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Objective: Our aim was to provide practical recommendations on the management of patients with metastatic castration-resistant prostate cancer (mCRPC) who have progressed after docetaxel plus androgen-deprivation therapy (ADT) or abiraterone plus ADT. Methods: Systematic literature review (SLR), nominal group meeting, and Delphi process. A panel of 12 experts was established who defined the scope, users, and sections of the document. We performed an SLR in order to assess the efficacy and safety of available drugs in patients with mCRPC. Abstracts from the American Society of Oncology and European Society for Medical Oncology meetings were also examined. The results were discussed during an expert meeting in which 14 recommendations were generated. The level of agreement with the recommendations was also tested by 13 additional experts following the Delphi process. Recommendations were voted by means of scores ranging from 0 (total disagreement) to 10 (total agreement). We defined agreement when at least 70% of the experts voted ⩾7. Next, we assigned a level of evidence and grade to the recommendation using the Oxford Centre for Evidence-based Medicine Levels of Evidence, following which the final document was drafted. Results: The literature search did not find any articles meeting the inclusion criteria. Finally, 13 out of 14 recommendations were accepted after two Delphi rounds (two were modified after the first round). They pertain to general and individual case-based treatment recommendations. Conclusions: In mCRPC patients who have progressed after docetaxel or abiraterone plus ADT in the metastatic hormone-sensitive prostate cancer setting, these recommendations may support treatment decision-making, due to the lack of evidence or other globally accepted sequencing algorithms.

The management of genitourinary cancer, including bladder, prostate, renal and testicular cancer, has evolved dramatically in recent years due to a better understanding of tumour genetic mutations, alterations in molecular pathways, and to the development of new kinds of drugs such as targeted therapies and immunotherapies. In the field of immunotherapy, new drugs focused on stimulating, enhancing and modulating the immune system to detect and destroy cancer, have been recently discovered. Research in oncology moves quickly and new data of great relevance for clinical practice are communicated every year. For this reason, a group of experts, focused exclusively on the treatment of genitourinary tumours and who get together every year in the BestGU conference to assess the latest progress in this field have summarized the most important advances in a single review, along with a critical assessment of whether these results should alter daily clinical practice.

Cabozantinib is an oral tyrosine kinase inhibitor (TKI) approved for the treatment of patients with advanced renal cell carcinoma (RCC) at a dose of 60 mg/day. As with other TKIs, cabozantinib is associated with high interpatient variability in drug clearance and exposure that can significantly impact safety and tolerability across a patient population. To optimize cabozantinib exposure (maintaining efficacy and tolerability) for the individual, patients may require treatment interruption with dose reduction (40 mg/day and then 20 mg/day). In the pivotal Phase 3 METEOR trial, cabozantinib significantly improved overall survival, progression-free survival and the objective response rate compared with everolimus in patients with advanced RCC who had received previous treatment with a VEGFR TKI. Dose reductions were common for patients receiving cabozantinib (60%) but effective as only 9% discontinued treatment due to adverse events (AEs). In this review, we discuss pharmacometric analyses that evaluated the impact of cabozantinib dose on efficacy and safety outcomes during the METEOR study. Exposure-response models demonstrate that the risk of experiencing adverse events and dose reduction is increased in patients with low cabozantinib clearance versus typical clearance and decreased in patients with high clearance. Dose reduction of cabozantinib to manage AEs is predicted to have minimal impact on efficacy as AEs are more likely to occur in patients with low clearance and higher exposure to cabozantinib. These analyses further support a dose modification strategy to optimize cabozantinib exposure for individual patients.

436 Background: Inhibition of the PD-1 pathway has demonstrated clinical benefit in metastatic urothelial carcinoma (mUC); however, response rates of 15% to 29% highlight the need for more effective therapies, especially for PD-L1- patients. Eganelisib is a first-in-class, novel, oral agent which selectively inhibits PI3K-γ, with the goal of improving the immune response to checkpoint inhibitors (CPI). Methods: Eligible patients (pts) with mUC who progressed on > 1 platinum-based chemotherapy regimen and were CPI naïve were enrolled. Pts were randomized 2:1 to receive eganelisib in combination with nivolumab (EN) or placebo with nivolumab (PN). Pts were stratified by baseline circulating monocytic myeloid derived suppressor cells (mMDSC) level. The primary endpoint was objective response rate (ORR) per RECIST v1.1 in pts with high baseline mMDSC levels. Other endpoints included ORR, progression free survival (PFS) and overall survival (OS) in all pts and PD-L1 +/- pts. Results: We report preliminary data (as of 9/1/2020) for the first 49 pts with 33 randomized to receive EN and 16 PN. Preliminary ORR/PFS is presented in the table below. Except for the mMDSC high subgroup, ORR and PFS were improved in the EN arm compared to the PN arm. The duration of exposure was a median of 15 weeks for EN and 11 for PN. Most common all-Gr AEs (EN vs PN %) were pyrexia (33 vs 0), decreased appetite (30 vs 19), pruritis (24 vs 6), rash (24 vs 6), asthenia (21 vs 31), and transaminase elevation (21 vs 6). Most common Gr≥3 AEs (EN vs PN %) include hepatotoxicity (15 vs 0), transaminase elevation (12 vs 6), and rash (9 vs 0). Following an early safety review, eganelisib dose was reduced from 40 to 30 mg, resulting in a reduction of hepatic AEs. Conclusions: Preliminary data demonstrates that the combination of eganelisib, once reduced to 30 mg, and nivolumab was well tolerated with hepatic and skin-related toxicities more common in the EN arm. When compared to PN, the combination demonstrated an improved ORR and PFS, especially in the PD-L1- subset. Updated efficacy, including PFS and OS, safety and translational data will be presented. Clinical trial information: NCT03980041 . [Table: see text]

5053 Background: Previous studies showed that men with HIV-associated germ cell cancer (HIV-GCC) have a similar cancer-free outcome compared with their HIV-negative counterparts. However, the overall survival (OS) was inferior and little data is available on treatment and outcome of HIV-GCC in the era of combined antiretroviral therapy (cART). Methods: Men living with HIV aged ≥ 18 years (yrs) with a diagnosis of histologically proven GCC made from 01/1996 to 07/2018 were included. Primary outcomes were OS and progression-free survival (PFS). Secondary outcomes included characteristics of GCC and HIV-infection, treatment and causes of death. Results: Data of 89 men from 23 institutions and 6 countries with a total of 92 HIV-GCC (2 synchronous and 1 metachronous bilateral GCC) were analysed, among them 64 (70%) seminomas and 28 (30%) nonseminomas. 10/89 (11%) cases were primary extragonadal GCC. Median age was 36 yrs (range, 22-52) and median time from HIV to GCC diagnosis was 5 yrs (range, 0-29). Median CD4 count at GCC diagnosis was 420 cells/µl (range, 3-1503) and 83% of pts were on cART. Stage I disease was found in 44/80 (55%) gonadal GCC (metachronous bilateral case included). Of 46 cases with stage II/III/extragonadal GCC 78%, 17% and 4% were assigned to the IGCCCG good, intermediate and poor prognosis group, respectively. Of the 44 stage I cases, 22 (50%) were followed by active surveillance, and 11 (25%) received adjuvant chemotherapy (CT) or radiotherapy. Relapses occurred in 14 pts (6 from stage I, 8 in pts primary disseminated GCC) and CT was applied to 13/14 pts, of which 3 received high-dose CT. Overall, 12/89 (13%) pts have died. Causes of death were refractory GCC (n = 5), an AIDS-defining illness (n = 3) and other (n = 4). After a median follow-up of 6.5 yrs (range, 0.3-20.9), the 5- and 10-year PFS rate was 81% and 73%, and the 5- and 10-year OS rate was 91% and 85%, respectively. There were no significant differences between the good and intermediate prognosis group or between pts with CD4 counts < 200/µl or ≥ 200/µl. Conclusions: The 5- and 10-year PFS and OS rates of men with HIV-GCC are similar to those reported for HIV-negative GCC. Pts with HIV-GCC should remain on cART and be managed in an identical fashion to HIV-negative pts.

5012 Background: Cisplatin-based neoadjuvant chemotherapy (CT) followed by radical cystectomy (RC) is a standard treatment for MIBC. PD-1/L1 inhibitors as single agent induce pathological complete responses (pCR) in this setting. Predictors of response are still ill defined. DUTRENEO trial aimed to prospectively explore the activity of anti-PDL1 + anti-CTLA4 vs CT in pts selected according to a tumor pro-inflammatory IFN-gamma signature (tumor immune score, TIS). Methods: Cisplatin-eligible pts with urothelial MIBC (cT2-T4a, N≤1, M0) candidates to RC were classified as “hot” or “cold” according to a tumor TIS determined by Nanostring technology. Patients with "hot" tumors were randomized to DU 1500 mg + TRE 75 mg every 4 weeks x 3 cycles or standard cisplatin-based CT (GEMCIS or MVACdd). Pts in the “cold” arm received standard CT. Primary endpoint was to achieve ≥8 pCR in the DU+TRE arm. PDL1 expression was assessed using immunohistochemistry. Results: 61 pts were recruited in 10 sites between oct-2018 and dec-2019. Pts randomized in the “hot” arms received standard CT (n = 22) or DU+TRE (n = 23) and had a pCR rate of 8/22 pts (36.4%) vs 8/23 pts (34.8%), respectively [OR = 0.923 (0.26 – 3.24)]. In the “cold” arm, 16 pts received CT obtaining a pCR rate of 68.8% (11/16 pts). There were more PDL1 low tumors in the "cold" TIS arm (10/12, 83.3%). pCR rate by PDL1 status is shown in the table. One pt in the DU+TRE arm refused RC. Full treatment was delivered to 81.3% of CT "cold" vs 59.1% of CT "hot" vs 73.9% in the DU+TRE arm pts. Grade 3-4 toxicities were more frequent in the CT arms. Conclusions: The combination of DU+TRE is safe and active in MIBC patients in the neoadjuvant setting. Nevertheless prospective stratification by a pro-inflammatory IFN-gamma signature failed to select patients more likely to benefit from IO vs CT in this context. Further studies are required to guide treatment selection. Clinical trial information: NCT03472274 . [Table: see text]

[Abstract] Background: A pivotal, randomized, phase III trial demonstrated a statistically significant superiority of sunitinib over interferon-α in metastatic renal cell carcinoma (mRCC) patients. Objective: To evaluate the effectiveness and safety of sunitinib in patients with advanced or mRCC in routine clinical practice. Methods: Retrospective pooled analysis of clinical data from three observational and prospective studies carried out between 2007 and 2011 in 33 Spanish hospitals. Tumor response, Progression-free survival (PFS) and overall survival (OS), and main sunitinib-related toxicities were registered. Results: 224 patients were analyzed. Median PFS 10.6 months (95% CI: 9.02–12.25), median OS 21.9 months (95% CI: 17.2–26.6). Objective response rate (ORR) 43.8% (95% CI: 36.8–50.7). Median time to PR was 3.8 months (95% CI: 3.86–5.99) and to CR 8.2 months (95% CI: 4.75–9.77). The most common ≥ grade-3 AEs were asthenia/fatigue (18.7%), hand-foot syndrome (6.2%), hypertension (5.8%) and neutropenia (4.8%). Hand-foot syndrome, diarrhea and mucositis were confirmed as independent predictors for PFS and/or OS in a multivariate analysis (p < 0.05) Conclusions: Outcomes with sunitinib in daily clinical practice resemble those obtained in clinical trials. Long-term benefit with sunitinib is possible in advanced RCC patients but the appropriate management of toxicities is mandatory to enable patients to remain on treatment.

Summary Background Currently, metastatic renal cell carcinoma is treated with sequential single agents targeting VEGF or mTOR. Here, we aimed to assess lenvatinib, everolimus, or their combination as second-line treatment in patients with metastatic renal cell carcinoma. Methods We did a randomised, phase 2, open-label, multicentre trial at 37 centres in five countries and enrolled patients with advanced or metastatic, clear-cell, renal cell carcinoma. We included patients who had received treatment with a VEGF-targeted therapy and progressed on or within 9 months of stopping that agent. Patients were randomised via an interactive voice response system in a 1:1:1 ratio to either lenvatinib (24 mg/day), everolimus (10 mg/day), or lenvatinib plus everolimus (18 mg/day and 5 mg/day, respectively) administered orally in continuous 28-day cycles until disease progression or unacceptable toxic effects. The randomisation procedure dynamically minimised imbalances between treatment groups for the stratification factors haemoglobin and corrected serum calcium. The primary objective was progression-free survival in the intention-to-treat population. This study is closed to enrolment but patients' treatment and follow-up is ongoing. This study is registered with ClinicalTrials.gov, number NCT01136733. Findings Between March 16, 2012, and June 19, 2013, 153 patients were randomly allocated to receive either the combination of lenvatinib plus everolimus (n=51), single-agent lenvatinib (n=52), or single-agent everolimus (n=50). Lenvatinib plus everolimus significantly prolonged progression-free survival compared with everolimus alone (median 14·6 months [95% CI 5·9–20·1] vs 5·5 months [3·5–7·1]; hazard ratio [HR] 0·40, 95% CI 0·24–0·68; p=0·0005), but not compared with lenvatinib alone (7·4 months [95% CI 5·6–10·2]; HR 0·66, 95% CI 0·30–1·10; p=0·12). Single-agent lenvatinib significantly prolonged progression-free survival compared with everolimus alone (HR 0·61, 95% CI 0·38–0·98; p=0·048). Grade 3 and 4 events occurred in fewer patients allocated single-agent everolimus (25 [50%]) compared with those assigned lenvatinib alone (41 [79%]) or lenvatinib plus everolimus (36 [71%]). The most common grade 3 or 4 treatment-emergent adverse event in patients allocated lenvatinib plus everolimus was diarrhoea (ten [20%]), in those assigned single-agent lenvatinib it was proteinuria (ten [19%]), and in those assigned single-agent everolimus it was anaemia (six [12%]). Two deaths were deemed related to study drug, one cerebral haemorrhage in the lenvatinib plus everolimus group and one myocardial infarction with single-agent lenvatinib. Interpretation Lenvatinib plus everolimus and lenvatinib alone resulted in a progression-free survival benefit for patients with metastatic renal cell carcinoma who have progressed after one previous VEGF-targeted therapy. Further study of lenvatinib is warranted in patients with metastatic renal cell carcinoma. Funding Eisai Inc.

[Abstract] Background: Several potential predictive markers of efficacy of targeted agents in patients with metastatic renal cell carcinoma (mRCC) have been identified. Interindividual heterogeneity warrants further investigation. Patients and methods: Multicenter, observational, retrospective study in patients with clear-cell mRCC treated with sunitinib. Patients were classified in two groups: long-term responders (LR) (progression-free survival (PFS)≥22 months and at least stable disease), and primary refractory (PR) (progressive disease within 3-months of sunitinib onset). Objectives were to compare baseline clinical factors in both populations and to correlate tumor expression of selected signaling pathways components with sunitinib PFS. Results: 123 patients were analyzed (97 LR, 26 PR). In the LR cohort, overall response rate was 79% and median duration of best response was 30 months. Median PFS and overall survival were 43.2 (95% confidence intervals[CI]:37.2-49.3) and 63.5 months (95%CI:55.1-71.9), respectively. At baseline PR patients had a significantly lower proportion of nephrectomies, higher lactate dehydrogenase and platelets levels, lower hemoglobin, shorter time to and higher presence of metastases, and increased Fuhrman grade. Higher levels of HEYL, HEY and HES1 were observed in LR, although only HEYL discriminated populations significantly (AUC[ROC]=0.704; cut-off=34.85). Increased levels of hsa-miR-27b, hsa-miR-23b and hsa-miR-628-5p were also associated with prolonged survival. No statistical significant associations between hsa-miR-23b or hsa-miR-27b and the expression of c-Met were found. Conclusions: Certain mRCC patients treated with sunitinib achieve extremely long-term responses. Favorable baseline hematology values and longer time to metastasis may predict longer PFS. HEYL, hsa-miR-27b, hsa-miR-23b and hsa-miR-628-5p could be potentially used as biomarkers of sunitinib response. PPfizer; SOGUG-2011-05 Ministerio de Economía, Industria y Competitividad; SAF2015-66015-R Ministerio de Economía, Industria y Competitividad; ISCIII-RETIC RD12/0036/0009 Ministerio de Economía, Industria y Competitividad; PIE 15/00076

This exploratory phase II clinical trial evaluated the antitumor activity, safety profile and pharmacokinetics of PM00104 (Zalypsis®) 3 mg/m2 1 h every 3-week intravenous infusion in patients with advanced and/or metastatic urothelial carcinoma progressing after first-line platinum-based chemotherapy. The primary efficacy end point was the disease control rate (DCR), defined as the percentage of patients with confirmed objective response or progression-free at 3 months, according to the response evaluation criteria in solid tumors. In a first stage (n = 19 patients evaluable for efficacy), only one patient achieved DCR (stable disease as best response and progression-free survival of 3.1 months). According to the 2-stage design used, the primary efficacy objective was unmet, and therefore, the trial was finalized without opening the second stage. The most common adverse events related to PM00104 were fatigue, anorexia, nausea, troponin I increase and neutropenia, which were transient and manageable with dose modifications or administration delays. Mean PK results (C max = 48.57 μg/l and area under the curve (AUC) = 154.97 h μg/l) were similar to those observed in a previous phase I trial evaluating the same dose and schedule. Few troponin I concentrations were higher than 0.10 ng/ml, and none of them were related to parameters of PM00104 exposure such as AUC or C max. No recommendation is given for further evaluation of PM00104 as single-agent treatment of patients with pretreated advanced and/or metastatic urothelial carcinoma. No new safety signals were observed.

Immunotherapy (IL-2 and INF-alpha) was the treatment of choice for advanced renal cell carcinoma (RCC) until antiangiogenic therapy with tyrosin kinase inhibitors was developed in the early 2000s. This clinical trial explored the efficacy and toxicity of sequential treatment of IL-2 plus INF-alpha followed by sorafenib. Eligibility criteria included measurable, non-resectable, histologically confirmed predominantly clear cell RCC, no prior systemic treatment, and ECOG PS 0-2. The treatment regimen was a 6-week cycle of subcutaneous IL-2 at 9 x 10(6) IU on days 1-6 of weeks 1, 2, 4 and 5 plus s.c. INF-alpha at 6 x 10(6) IU on days 1, 3 and 5 of weeks 1-6. Responders received 6 additional weeks of this regimen. All patients received oral sorafenib (400 mg bid) after immunotherapy until disease progression. The primary endpoint was progression-free survival. Forty-one patients were enrolled, median age 57 years. ECOG was 0/1 in 17/20 patients, 35 patients had prior nephrectomy and 18 patients pure clear cell cancer. Median PFS was 7.4 months (95 % CI 6.5-13.1) and OS was 16.6 months (95 % CI not reached). In 36 patients evaluable for response, ORR was 44.4 % and control rate was 94.4 %. Most adverse events (AEs) were Grade 1 or 2 toxicities (84.7 %). During immunotherapy the most common AEs were pyrexia (82.9 %), asthenia (56.1 %) and anorexia (46.3 %), whereas during sorafenib were diarrhoea (48.8 %) and hand-foot syndrome (46.3 %). A sequential regimen of IL-2 and INF-alpha followed by sorafenib showed effectiveness and manageable toxicity in patients with advanced RCC.

Context Controversies and uncertainties among integral management of advanced castration resistant prostate cancer continue to exist despite the number of evidence based clinical practice guidelines published with high international consensus. Objective To develop a document that reviews the management of controversies in advanced castration resistant prostate cancer, with recommendations from the definition, to the management in hormonal maneuvers, first-line treatment and second-line with new treatments as cabazitaxel or abirarerone and the multidisciplinary approach of the pathology with the goal of finding the most efficient, best time to act and safety. Evidence Acquisition Two meetings of a multidisciplinary group of experts involved in the management of this disease (oncologist and urologist) where pooled analysis of original literature and reached consensus document of recommendations on castration resistant prostate cancer, reviewing and attempting to address the current controversies of the disease. Evidence Synthesis This document is endorsed by the corresponding Scientific Associations and Working Groups involved in the current management of Genitourinary Tumours: the Spanish Association of Urology (AEU) with the Uro-Oncoloy Group (GUO) and the Spanish Oncology of Genitourinary Group (SOGUG). Conclusions With the adaptation and implementation of this Document of Recommendations for clinical practice are available for the first time, a real road map for quality, efficiency and safety in the management of patients with CRPC.

Resumen Contexto En el manejo integral del cancer de prostata avanzado resistente a la castracion siguen existiendo incertidumbres y controversias, a pesar de la existencia de numerosas guias de practica clinica basadas en la evidencia, internacionalmente consensuadas. Objetivo Elaborar un documento en el que se revise el manejo de controversias en el cancer de prostata avanzado resistente a la castracion, con recomendaciones desde su definicion hasta el manejo de maniobras hormonales y el tratamiento de primera y segunda linea con nuevos farmacos como cabazitaxel y abiraterona, asi como el abordaje multidisciplinario de la patologia con el objetivo de buscar la alternativa mas eficiente, el mejor momento de actuar y la mayor seguridad. Adquisicion de la evidencia Se realizaron 2 reuniones de un grupo de expertos multidisciplinarios implicados en el manejo de esta enfermedad (urologos y oncologos) donde se pusieron en comun el analisis bibliografico de articulos originales y se consensuo este documento de recomendaciones sobre el cancer de prostata resistente a la castracion, revisando e intentando dar respuesta a las actuales controversias de la enfermedad. Sintesis de la evidencia Este documento esta avalado por las principales sociedades cientificas y grupos de trabajo implicados en el manejo actual de los tumores genitourinarios: la Asociacion Espanola de Urologia (AEU), el Grupo de Urologia Oncologica (GUO) y el Grupo Espanol de Oncologia Genitourinaria (SOGUG). Conclusiones Con la adaptacion e implementacion de este documento de recomendaciones a la practica clinica se dispone, por primera vez, de una verdadera hoja de ruta de calidad, eficiencia y seguridad del manejo de los pacientes con cancer de prostata avanzado resistente a la castracion.

The approval and use of molecular targeted agents for the first-line treatment of metastatic renal cell carcinoma (mRCC) has substantially improved the clinical outcome of patients. Although eventually all patients progress, hopes have been renewed with the approval of everolimus for patients who progress on or after treatment with tyrosine kinase inhibitors. In order to improve the prognosis for these patients, it is imperative to understand the reasons why patients with mRCC fail on first-line treatment. Currently, progression is assessed on the basis of the Response Evaluation Criteria in Solid Tumors, but it is known that targeted agents tend to cause disease stabilization rather than a significant decrease in tumor mass. Therefore, it may be time to evaluate the need to incorporate additional diagnostic methods in the assessment of disease response. Equally important is the study of the factors that determine the success or failure of second-line therapy in order to increase the chances of delivering the most effective and personalized therapy possible. In this article, we review the evidence related to the evaluation of patients with mRCC who fail on first-line treatment with targeted agents, including the systems to assess response and progression, the prognostic factors, the prognostic models that have been created based on these factors, and what is known about predictive biomarkers of disease outcome.

Metastatic renal cell carcinoma is resistant to conventional treatment with chemotherapy. Recently the use of molecular-targeted therapies with multikinase inhibitors has been recommended as first-choice therapy because they inhibit cell proliferation and tumour angiogenesis. Sorafenib is a well tolerated tyrosine kinase inhibitor that initially demonstrated efficacy in the treatment of patients with metastatic RCC who progressed after immunotherapy. Expanded-access studies in Europe and North America showed the safety and efficacy of sorafenib in special populations such as elderly, renal failure and cerebral metastases, as well as patients with no prior therapy. No cross-resistance has been suggested in non-randomized trials when used in second line treatment after other targeted therapies. Ongoing clinical trials will better define the role of sorafenib in first and second line either as monotherapy or in combination, as well as the best strategies for the sequential use of this drug.

Purpose Pneumonitis has occurred in patients treated with inhibitors of the mammalian target of rapamycin (mTOR). In a phase III study of patients with previously untreated, poor-prognosis, advanced renal cell carcinoma (ARCC), the mTOR inhibitor temsirolimus improved survival compared with interferon. We performed a retrospective, independent, blinded radiographic review of chest computed tomography (CT) images of patients in this study to characterize temsirolimus-related pneumonitis. Patients and Methods Patients were treated with intravenous temsirolimus 25 mg once weekly or subcutaneous interferon alfa 3 million units, with an increase to 18 million units, thrice weekly. Drug-related pneumonitis was identified based on sequential chest CT images, required every 8 weeks, showing changes consistent with pneumonitis and not pneumonia (infection) or disease progression as correlated with clinical data. Cumulative probability of drug-related pneumonitis was estimated using the Kaplan-Meier method. Results Eight (6%) of 138 and 52 (29%) of 178 evaluable patients on interferon and temsirolimus treatment, respectively, developed radiographically identified drug-related pneumonitis. Time to onset of pneumonitis was significantly shorter on the temsirolimus arm than on the interferon arm (log-rank P < .001). Estimated cumulative probability of pneumonitis at 8 and 16 weeks from first dose was 21% and 31%, respectively, on the temsirolimus arm and 6% and 8%, respectively, on the interferon arm. Respiratory symptoms were observed around time of onset of radiographically diagnosed temsirolimus-related pneumonitis in 16 (31%) of 52 patients. Conclusion Patients with ARCC receiving temsirolimus should be monitored closely for development of pneumonitis, and their management should be altered if clinical symptoms appear.

Brain metastases of testicular germ cell tumor (TGCT) are a rare event. Prognostic is poor and there is not much evidence on optimal management of these patients. A review of case records of germ cell tumor patients within the Spanish Germ Cell Cancer Group data base from 1994 to 2012 was conducted. Thirty-three out of 6,200 cases (0.5 %). Nineteen patients (57 %) group 1: synchronous, 13 (40 %) group 2: metachronous and only one developed brain metastasis during cisplatin-based chemotherapy (excluded from the analysis). Median serum BHCG levels at initial diagnosis was higher in group 1, whereas elevated AFP serum levels were more common in group 2. Histology in the primary tumor: chorionic carcinoma for group 1 versus embryonal carcinoma for group 2. Mainly solitary brain metastasis in group 2 (54 versus 21 %, respectively). The median overall survival from the diagnosis of central nervous system involvement was 16 months for group 1 (CI 95 % 13.9-18) and 23 months (95 % CI 0-165) for group 2 (log rank p = 0.84). Long-term survivors were practically identical in the two groups (38.9 % group 1 versus 38.5 % group 2). Regardless of the timing of brain metastasis, those patients that achieved complete response to the treatment had better survival (log rank p 0.003). Although some distinctive clinical characteristics have been found between patients with synchronous versus metachronous brain metastasis from TGCT, the timing of brain metastasis did not seem to have prognostic influence, but due to the retrospective nature of the analysis and the results should be interpreted with caution.

Background: Biomarkers for metastatic castration-resistant prostatic cancer (mCRPC) are an unmet medical need. Methods: The prognostic and predictive value for survival and response to salvage hormonal therapy (SHT) of baseline testosterone level (TL) was analysed in a cohort of 101 mCRPC patients participating in 9 non-hormonal first-line chemotherapy phase II-III trials. Inclusion criteria in all trials required a TL of < 50 ng dl(-1). Results: Median age: 70 years; visceral metastases: 19.8%; median prostate-specific antigen (PSA): 50.7 ng ml(-1); median TL: 11.5 ng dl(-1). Median overall survival (OS; 24.5 months) was significantly longer if baseline TL was above (High TL; n=52) than under (Low TL; n=49) the TL median value (32.7 vs 22.4 months, respectively; P=0.0162, hazard ratio (HR) =0.6). The presence of anaemia was an unfavourable prognostic factor (median OS: 20.6 vs 28.4 months; P=0.0025, HR=1.88 (CI95%: 1.01-3.48)). Patients presenting both anaemia and low testosterone had a worse outcome compared to those with one or none of them (median OS: 17.9 vs 22.4 vs 38.1 months; P=0.0024). High vs Low TL was associated with PSA response rate (55.6% vs 21.7%) in 41 patients receiving SHT. Conclusion: Testosterone level under castration range was a prognostic factor for survival mCRPC patients. The PSA response to SHT differed depending on TLs. Testosterone levels might help in treatment decision.

The term castration-resistant prostate cancer (CRPC) encompasses a wide variety of patients with different prognoses. The combination of docetaxel and prednisone is considered as the standard first-line chemotherapy. For years, patients progressing on docetaxel have been managed with second- and third-line hormone therapies, re-treatment with docetaxel, or combined mitoxantrone and prednisone. Recently published results of four studies using different drugs: cabazitaxel (CBZ), abiraterone (AA), enzalutamide (ENZ), and radium 223, showed an increased survival in such patients. In this article, authors make some considerations about criteria guiding the choice of a second-line chemotherapy after docetaxel in patients with metastatic CRPC, and propose an algorithm based on scientific evidence and consensus for rational use of cabazitaxel in this scenario.

Controversies and uncertainties among integral management of advanced castration resistant prostate cancer continue to exist despite the number of evidence based clinical practice guidelines published with high international consensus.To develop a document that reviews the management of controversies in advanced castration resistant prostate cancer, with recommendations from the definition, to the management in hormonal maneuvers, first-line treatment and second-line with new treatments as cabazitaxel or abirarerone and the multidisciplinary approach of the pathology with the goal of finding the most efficient, best time to act and safety.Two meetings of a multidisciplinary group of experts involved in the management of this disease (Oncologist and Urologist) where pooled analysis of original literature and reached consensus document of recommendations on castration resistant prostate cancer, reviewing and attempting to address the current controversies of the disease.This document is endorsed by the corresponding Scientific Associations and Working Groups involved in the current management of Genitourinary Tumours: the Spanish Association of Urology (AEU) with the Uro-Oncoloy Group (GUO) and the Spanish Oncology of Genitourinary Group (SOGUG).With the adaptation and implementation of this Document of Recommendations for clinical practice are available for the first time, a real road map for quality, efficiency and safety in the management of patients with CRPC.

Background Treatment options remain limited for patients with castration-resistant prostate cancer (CRPC). We evaluated eribulin mesylate (E7389), a nontaxane halichondrin B analog microtubule inhibitor, in patients with metastatic CRPC with or without previous taxane exposure. Patients and methods Men with histologically proven CRPC, with or without prior taxane exposure, were enrolled in an open-label, single-arm phase II trial. Patients received eribulin mesylate 1.4 mg/m2 as a 2- to 5-min i.v. bolus infusion on days 1 and 8 of a 21-day cycle. The primary efficacy end point was prostate-specific antigen (PSA) response rate. Results In total, 108 patients were assessable for safety (50 were taxane-pretreated) and 105 for efficacy in the per-protocol population. The median age of patients was 71 years and median number of cycles was 4. PSA decreases of ≥50% were achieved in 22.4% and 8.5% of taxane-naive and taxane-pretreated patients, respectively. The most common grade 3/4 adverse event was neutropenia, seen in 22.4% of chemo-naive and 40% of taxane-pretreated men. Grade 3 peripheral neuropathy occurred in none of the taxane-naive patients and 6.0% of taxane-pretreated patients. Conclusion Eribulin mesylate demonstrated activity and a relatively favorable toxicity profile in metastatic CRPC.

The field of urothelial carcinoma has shown considerable advances in terms of diagnosis, staging, and treatment. The increasing knowledge of molecular pathways and genes involved in the occurrence of this tumor has encouraged the search for new, more effective and less toxic therapies, and has prompted the design and development of clinical trials. However, the speed at which results are published makes it difficult for clinicians to cover the vast amount of information available. Moreover, in clinical practice some gaps remain concerning treatment options for patients who have progressed after first-line cisplatin-based combinations, who cannot tolerate cisplatin-based chemotherapy, or who have received platinum-based neoadjuvant or adjuvant therapy, and thus cannot be offered this option on disease progression. The purpose of this review is to issue a series of recommendations on the optimal management of early and advanced urothelial carcinoma based on current evidence and the available updated guidelines.

Gerald HJ Mickisch1, Björn Schwander2, Bernard Escudier3, Joaquim Bellmunt4, José P Maroto5, Camillo Porta6, Stefan Walzer7, Uwe Siebert8,91Department of Urology, Center of Operative Urology Bremen, Bremen, Germany; 2Department of Outcomes Research, AiM GmbH Assessment-in-Medicine, Lörrach, Germany; 3Immunotherapy Unit, Institut Gustave Roussy, Villejuif, France; 4Department of Medical Oncology, University Hospital del Mar UPF, Barcelona, Spain; 5Department of Medical Oncology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; 6Department of Medical Oncology, IRCCS San Matteo University Hospital Foundation, Pavia, Italy; 7Global Health Economics, F Hoffmann-La Roche Pharmaceuticals AG, Basel, Switzerland; 8Department of Public Health, Medical Decision Making and Health Technology Assessment, UMIT - University for Health Sciences, Medical Informatics and Technology, Hall i.T., Austria; 9Department of Health Policy and Management, Harvard School of Public Health, Boston, MA, USABackground: The vascular endothelial growth factor inhibitor bevacizumab (BEV) given in combination with interferon-α-2a (IFN), and the tyrosine kinase inhibitors (TKIs) sunitinib (SUN) and pazopanib (PAZ), have all shown significant increase in progression-free survival (PFS) in first-line metastatic renal-cell carcinoma (mRCC) therapy. These targeted therapies are currently competing to be primary choice; hence, in the absence of direct head-to-head comparison, there is a need for valid indirect comparison assessment.Methods: Standard indirect comparison methods were applied to independent review PFS data of the pivotal Phase III trials, to determine indirect treatment comparison hazard-ratios (HR) with 95% confidence intervals (95% CI). As BEV+IFN and SUN have been compared to IFN, indirect comparison was enabled by the common IFN comparator arms. As PAZ was compared to placebo (PLA), a connector trial (IFN vs PLA) was required for the indirect comparison to BEV+IFN. Sensitivity analyses taking into account real-life influence of patient compliance on clinical outcomes were performed.Results: The indirect efficacy comparison resulted in a statistically nonsignificant PFS difference of BEV+IFN vs SUN (HR: 1.06; 95% CI: 0.78–1.45; P = 0.73) and of BEV+IFN vs PAZ (range based on different connector trials; HR: 0.74–1.03; P = 0.34–0.92). Simulating real-life patient compliance and its effectiveness impact showed an increased tendency towards BEV+IFN without reaching statistical significance.Conclusions: There is no statistically significant PFS difference between BEV+IFN and TKIs in first-line mRCC. These findings imply that additional treatment decision criteria such as tolerability and therapy sequencing need to be considered to guide treatment decisions.Keywords: indirect treatment comparison, progression-free survival, renal cell carcinoma, bevacizumab, sunitinib, pazopanib

4550 Background: Pemetrexed (P) plus cisplatin (C) combination is effective against several malignant tumors. Single-agent P has shown antitumor activity in advanced urothelial cancer; we performed a phase I/II study to define the maximum tolerated dose of biweekly P plus C combination. Here, we report the final results of the phase II study. Methods: Eligible patients (pts) had locally advanced or metastatic transitional cell carcinoma of the urothelium not suitable for curative therapy, performance status (PS) 0-2, estimated life expectancy of at least 12 weeks, and adequate organ function. P and C were administered on days 1 and 15 of each 28-day cycle, up to a maximum of 6 cycles. Pts received the recommended dose from phase I, with P at 400 mg/m2 plus C at 50 mg/m2 (folic acid and vitamin B12 supplementation were also administered). Primary objective was overall response rate (ORR) according to RECIST 1.0. Results: Thirty-eight pts were recruited, 32 (84.2%) pts had bladder cancer with a mean diagnosis time of 1 (range 0-7) year and 30 (78.9%) had metastatic disease; 19 (50%) pts had visceral metastasis and 2 (5.3%) pts had a PS 2. Only 2 pts did receive adjuvant systemic therapy. Median number of cycles was 3 (range 0-7). Twelve (31.6%) pts discontinued the study treatment due to toxicity. The most common treatment-related AEs (> 20%) were asthenia (n=27 pts), nausea and vomiting (n=21, respectively), diarrhea (n=18), anorexia (n=17), mucosal inflammation (n=14), and constipation (n=8). Most treatment-related AEs were of mild or moderate severity. Neutropenia (n=5) and asthenia (n=3) were the most frequent Grade 3 or 4 treatment-related AEs. Serious related AEs were observed in 8 (21.1%) pts. ORR was 39.5% (95% CI 24.0-56.6): 2 (5.3%) pts achieved complete response and 13 (34.2%) pts, partial response. Median progression free survival was 6.7 months, and median overall survival was 10.5 months. Conclusions: In this study, biweekly P (400 mg/m2) plus C (50 mg/m2) combination showed anti-tumor activity in pts with advanced urothelial cancer, with an acceptable safety profile. Clinical trial information: NCT00374868.

4560 Background: Metastases of testicular germ cell tumors (TGCT) to brain are a rare event. Prognostic is poor and there is little evidence on optimal management of these patients. Methods: A retrospective review of case records of germ cell tumor patients within the Spanish Germ Cell Cancer Group from 1994 to 2012 was conducted. Results: Thirty-tree cases of testicular germ cell tumors from 17 institutions were reported. Nineteen patients (57%) presented with brain metastases at primary diagnosis (group 1: synchronous), thirteen (40%) developed brain metastases at relapse (group 2: metachronous) and only one patient developed brain metastasis during cisplatin based-chemotherapy (3%) (excluded from the analysis). Main demographics and comparison between series are shown on table. Median serum BHCG levels at initial diagnosis were higher in group 1(279.083 versus 175.873), whereas those of AFP were higher in group 2(1320 versus 4181). The most common histology in the primary tumor was choriocarcinoma for group; versus embryonal carcinoma for group 2. Patients had neurological symptoms at diagnosis of brain metastases (63% synchronic/93% metachronus). Performance status was also poor (PS 2-3: 52,6%group 1-62,2% group 2). Four patients (21%) in group 1 had a solitary brain lesion vs seven (54%) on group 2. Median time since last dose of cisplatin to development of brain metastases on group 2 was 6 months (3-22).Median overall survival was 16 months (95% CI 5,3-26,6): group 1: 16 (95% CI 13,9-18);23 group 2 (95% CI 0-165). We have not found significant differences in survival between both groups. Overall 37,5% of patients achieved long-term survival (38,9% in group 1 versus 38,5% in group 2). Patients achieving complete response of brain metastases had a better survival (log rank p:0,003). Conclusions: Long term survival can be achieved in approximately 1/3 of patients with brain metastases. Chemotherapy remains the cornerstone of treatment. Selection bias because of the retrospective nature of review should make us be careful with the conclusions.

Background Study results demonstrated that IFN augments BEV activity and improves median PFS in pts with mRCC. Thus, combination BEV + IFN is a standard first-line treatment option for mRCC. Combining BEV with the mTOR inhibitor EVE may be an efficacious and well-tolerated treatment option. The open-label, phase II RECORD-2 trial compared first-line EVE + BEV and IFN + BEV in mRCC. Patients and methods: Therapy-naive pts with clear cell mRCC and prior nephrectomy were randomized 1:1 to BEV 10 mg/kg IV every 2 weeks with either EVE 10 mg oral daily or IFN (9 MIU SC 3 times/week, if tolerated). Tumour assessments were every 12 weeks. Primary objective was treatment effect on progression-free survival (PFS) per central review based on an estimate of the chance of a subsequent phase III trial success (50% threshold for phase II success). Results In EVE + BEV (n = 182) and IFN + BEV (n = 183) arms, median age was 60/60 years, 76/72% of pts were men, MSKCC risk was favourable/intermediate/poor in 36/57/7% and 36/57/7% of pts, and 43/46% of pts had >2 organs involved, respectively. For EVE + BEV and IFN + BEV, median treatment duration was 8.5/8.3 months, respectively; 23/26% of pts discontinued due to AEs. In EVE + BEV and IFN + BEV arms, median PFS by central review was 9.3/10.0 months (HRIFN/EVE, 0.91; 95% CI, 0.69-1.19; P =0.485), respectively; probability of subsequent phase III success was 5.1%. Results of central and local PFS analysis were consistent. Objective response rate was 27/28% in EVE + BEV and IFN + BEV arms, respectively. Median overall survival (OS) was not reached in the EVE + BEV arm and was 25.9 months (95% CI: 21.1, 30.2) in the IFN + BEV arm. Most frequent AEs (%) were stomatitis (63), proteinuria (49), diarrhoea (39), hypertension (38), and epistaxis (35) in EVE + BEV arm and decreased appetite (45), fatigue (41), proteinuria (37), and pyrexia (35) in IFN + BEV arm. Conclusions In RECORD-2, PFS and tolerability were similar for first-line EVE + BEV and IFN + BEV. Final OS analysis will occur after 2-year follow-up. Disclosure A. Ravaud: Alain Ravaud is a member of global, European, and/or French boards on urological tumors for Pfizer, Novartis, GlaxoSmithKline, Bayer-Schering, and Dendreon, and has received institutional grant support from Pfizer, Novartis, and Roche. O. Anak: Ozlem Anak is an employee of Novartis Pharma AG. D. Pelov: Diana Pelov is an employee of Novartis Pharmaceuticals Corporation. A. Louveau: Anne-Laure Louveau is an employee of Novartis Pharma S.A.S. T. M-H: Tay M-H is a speaker for an advisory board for Novartis Pharmaceuticals Corporation. B. Melichar: Bohuslav Melichar has received honoraria from Novartis and Roche and served on an advisory board for Roche. All other authors have declared no conflicts of interest.

Background Treatment options for patients with papillary renal cell carcinoma (RCC) are limited. Everolimus, a mammalian target of rapamycin (mTOR) inhibitor, has demonstrated efficacy in clear cell metastatic RCC; mTOR signaling is also dysregulated in papillary RCC. The ongoing RAPTOR (RAD001 in Advanced Papillary Tumor Program in Europe; ClinicalTrials.gov, NCT00688753) trial is evaluating everolimus monotherapy in treatment-naive patients with advanced papillary RCC. Here, we present the results of a preliminary analysis. Patients and methods RAPTOR is an open-label, single-arm, multicentre phase II trial. Adult patients with advanced type I or type II papillary RCC and ECOG performance status of 0 or 1 were enrolled. Prior systemic therapy for RCC was not permitted. Patients received oral everolimus 10 mg once daily until disease progression or unacceptable toxicity. The primary end point is proportion of patients progression free at 6 months. Results At data cut-off (April 11, 2012), 71 of 92 (77%) enrolled patients were eligible for analysis according to central pathology review (confirmed papillary renal cancer); 16 of the 92 patients were still on treatment. Most patients were men (73%) and most were Conclusions Results of this interim analysis have demonstrated that everolimus provides clinical benefit to patients with advanced papillary RCC. These results support the further evaluation of everolimus as a first-line treatment option for patients with advanced papillary RCC. Disclosure B. Escudier: Bernard Escudier has served as a consultant to and received honoraria from Bayer, Pfizer, Roche, Novartis, GlaxoSmithKline, and Aveo. S. Bracarda: Sergio Bracarda has served as an advisory board member to Pfizer, GlaxoSmithKline, Novartis, and Bayer, and has received honoraria from Pfizer and Novartis. K. Slimane: Khemaies Slimane is an employee of Novartis Pharma S.A.S. C. May: Christoph May is an employee of Novartis Pharma GmbH. C. Porta: Camillo Porta served as consultant/speaker for Novartis, Pfizer, GSK, Hoffman La Roche, Bayer-Schering, Aveo Pharmaceuticals, Astellas, Boehringer Ingellheim, and Recordati and received research grants from Novartis and Bayer-Schering. V. Grunwald: Viktor Grunwald served as consultant to Roche, Bayer, Novartis, Pfizer, GlaxoSmithKline, and Aveo/Astellas, received honoraria from GlaxoSmithKline, Novartis, and Pfizer, and received research funding from Pfizer and GlaxoSmithKline. All other authors have declared no conflicts of interest.

e15159 Background: To analyze the prognostic value for survival of the absolute levels of serum testosterone in patients under the definition of CRPC (PSA and/or clinical progression with a testosterone level below 50 ng/dL). Methods: 49 patients were included in 4 non-hormonal first line phase II-III trials in our institution since August 2006 until Jan 2012 for metastatic CRPC. Inclusion criteria of those trials uniformly required castrate levels of testosterone. Survival was calculated since the date of entrance in the trial. Results: Median age was 71 years (53-89). 9/49 (18%) of the patients had visceral metastases. Median PSA was 66.7 U/L (0.1-936). Median testosterone level was 11.54 ng/dL (range 0.2-49.9). All patients had metastatic prostate cancer, previous treatment consisted of at least 2 hormonal maneuvers (adding or stopping antiandrogen for a wash-up period of 42 days for bicalutamide). All patients received at least one line of chemotherapy for CRPC as part of the trial or after the completion of the trial. Median survival was 21.85 months. For 26 patients with a serum testosterone level below the median value, median survival was 17 months and 35.45 months for those patients with a testosterone level over 11.51 ng/dL (p value 0.036). Conclusions: Testosterone serum levels even under castration level (below 50 ng/dL) were a prognostic factor for survival in patients with metastatic prostate cancer considered castration resistant.

e15001 Background: Platinum-based chemotherapy (CT) is beneficial as first-line treatment of advanced UC. However, the majority of patients develop recurrent disease with poor long-term survival rates. Attempts to improve second-line treatments have evaluated single agents and multi-drug combinations, neither of which has managed to improve survival or achieve durable responses. Z is a cytotoxic agent that induces apoptosis by acting at cell cycle level, has DNA-binding properties and inhibits transcriptional responses. Z has shown anti-tumor activity in vitro and in vivo in xenograft models. Based on the activity observed in a phase I study (1PR and 2 SD) in advanced bladder cancer, we have designed a phase II study to explore the efficacy of Z in this setting. Methods: Patients with histologically-confirmed advanced or metastatic UC, who had failed one prior line of platinum-based CT, with proven progression or relapse before study entry, were included. Patients were treated with a Z intravenous infusion of 3 mg/m2 over 1-hour and every 3 weeks. A two-stage design was chosen; at least four (of 17) evaluable patients had to reach the primary endpoint during the first stage in order to progress into a second stage of up to 37 patients. The primary endpoint was tumor control rate (TCR): percentage of patients with objective response (OR) of any duration or patients alive and progression-free (PFS) at three months. Results: Twenty patients of a median age of 71 years (r: 54-83) were enrolled after a median of one prior treatment line (r:1-2). One patient was considered non-evaluable. No ORs were observed and only one patient had PFS ≥ 3 months. The median time on treatment was 1.68 months (r: 0.76-4.21). Toxicity consisted mostly of grade 1-2 fatigue, anorexia and nausea. Five patients had isolated troponin I increases (with no ECG or LVEF findings). Hematological toxicity was mild, one patient had grade 3 neutropenia and one patient had grade 3 thrombocytopenia. Conclusions: Only one patient reached the primary endpoint (TCR) during the first stage; consequently, the study was closed and no further development was considered.

273 Background: Eribulin mesylate (E) is a synthetic analog of the natural, marine-sponge product halichondrin B. A phase (Ph) II study of E monotherapy in urothelial carcinoma with no prior cytotoxic therapy for advanced disease reported an overall response rate of 38% (95% CI: 23%, 54%; Quinn et al ASCO 2010, abstract 4539). Therefore, we combined E with gemcitabine (G) and cisplatin (C) to assess the feasibility, safety, and preliminary activity of the combination, in patients (pts) with advanced bladder cancer. This is an open-label, multicenter study consisting of a Ph Ib and Ph II portion. Methods: In the Ph Ib portion, three ascending doses of E were to be administered IV on days 1 and 8 q21d to determine the MTD with standard doses of G (1000 mg/m2, days 1 and 8 q21d) and C (70 mg/m2, day 1). In Ph II, pts are randomized 1:1 to E plus G/C, or G/C alone. Results: Nine pts (median age: 59 years; 7 male/2 female) entered Ph Ib. Pts received E 0.7 mg/m2 (n=3) or 1.0 mg/m2 (n=6), with standard dose G/C. Thirty-four cycles were given (2 pts are ongoing). One dose-limiting toxicity (DLT) was observed at 1.0 mg/m2 (Gr 4 thrombocytopenia). The 1.4 mg/m2 dose of E was not explored due to an investigator consensus that, with that dose, the probability of DLTs (severe hematologic toxicity) developing was high. Thus, the MTD was not achieved or defined. The recommended Ph II dose (RP2D) of E in combination with G/C was established as 1.0 mg/m2. Most common adverse events at the RP2D were nausea (83%), neutropenia (83%), fatigue (83%), thrombocytopenia (83%), anemia (83%), and anorexia (50%). Best responses at 1.0 mg/m2 were 1 complete response (CR) (unconfirmed) and 4 partial responses (PR) (all confirmed). Overall response for both cohorts was 89% – 2 CRs (1 confirmed, 1 unconfirmed) and 6 PRs (4 confirmed, 2 unconfirmed). Six pts have been randomized into the Ph II portion of the study to date. Conclusions: E combined with standard G/C chemotherapy is feasible and has encouraging clinical activity. Hematologic toxicity is the main limiting factor.

e15091 Background: Patients with bladder tumors are at high risk of developing second urinary and non-urinary neoplasms. In addition, risk factors of cardiovascular and non-cardiovascular mortality such as smoking are common. We analyze the incidence of second tumors in conservatively managed patients with good prognosis invasive bladder cancer. Methods: From January 2000 to December 2010, 54 patients (9 women, 45 men) were treated with maximum transurethral resection (TUR). After TUR, 40 patients received either 3 cycles of chemotherapy (CT) with cisplatin 75 mg/m2 or carboplatin AUC 5, if creatinine clearance was below 55 mL/min, plus gemcitabine 1 gr/m2. 14 (26%) patients not candidates or not willing a cystectomy received concomitant chemoradiotherapy (CRT). A new TUR and biopsies were performed in all patients after completing the therapy and later biannually for the first year. Patients with cT4 tumors, other histology than transitional cell cancer and patients with hydronephrosis or multifocal carc...

270 Background: Preclinical studies suggest enhanced radiation-induced cell death when VEGFR inhibitor therapies are combined with RT. Methods: Patients with localized muscle invasive urothelial carcinoma of the bladder in clinical stage T2-3 N0 M0, who were not eligible or rejected radical cystectomy, ECOG PS 0-2, and adequate hematological, renal and hepatic function, were enrolled in this phase I study to assess safety and identify the dose limiting toxicity (DLT), maximum tolerated dose (MTD) and recommended dose (RD) of sorafenib and RT. A 3+3 dose escalation design with cohorts of 3-6 patients was used. Treatment consisted of TUR, followed by normofractionated (2 Gy/day) external-beam RT with high-energy photons, 46 Gy to minor pelvis and 66 Gy to bladder, combined with sorafenib given po continuously. Sorafenib was started two weeks before RT and was administered for 12 weeks, finishing 4 weeks after RT. Dose levels 1, 2 and 3 corresponded to sorafenib 200 mg qd, 200 mg bid and 800 mg bid. Pathological response was assessed by post-treatment TUR. Results: Ten patients were included: median age 71 years (44-84); gender 7M: 3F. Patients were treated at 3 dose levels, the MTD was reached at level 3 and the RD was: sorafenib 200 mg bid with RT. Two DLTs occurred, both at the third dose level: diarrhea grade 3 and digestive bleeding grade 3 with secondary anemia and hemodynamic angor in a patient with previous small bowel angiodysplasia. The most frequent toxicity was diarrhea. Other grade 1-2 toxicities included rash, fatigue, hand-foot syndrome, hypertension, dysuria and urinary frequency. One patient developed late radiation cystitis. Pathological complete response was achieved in 8 of 9 patients evaluated. Salvage cystectomy has been performed in one patient due to recurrent superficial bladder tumor. After a median follow up of 30 months, 6 patients remain disease-free with intact bladder. Conclusions: The combination of sorafenib and RT appears to be feasible and safe allowing long-term bladder preservation in selected patients. A phase II study to assess the activity of this promising combination is warranted.

e15105 Background: Until recent developments in treatment of PPuCT (cabezitaxel, abiraterone) progressing after docetaxel, second line therapies were scarce. In our Hospital, Docetaxel as first lin...

4533 Background: Bone metastases from castrate-resistant prostate cancer (CRPC) are associated with osteoclast-mediated bone destruction and skeletal-related events (SREs). Denosumab is a fully hum...

LBA4519 Background: About 50% of pts with advanced UC are not eligible for cisplatin based CHT (“unfit”) due to impaired renal function, performance status (PS) or comorbidity. This is the first randomized phase II/III trial comparing two chemotherapy regimens in this pts group. Methods: The primary objective of the phase III part of this study was to compare the overall survival (OS) of CHT naïve pts with measurable disease and an impaired renal function (GFR30 ml/min) and/or PS 2 who were randomized to receive either GC (G 1000 mg/m2 d1 and 8 and C AUC 4.5) q21 days or M-CAVI (M 30 mg/m2 d1 and 15 and 22, C AUC 4.5 d1 and VI 3 mg/m2 d1 and 15 and 22) q28 days. In order to detect an increase of 50% in median survival on GC compared to M-CAVI (13.5 versus 9 months) based on a two sided logrank test at error rates alpha=0.05 and beta=0.20, 225 pts were required. Secondary endpoints were overall response rate (ORR) and progression free survival (PFS). Results: 238 pts, 119 in each arm, were randomized between January 2001 and March 2008 by 29 institutions. The median follow-up is 4.5 years. Two pts were ineligible and two other pts never started treatment. Best ORRs (CR + PR) were 41.2% (36.1% confirmed response) on GC versus 30.3% (21.0% confirmed response) on M-CAVI (p = 0.08). Median OS was 9.3 months on GC and 8.1 months on M-CAVI (p = 0.64). There was no difference in PFS between the two arms (p = 0.78). OS, PFS and ORR were similar in each of the risk groups (reason unfit for cisplatin and Bajorin risk group). Severe acute toxicity (SAT) (death, grade 4 thrombocytopenia with bleeding, or grade 3/4 renal toxicity, neutropenic fever or mucositis) was observed in 9.3% of pts on GC (2 toxic deaths) and 21.2% on M-CAVI (4 toxic deaths). The most common grade 3/4 toxicities were leucopenia (44.9%, 46.6%), neutropenia (52.5%, 63.5%), febrile neutropenia (4.2%, 14.4%), thrombocytopenia (48.3%, 19.4%), and infection (11.8%, 12.7%) on GC and M-CAVI, respectively. Conclusions: There were no significant differences in efficacy between the two treatment groups. The incidence of SATs was slightly higher on M-CAVI. [Table: see text]

4540 Background: There is a need for improving therapy in "unfit" patients (pts) who are not able to receive standard cisplatinum-based chemotherapy and to look for response predictors. VEGF is expressed in transitional cell carcinoma and its overexpression is associated with an aggressive behavior; targeting angiogenesis maybe a rational approach. Methods: This is a multicenter, open-label, phase II clinical trial assessing oral sunitinib at 50 mg daily in a 4/2-week schedule as first-line in "unfit" urothelial cancer pts. Eligibility criteria to define "unfit" included creatinine clearance under 60 ml/min but over 30 ml/min and performance status ≥ 1 (ECOG). Pretreatment sequential serum samples and measurements of Hounsfield units were collected in pts undergoing treatment. 14 potential serum markers (cytoquines, soluble receptors, growth factors and methaloproteases) were studied (xMAP Technology of Luminex Corp). Results: 37 pts with median age of 75 years were enrolled between July 2006 and Septembe...

4612 Background: There are currently three licensed first-line metastatic renal cell carcinoma (mRCC) targeted therapies, allowing the therapy of a broad first-line mRCC population with good or int...