored a forum, "Novel Neoadjuvant Therapy for Bladder Cancer," which brought leading clinical and laboratory-based scientists together with the advocacy community.ResultsThe group designed a neoadjuvant clinical trial to compare the clinical efficacy of the two frontline chemotherapy regimens (gemcitabine plus cisplatin versus MVAC) and the ability of a gene expression profiling-based algorithm (CoXEN) to predict complete pathological response. The trial was recently opened under the leadership of the Southwest Oncology Group (SWOG, S1314), receiving support for the biomarker studies from the NCI's BISQFP resource. A second clinical trial was planned that will examine the relationship between expression of the DNA repair protein MRE11 and complete response in patients treated with concurrent 5-fluorouracil/mitomycin C plus radiation.ConclusionThe meeting provided a unique opportunity to launch a collective effort to establish molecular-based therapies for muscle-invasive urothelial cancer. The goal is to use this framework to develop comparable trials with immunotherapy in non-muscle invasive cancers and to exploit the neoadjuvant platform to develop targeted therapy in muscle-invasive disease.