Background

CC is a rare cancer for which there are limited effective therapies. IDH1 mutations occur in up to ∼15% of CC, resulting in production of the oncometabolite, D-2-hydroxyglutarate (2-HG), which promotes oncogenesis. IVO (AG-120) is a first-in-class, oral, small-molecule inhibitor of the mutant IDH1 (mIDH1) protein.

Methods

Patients (pts) with mIDH1 CC were randomized 2:1 to IVO (500 mg once daily) or matched PBO and stratified by number of prior systemic therapies (1 or 2). Key eligibility: unresectable or metastatic mIDH1 CC based on central testing; ECOG PS 0–1; measurable disease (RECIST v1.1). Crossover from PBO to IVO was permitted at radiographic PD. Primary endpoint: progression-free survival (PFS) by central review. Secondary endpoints included safety, ORR, PFS (local investigator review), and overall survival (OS; by ITT). Crossover-adjusted OS was derived using rank preserved structural failure time (RPSFT).

Results

As of 31Jan2019, 185 pts were randomized to IVO (n = 124) or PBO (n = 61). Median age 62 y, M/F 68/117, 91% intrahepatic CC, 92% metastatic disease, 43% had 2 prior therapies. Primary endpoint (PFS by central review) was met: HR = 0.37 (95% CI 0.25, 0.54; p < 0.001); median PFS was 2.7 (IVO) vs. 1.4 (PBO) mo. PFS rates at 6 and 12 mo were 32.0% and 21.9% in IVO arm; no PBO pts were progression-free for ≥6 mo at data cutoff. ORR for IVO was 2.4% (3 PRs), with 50.8% SD (n = 63) vs. 0% ORR in PBO and 27.9% SD (n = 17). By ITT analysis, median OS was 10.8 mo for IVO and 9.7 mo for PBO (HR = 0.69; one-sided p = 0.06) with 57% of PBO pts crossed over to IVO. The RPSFT-adjusted median OS was 6 mo for PBO (HR = 0.46; p = 0.0008). PFS by local review HR = 0.47 (p < 0.001). Common TEAEs (>15%) in IVO arm: nausea (32.1%), diarrhea (28.8%), fatigue (23.7%), cough (19.2%), abdominal pain (18.6%), ascites (18.6%), decreased appetite (17.3%), anemia (16.0%), vomiting (16.0%). Grade ≥3 adverse events reported in 46% IVO vs. 36% PBO. There were no treatment-related deaths.

Conclusions

IVO resulted in significant improvement in PFS and favorable OS trend vs. PBO. This is the first pivotal study demonstrating the clinical benefit of targeting mIDH1 in pts with advanced mIDH1 CC.

Clinical trial identification

NCT02989857.

Editorial acknowledgement

Yvonna Fisher-Jeffes of Agios Pharmaceuticals, Inc and Helen Varley of Envision Pharma Group.

Legal entity responsible for the study

Agios Pharmaceuticals, Inc.

Funding

Agios Pharmaceuticals, Inc.

Disclosure

G.K. Abou-Alfa: Advisory / Consultancy, Research grant / Funding (institution): 3DMedcare; Advisory / Consultancy: ActaBiologica; Advisory / Consultancy, Research grant / Funding (institution): Agios; Advisory / Consultancy: Alignmed; Advisory / Consultancy: Amgen; Advisory / Consultancy: Antengene; Advisory / Consultancy: Aptus; Research grant / Funding (institution): Array; Advisory / Consultancy: Aslan; Advisory / Consultancy: Astellas; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution): Beigene; Advisory / Consultancy: Bioline; Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy: Boston Scientifc; Advisory / Consultancy: Bridgebio; Advisory / Consultancy: Carsgen; Advisory / Consultancy, Research grant / Funding (institution): Casi; Advisory / Consultancy, Research grant / Funding (institution): Celgene; Advisory / Consultancy: Cipla; Advisory / Consultancy: CytomX; Advisory / Consultancy: Daiichi; Advisory / Consultancy: Debio; Advisory / Consultancy: Delcath; Advisory / Consultancy: Eisai; Advisory / Consultancy, Research grant / Funding (institution): Exelixis; Research grant / Funding (institution): Genentech; Advisory / Consultancy: Genoscience; Advisory / Consultancy, Research grant / Funding (institution): Halozyme; Advisory / Consultancy: Hengrui; Advisory / Consultancy, Research grant / Funding (institution): Incyte; Advisory / Consultancy: Inovio; Advisory / Consultancy: Ipsen; Advisory / Consultancy: Jazz; Advisory / Consultancy: Janssen; Advisory / Consultancy: Kyowa Kirin; Advisory / Consultancy: LAM; Advisory / Consultancy, Research grant / Funding (institution): Lilly; Advisory / Consultancy: Loxo; Research grant / Funding (institution): Mabvax; Advisory / Consultancy: Merck; Advisory / Consultancy: Mina; Research grant / Funding (institution): Novartis; Advisory / Consultancy: Novella; Research grant / Funding (institution): OncoQuest; Advisory / Consultancy: Onxeo; Advisory / Consultancy: PCI Biotech; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Pieris; Research grant / Funding (institution): Polaris; Research grant / Funding (institution): Puma; Advisory / Consultancy, Research grant / Funding (institution): QED; Advisory / Consultancy: Redhill; Research grant / Funding (institution): Roche; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Servier; Advisory / Consultancy: Silenseed; Advisory / Consultancy: Sillajen; Advisory / Consultancy: Sobi; Advisory / Consultancy: Targovax; Advisory / Consultancy: Tekmira; Advisory / Consultancy: Twoxar; Advisory / Consultancy: Vicus; Advisory / Consultancy: Yakult; Advisory / Consultancy: Yiviva. T. Macarulla Mercade: Honoraria (self), Research grant / Funding (institution): Roche; Honoraria (self): Sanofi; Honoraria (self): Tesaro; Honoraria (self), Advisory / Consultancy: Shire; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Celgene; Advisory / Consultancy: QDE; Advisory / Consultancy, Travel / Accommodation / Expenses: H3B; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Sanofi/Aventis; Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy: Baxalta; Honoraria (self): Genzyme; Research grant / Funding (institution): Agios; Research grant / Funding (institution): Aslan; Research grant / Funding (institution), Travel / Accommodation / Expenses: Bayer; Research grant / Funding (institution): Genentech; Travel / Accommodation / Expenses: Merck; Research grant / Funding (institution): Hallozyme; Research grant / Funding (institution): Immunomedics; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Merrimarck; Research grant / Funding (institution): Millennium; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Novocure; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Pharmacyclics. M. Javle: Research grant / Funding (self): QED; Research grant / Funding (self): Novartis; Honoraria (self): Taiho; Research grant / Funding (self): Meclun; Honoraria (self): Seattle Genetics; Research grant / Funding (institution): Arqule; Honoraria (self): Merck; Research grant / Funding (institution): Lilly; Advisory / Consultancy: Origimed; Advisory / Consultancy: More Health; Advisory / Consultancy: EDO. R.K. Kelley: Advisory / Consultancy, Research grant / Funding (institution): Agios; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution): BMS; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Exelixis; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): QED; Research grant / Funding (institution): Taiho; Research grant / Funding (institution): MedImmune; Research grant / Funding (institution): EMD Serono; Advisory / Consultancy: Target Pharma Solutions; Advisory / Consultancy: Genentech/Roche. J.M. Cleary: Honoraria (self), Travel / Accommodation / Expenses: Agios; Honoraria (self), Travel / Accommodation / Expenses: BMS; Research grant / Funding (self): Merck; Research grant / Funding (self): Tesaro; Travel / Accommodation / Expenses: Roche. D.V. Catenacci: Honoraria (self): Astellas; Honoraria (self): Five Prime; Honoraria (self): BMS; Honoraria (self): Merck; Honoraria (self): Lilly; Honoraria (self): Taiho; Honoraria (self): Daichii Sankyo; Honoraria (self): Genentech/Roche; Honoraria (self): Foundation Medicine; Honoraria (self): Tempus; Honoraria (self): Guardant Health. M.J. Borad: Research grant / Funding (institution): Senhwa Pharmaceuticals; Research grant / Funding (institution): Adaptimmune; Research grant / Funding (institution): Agios Pharmaceuticals; Research grant / Funding (institution): Halozyme Pharmaceuticals; Research grant / Funding (institution): Celgene Pharmaceuticals; Research grant / Funding (institution): EMD Merck Serono; Research grant / Funding (institution): Toray; Research grant / Funding (institution): Dicerna; Research grant / Funding (institution): Taiho Pharmaceuticals; Research grant / Funding (institution): Sun Biopharma; Research grant / Funding (institution): Isis Pharmaceuticals; Research grant / Funding (institution): Redhill Pharmaceuticals; Research grant / Funding (institution): Boston Biomed; Research grant / Funding (institution): Basilea; Research grant / Funding (institution): Incyte Pharmaceuticals; Research grant / Funding (institution): Mirna Pharmaceuticals; Research grant / Funding (institution): MedImmune; Research grant / Funding (institution): Bioline; Research grant / Funding (institution): Sillajen; Research grant / Funding (institution): ARIAD; Research grant / Funding (institution): PUMA; Research grant / Funding (institution): Novartis Pharmaceuticals; Research grant / Funding (institution): QED Pharmaceuticals; Research grant / Funding (institution): Pieris; Honoraria (self): Exelixis; Honoraria (self): G1 Therapeutics; Honoraria (self): Immunovative Therapies; Shareholder / Stockholder / Stock options: OncBioMune Pharmaceuticals; Honoraria (self): Western Oncolytics; Honoraria (self): Lynx Group; Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self): Inspyr Therapeutics; Honoraria (self): ADC Therapeuctics; Shareholder / Stockholder / Stock options: Intercept; Shareholder / Stockholder / Stock options: AVEO. J.A. Bridgewater: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Merck Serono; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Servier; Advisory / Consultancy: Roche; Advisory / Consultancy: Bayer; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Incyte; Advisory / Consultancy: Basilea; Speaker Bureau / Expert testimony: Celgene; Speaker Bureau / Expert testimony, Research grant / Funding (self): Amgen; Travel / Accommodation / Expenses: MDS Oncology; Travel / Accommodation / Expenses: Bristol-Myers Squibb/Medarex; Travel / Accommodation / Expenses: Bristol-Myers Squibb. W.P. Harris: Advisory / Consultancy: NeoTherma; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution): Eisai; Advisory / Consultancy, Research grant / Funding (institution): Exelixis; Advisory / Consultancy, Research grant / Funding (institution): Bristo-Myers Squibb; Research grant / Funding (institution): ArQule; Research grant / Funding (institution): Halozyme; Research grant / Funding (institution): BTG; Research grant / Funding (institution): MedImmune; Research grant / Funding (institution): Agios; Research grant / Funding (institution): Merck. A.G. Murphy: Research grant / Funding (self): Bristol-Myers Squibb. D. Oh: Advisory / Consultancy: Genentech/Roche; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Merck Serono; Advisory / Consultancy: Bayer; Advisory / Consultancy: Taiho; Advisory / Consultancy: ASLAN; Advisory / Consultancy: Halozyme; Research grant / Funding (institution): Array; Research grant / Funding (institution): Eli Lilly. B. Wu: Shareholder / Stockholder / Stock options, Licensing / Royalties, Full / Part-time employment: Agios. L. Jiang: Shareholder / Stockholder / Stock options, Full / Part-time employment: Agios. C. Gliser: Shareholder / Stockholder / Stock options, Full / Part-time employment: Agios. S.S. Pandya: Shareholder / Stockholder / Stock options, Full / Part-time employment: Agios. J.W. Valle: Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Celgene; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Ipsen; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Novartis; Advisory / Consultancy, Travel / Accommodation / Expenses: NuCana; Advisory / Consultancy, Speaker Bureau / Expert testimony: Abbott; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Speaker Bureau / Expert testimony: Sirtex; Advisory / Consultancy: Agios; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Baxalta; Advisory / Consultancy: Bioven; Advisory / Consultancy: Delcath; Advisory / Consultancy: Genoscience Pharma; Advisory / Consultancy: Incyte; Advisory / Consultancy: Keocyt; Advisory / Consultancy: Lilly; Advisory / Consultancy: Merck; Advisory / Consultancy: Midatech; Advisory / Consultancy: Mundipharma; Advisory / Consultancy: PCI Biotech; Advisory / Consultancy: Pieris Pharmaceuticals; Advisory / Consultancy: QED Pharmaceuticals. A.X. Zhu: Advisory / Consultancy: Eisai; Advisory / Consultancy, Research grant / Funding (self): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (self): Merck; Advisory / Consultancy, Research grant / Funding (self): Novartis; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy, Research grant / Funding (self): Bayer; Advisory / Consultancy, Research grant / Funding (self): Lilly; Advisory / Consultancy: Exelixis; Advisory / Consultancy: Roche/Genentech. All other authors have declared no conflicts of interest.

Background

Chemotherapy (CT) for advanced ESCC offers poor long-term survival. We report the final analysis from the phase III ATTRACTION-3 study of the programmed death (PD)-1 inhibitor nivolumab (NIVO) versus CT in patients (pts) with unresectable advanced or recurrent ESCC refractory or intolerant to 1 prior fluoropyrimidine/platinum-based CT.

Methods

Pts were enrolled regardless of PD-ligand 1 (PD-L1) expression and randomized 1:1 to either NIVO (240 mg Q2W) or investigator’s choice of paclitaxel or docetaxel. Primary endpoint was overall survival (OS).

Results

419 pts were randomized (NIVO = 210, CT = 209). At a minimum follow-up of 17.6 months (mo; time from randomization of the last pt to data cutoff), NIVO showed a statistically significant improvement in OS vs CT (HR for death 0.77 [95% CI, 0.62–0.96; P = 0.02]; median OS, 10.9 vs 8.4 mo; Table). The proportion of pts alive at 18 mo was numerically larger with NIVO vs CT (31% vs 21%; Table). HRs for the risk of death favored NIVO over CT across tumor PD-L1 expression levels (PD-L1 ≥1%, HR 0.69 [95% CI, 0.51 to 0.94]; PD-L1 <1%, HR 0.84 [95% CI, 0.62 to 1.14]). The Table shows objective response rate (ORR), duration of response (DOR), and progression-free survival (PFS). Fewer treatment-related adverse events (TRAEs) were reported with NIVO (any grade, 66%; grade 3–4, 18%) vs CT (any grade, 95%; grade 3–4, 63%; Table). NIVO showed a statistically significant overall improvement in quality of life vs CT through on-treatment week 42 in both the EQ-5D visual analog scale (least square [LS] mean, 6.9; 95% CI, 3.0–10.9; P < 0.001) and EQ-5D utility index (LS mean, 0.076; 95% CI, 0.011–0.142; P = 0.023).Table:

LBA11

Conclusions

NIVO demonstrated superior OS and a favorable safety profile vs CT in pts with previously treated advanced ESCC, with survival benefit observed regardless of tumor PD-L1 expression. NIVO may represent a new standard second-line treatment option for pts with advanced ESCC.

Clinical trial identification

NCT02569242.

Editorial acknowledgement

Professional medical writing assistance and editorial assistance were provided by Jennifer Granit, PhD, and Christine Craig of Parexel, funded by Bristol-Myers Squibb.

Legal entity responsible for the study

Ono Pharmaceutical Co, Bristol-Myers Squibb.

Funding

Ono Pharmaceutical Co, Bristol-Myers Squibb.

Disclosure

B.C. Cho: Research grant / Funding (self): Novartis, Bayer, AstraZeneca, MOGAM Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono, Dizal Pharma, MSD ; Licensing / Royalties: Champions Oncology; Shareholder / Stockholder / Stock options: TheraCanVac Inc; Honoraria (self): Novatis, Bayer, AstraZeneca, MOGAM Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono, Dizal Pharma, MSD; Advisory / Consultancy: Novatis, AstraZeneca, Boehringer Ingelheim, Roche, BMS, Ono, Yuhan, Pfizer, Eli Lilly, Janssen, Takega, MSD; Speaker Bureau / Expert testimony: Novartis. K. Kato: Advisory / Consultancy: Ono Pharmaceutical, BeiGene, MSD, Oncolys BioPharma; Research grant / Funding (institution): Ono Pharmaceutical, Shionogi, MSD, Beigene. M. Takahashi: Research grant / Funding (self): Ono Pharmaceutical; Speaker Bureau / Expert testimony: Ono Pharmaceutical, Brystol-Myers Squibb, Daichi-Sankyo. M. Okada: Speaker Bureau / Expert testimony: Tahio Pharmaceutical, Johnson & Johnson, Coviden, Lilly, Chugai Pharma; Research grant / Funding (institution): Taiho Pharmaceutical, Nippon Kayaku, Chugai Pharma, Coviden, Johnson & Johnson, Daiichi Sanko, Yakult Honsha, Lilly Japan, Nihon Medi-Physics, Pfizer, Mochida Pharmaceuticals Co. Ltd, Shionogi. S. Kadowaki: Research grant / Funding (institution): Ono Pharmaceutical, Lilly Japan, Taiho Pharmaceutical, Boehringer Ingelheim, Bristol-Myers Squibb. Y. Doki: Speaker Bureau / Expert testimony: Taiho Pharmaceutical, Chugai Pharmaceutical, Eli Lilly, Daiichi Sankyo, Yakult Honsha, Takeda Pharmaceutical, Kaken Pharmaceutical, Abbott Japan; Research grant / Funding (self): Taiho Pharmaceutical, Chugai Pharmaceutical, Ono Pharmaceutical, Eli Lilly, MSD, Daiichi Sankyo, Yakult Honsha, Takeda Pharmaceutical, Kaken Pharmaceutical, Abbott Japan, Eisai, Shionogi . C. Yen: Honoraria (self): Lilly, Merck Sharp & Dohme, Amgen, Eisai; Advisory / Consultancy: Lilly, Merck Sharp & Dohme; Speaker Bureau / Expert testimony: Lilly, Ono Pharmaceutical, Eisai, Effective Pharmaceuticals. S. Kim: Research grant / Funding (institution): Novartis, Genzyme, Dongkook Pharma. C. Hsu: Advisory / Consultancy: Ono Pharmaceutical, Lilly, MSD, Novartis; Honoraria (self): Bristol-Myers Squibb, Ono Pharmaceutical, Merck Sharp & Dohme; Research grant / Funding (institution): Ono Pharmaceutical, AstraZeneca, MSD, Genentech. I. Xynos: Shareholder / Stockholder / Stock options: Bristol-Myers Squibb. M. Kodani: Shareholder / Stockholder / Stock options: Ono Pharmaceutical Co. Ltd. Y. Kitagawa: Honoraria (self): Ethicon, Olympus, Ono Pharmaceutical, Tahi Pharmaceutical, Chugai Pharma, Nippon Kayaku, Asahi Kasei; Research grant / Funding (institution): Astellas, Otsuka, Kaken Pharmaceutical, Kyowa Hakko Kirin, Kowa, CSL Behring, Shionogi, Saiichi Sankyo, Taiho Pharmaceutical, Takeda, Chugai Pharma, Tsumura & Co., Teijin Pharma, Medtronic, Boehringer Ingelheim, Merck Serono, Novartis, Ajinomoto, Asahi Ka. All other authors have declared no conflicts of interest.

Background

Loss-of-function alterations in HRR genes are associated with response to PARP inhibition. PROfound (NCT02987543) is a randomized, open-label, phase III trial evaluating efficacy and safety of olaparib (ola) vs enzalutamide (enza) or abiraterone (abi) in patients (pts) with mCRPC with alterations in any of 15 predefined genes with a direct or indirect role in HRR whose disease had progressed on prior new hormonal agent (NHA) therapy.

Methods

Qualifying tumour tissue HRR alterations were centrally and prospectively identified using an investigational next-generation sequencing test (Foundation Medicine, Inc). Cohort A included pts with alterations in BRCA1, BRCA2 or ATM; Cohort B pts with any 1 of 12 other HRR alterations (BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D or RAD54L). Pts were randomized (2:1) to ola (300 mg bid) or physician’s choice (pcNHA) of enza (160 mg/d) or abi (1000 mg/d + prednisone 5 mg bid). Primary endpoint was radiographic progression-free survival (rPFS) in Cohort A, assessed by blinded independent central review (BICR) and analysed via stratified log-rank test. Crossover to ola was allowed after BICR progression.

Results

4425 men were screened; 245 randomized to Cohort A, 142 to Cohort B (65.6% had prior taxane). Efficacy is shown in Table. Most common adverse events (AEs) were anaemia (46.1 v 15.4%), nausea (41.4 v 19.2%), decreased appetite (30.1 v 17.7%) and fatigue (26.2 v 20.8%) for ola vs pcNHA; 16.4 and 8.5% of pts, respectively, discontinued due to AE.Table: LBA12_PR

Efficacy summary*

Conclusions

In pts with mCRPC and HRR alterations with prior NHA treatment, ola improved rPFS and ORR vs pcNHA, with a favourable trend for OS despite crossover. Safety was generally consistent with the known profile of ola. PROfound is the first positive phase III biomarker-selected study evaluating a targeted treatment in pts with mCRPC.

Clinical trial identification

NCT02987543.

Editorial acknowledgement

Medical writing assistance was provided by Debbi Gorman, PhD, from Mudskipper Business, Ltd and funded by AstraZeneca and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (MSD).

Legal entity responsible for the study

AstraZeneca and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (MSD).

Funding

AstraZeneca and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (MSD).

Disclosure

M. Hussain: Honoraria (self), Women in Pca (lectures): Sanofi/Genzyme; Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses, Lectures: Genentech; Honoraria (self), Lectures: Research to Practice; Honoraria (self), Lectures: Aptitude Health; Honoraria (self), Covering 2019 GU ASCO (lectures): Epics; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses, Ad board: AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses, Ad board: Bayer; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses, Ad board: Pfizer; Honoraria (self), Lectures: PER; Honoraria (self), Travel / Accommodation / Expenses, Lectures: Astellas. J. Mateo: Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Travel / Accommodation / Expenses: Janssen; Advisory / Consultancy: Roche; Speaker Bureau / Expert testimony: Astellas; Speaker Bureau / Expert testimony: Sanofi. K. Fizazi: Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy: Astellas; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: AAA; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Curevac; Honoraria (self), Advisory / Consultancy: Essa; Honoraria (self), Advisory / Consultancy: Janssen; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: Orion; Honoraria (self), Advisory / Consultancy: Sanofi. F. Saad: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Janssen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Astellas. N.D. Shore: Advisory / Consultancy: Amgen; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Bayer; Advisory / Consultancy: BMS; Advisory / Consultancy: Dendreon; Advisory / Consultancy: Ferring; Advisory / Consultancy: Janssen; Advisory / Consultancy: Merck; Advisory / Consultancy: MDx Health; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Tolmar. S. Sandhu: Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: BMS; Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Merck Serono; Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Janssen; Honoraria (institution), Advisory / Consultancy: Merck Sharp and Dohme; Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Roche Genentech; Honoraria (institution), Advisory / Consultancy, Travel / Accommodation / Expenses: Amgen; Research grant / Funding (institution): Endocyte; Research grant / Funding (institution), Travel / Accommodation / Expenses: Merck. K.N. Chi: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Janssen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Astellas; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Bayer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Roche; Honoraria (self), Research grant / Funding (institution): Sanofi; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Janssen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Astellas; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Bayer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Roche; Honoraria (self), Research grant / Funding (institution): Sanofi; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca. O. Sartor: Shareholder / Stockholder / Stock options: Eli Lilly, GlaxoSmithKline, Noria; Advisory / Consultancy: Bayer HealthCare Pharmaceuticals, Bellicum Pharmaceuticals, Johnson & Johnson, Sanofi, AstraZeneca, Dendreon, Endocyte, Constellation Pharmaceuticals, Advanced Accelerator Applications, Pfizer, Bristol-Myers Squibb, Celgene, Bavarian Nordic, Oncogenex, EM; Research grant / Funding (institution): Bayer HealthCare Pharmaceuticals, Johnson & Johnson, Sanofi, Endocyte, Innocrin Pharma, Merck, InVitae; Speaker Bureau / Expert testimony: Sanofi; Travel / Accommodation / Expenses: Bayer HealthCare Pharmaceuticals, Johnson & Johnson, Sanofi, AstraZeneca, Progenics. N. Agarwal: Advisory / Consultancy: Astellas; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy: Argos; Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution): Clovis Oncology; Advisory / Consultancy, Research grant / Funding (institution): Eisai; Advisory / Consultancy, Research grant / Funding (institution): Exelixis; Advisory / Consultancy, Research grant / Funding (institution): EMD Serono; Advisory / Consultancy, Research grant / Funding (institution): Ely Lilly; Advisory / Consultancy: Foundation One; Advisory / Consultancy, Research grant / Funding (institution): Genentech; Advisory / Consultancy, Research grant / Funding (institution): Janssen; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant / Funding (institution): Medivation; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Nektar; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy: Pharmacyclics; Research grant / Funding (institution): Bavarian Nordic, Calithera, Celldex, GSK, Immunomedics, New Link Genetics, Prometheus, Rexahn, Sanofi, Takeda, Tracon. D. Olmos: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Astellas; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Bayer; Advisory / Consultancy, Research grant / Funding (institution): Genentech; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Janssen; Speaker Bureau / Expert testimony: Sanofi-Aventis; Research grant / Funding (institution): Genentech/Roche; Research grant / Funding (institution): Medivation; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Tokai; Travel / Accommodation / Expenses: Ipsen; Travel / Accommodation / Expenses: Roche; Officer / Board of Directors, Directors Board Committee, Member: EORTC; Non-remunerated activity/ies: BioOncoTech & Tokai. A. Thiery-Vuillemin: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Sanofi; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Janssen; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Ipsen; Honoraria (self): Roche/Genentech; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: BMS; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Honoraria (self), Advisory / Consultancy: Astellas Pharma; Advisory / Consultancy, Travel / Accommodation / Expenses: Roche. P. Twardowski: Speaker Bureau / Expert testimony: Sanofi; Advisory / Consultancy, Speaker Bureau / Expert testimony: Bayer; Speaker Bureau / Expert testimony: Astellas; Speaker Bureau / Expert testimony: Pfizer; Speaker Bureau / Expert testimony: Janssen; Advisory / Consultancy: BMS. N. Mehra: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Astellas; Advisory / Consultancy, Research grant / Funding (institution): Janssen; Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Research grant / Funding (institution): Sanofi. C. Goessl: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. J. Kang: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. J. Burgents: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck and Co, Inc.. W. Wu: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. A. Kohlmann: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. C.A. Adelman: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. J. de Bono: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Astellas; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Genentech/Roche; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Sanofi; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Bayer; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Merck Serono; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Travel / Accommodation / Expenses: GSK; Licensing / Royalties, Abiraterone rewards to inventors with royalties paid to institution, no personal income: Janssen Oncology; Travel / Accommodation / Expenses, Non-remunerated activity/ies: Genmab, Orion Pharma, Taiho Pharma, Vertex; Licensing / Royalties, A patent PARP inhibitors and DNA repair defects with royalties paid to institution, no personal income: N/A.

Background

Taxanes (docetaxel [DOC], CBZ) and androgen receptor-targeted therapies (ARTs; ABI, ENZ) are standard of care in mCRPC. The optimal treatment sequence is unknown. CARD (NCT02485691) compared CBZ vs ABI or ENZ in patients with mCRPC previously treated with DOC and the alternative ART.

Methods

Patients with mCRPC previously treated with ≥ 3 cycles of DOC and progressing ≤ 12 months (mo) on an alternative ART, in any order, were randomized 1:1 to CBZ (25 mg/m² IV Q3W + prednisone + G-CSF) vs ABI (1000 mg PO + prednisone) or ENZ (160 mg PO). Randomization was stratified by ECOG PS (0/1 vs 2), time to progression on prior ART (≤ 6 vs 6–12 mo) and ART timing (before vs after DOC). Primary endpoint was radiographic PFS (rPFS), with 196 rPFS events needed to test HR 0.67 for CBZ (80% power, 2-sided alpha 0.05). Secondary efficacy endpoints and safety were assessed.

Results

Overall, 255 patients (median age 70, 31.0% ≥ 75 yrs) were randomized. Median number of cycles was higher for CBZ vs ART (7 vs 4). rPFS was significantly improved with CBZ vs ART (median 8.0 vs 3.7 mo; HR 0.54; 95% CI 0.40–0.73; p < 0.0001). CBZ also robustly improved OS (median 13.6 vs 11.0 mo; HR 0.64; 95% CI 0.46–0.89; p = 0.0078) despite crossover, as well as PFS (median 4.4 vs 2.7 mo; p < 0.0001), confirmed PSA50 response (35.7% vs 13.5%; p = 0.0002) and tumor response (36.5% vs 11.5%; p = 0.004). Pain response and time to symptomatic skeletal events were also significantly improved with CBZ. Grade ≥ 3 adverse events (AEs) occurred in 56.3% vs 52.4% of patients with CBZ vs ART. For CBZ vs ART, main grade ≥ 3 AEs were: renal disorders (3.2% vs 8.1%); infections (7.9% vs 7.3%); musculoskeletal pain/discomfort (1.6% vs 5.6%); cardiac disorders (0.8% vs 4.8%); spinal cord/nerve root disorders (2.4% vs 4.0%); asthenia/fatigue (4.0% vs 2.4%); diarrhea, peripheral neuropathy and febrile neutropenia (3.2% vs 0% for each). AEs led to death in 7 vs 14 patients (5.6% vs 11.3%) for CBZ vs ART.

Conclusions

CBZ significantly improved clinically important patient outcomes including rPFS and OS vs ART in patients with mCRPC previously treated with DOC and an alternative ART. CBZ should be the preferred option in this setting. Sanofi funded.

Clinical trial identification

NCT02485691.

Editorial acknowledgement

Editorial support was provided by Amber Wood, Danielle Lindley and Tina Wasmeier of MediTech Media and funded by Sanofi.

Legal entity responsible for the study

Sanofi.

Funding

Sanofi.

Disclosure

R. de Wit: Advisory / Consultancy, Speaker Bureau / Expert testimony, Advisory Boards and speaker fees: Sanofi; Advisory / Consultancy, Speaker Bureau / Expert testimony, Advisory Boards and speaker fees: Janssen; Advisory / Consultancy, Research grant / Funding (institution), Advisory Boards and institutional grants: Sanofi; Advisory / Consultancy, Research grant / Funding (self), Advisory Boards and institutional grants: Merck; Advisory / Consultancy, Research grant / Funding (institution), Advisory Boards and institutional grants: Bayer; Advisory / Consultancy, Research grant / Funding (self), Advisory Boards and institutional grants: Clovis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Roche. G. Kramer: Honoraria (self), Personal fess: Sanofi, Astellas, Takeda, Bayer, Janssen, Novartis, Ipsen, AstraZeneca; Research grant / Funding (self), Grant: Sanofi, Bayer. J. Eymard: Advisory / Consultancy, Board participation for Sanofi Aventis: Sanofi Aventis. J.S. de Bono: Honoraria (self), Advisory / Consultancy: AstraZeneca ; Honoraria (self), Advisory / Consultancy: Sanofi; Honoraria (self), Advisory / Consultancy: Astellas Pharma; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: Genentech/Roche ; Honoraria (self), Advisory / Consultancy: Janssen Oncology; Honoraria (self), Advisory / Consultancy: Menarini Silicon Biosystems; Honoraria (self), Advisory / Consultancy: Daiichi Sankyo; Honoraria (self), Advisory / Consultancy: Sierra Oncology; Honoraria (self): Bioexcell; Advisory / Consultancy: Bayer; Advisory / Consultancy: Merck Sharp & Dohme; Advisory / Consultancy: Merck Serono; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: Celgene; Advisory / Consultancy: Taiho Pharmaceutical; Advisory / Consultancy: Genmab; Advisory / Consultancy: GlaxoSmithKline; Advisory / Consultancy: Orion Pharma GmbH; Advisory / Consultancy: Eisai, BioXCel therapeutics. C.N. Sternberg: Honoraria (self): Janssen; Honoraria (self): AstraZeneca; Honoraria (self), Advisory / Consultancy: Sanofi; Honoraria (self): Astellas; Advisory / Consultancy: Bayer; Advisory / Consultancy: Pfizer; Honoraria (institution), Research grant / Funding (institution): Roche-Genentech, Bayer, Sanofi Genzyme, Janssen, Medivation, Exelixis. K. Fizazi: Honoraria (institution), Advisory / Consultancy: Amgen; Honoraria (institution), Advisory / Consultancy: Astellas; Honoraria (institution), Advisory / Consultancy: Astrazeneca; Honoraria (institution), Advisory / Consultancy: AAA; Honoraria (institution), Advisory / Consultancy: Bayer; Honoraria (institution), Advisory / Consultancy: Curevac; Honoraria (institution), Advisory / Consultancy: Essa; Honoraria (institution), Advisory / Consultancy: MSD; Honoraria (institution), Advisory / Consultancy: Orion; Honoraria (institution), Advisory / Consultancy: Sanofi. B. Tombal: Research grant / Funding (self): Astellas; Research grant / Funding (self): Janssen; Research grant / Funding (self), Non-remunerated activity/ies: Sanofi-Genzyme; Research grant / Funding (self): Amgen; Research grant / Funding (self): Ferring. A. Bamias: Honoraria (self): Astellas; Honoraria (self): Sanofi; Research grant / Funding (self): Janssen. J. Carles: Advisory / Consultancy, Speaker Bureau / Expert testimony: Bayer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Johnson and Johnson; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy, Speaker Bureau / Expert testimony: Astellas Pharma; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Sanofi; Advisory / Consultancy: MSD Oncology; Advisory / Consultancy: Roche; Advisory / Consultancy: AstraZeneca; Speaker Bureau / Expert testimony: Asofarma. R. Iacovelli: Honoraria (self): Sanofi; Honoraria (self): Janssen; Honoraria (self): Pfizer; Honoraria (self): IPSEN; Honoraria (self): Novartis; Honoraria (self): BMS; Honoraria (self): MSD. B. Melichar: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: BMS; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Novartis; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Merck Serono; Honoraria (self), Advisory / Consultancy: Sanofi; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Janssen; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Astellas; Honoraria (self), Advisory / Consultancy: Servier; Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy: Pfizer. A. Ozatilgan: Shareholder / Stockholder / Stock options, Full / Part-time employment: Sanofi. C. Geffriaud-Ricouard: Full / Part-time employment: Sanofi. D. Castellano: Honoraria (self), Personal fees: Pfizer; Honoraria (self), Personal fees: Roche; Honoraria (self), Personal fees: Sanofi; Honoraria (self), Personal fees: Janssen; Honoraria (self), Personal fees: Astellas; Honoraria (self), Personal fees: Bayer; Honoraria (self), Personal fees: BMS; Honoraria (self), Personal fees: MSD; Honoraria (self), Personal fees: Merck Serono; Honoraria (self), Personal fees: Pierre Fabre; Honoraria (self), Personal fees: AstraZeneca; Honoraria (self), Personal fees: Lilly. All other authors have declared no conflicts of interest.

Background

First-line (1L) mUC treatment (tx) includes cisplatin (cis)- or carboplatin (carbo)-based chemotherapy or checkpoint inhibitors, depending on patient (pt) eligibility and PD-L1 status. IMvigor130 is a phase 3, global, multicentre, randomised, partially blinded study evaluating atezo (anti–PD-L1) alone or with PBC vs placebo + PBC in untreated mUC.

Methods

IMvigor130 enrolled 1213 PBC-eligible pts with mUC. Pts were randomised 1:1:1 to Arm A (atezo + PBC [gemcitabine (gem) + either cis or carbo]), Arm B (atezo) or Arm C (placebo + PBC). Gem 1000 mg/m² IV was given on Day (D) 1 and D8, carbo AUC 4.5 IV or cis 70 mg/m² IV on D1 and atezo/placebo or atezo 1200 mg IV on D1 of each 3-wk tx cycle. Tumours were assessed at baseline and every 9 wk until (INV)-assessed PD per RECIST 1.1 or other events. Coprimary efficacy endpoints are INV-assessed PFS and OS (Arm A vs C) and OS (Arm B vs C, hierarchical approach) per RECIST 1.1. Final PFS (Arm A vs C) and interim OS are shown here.

Results

With a median follow-up of 11.8 mo, median PFS was 8.2 mo in Arm A vs 6.3 mo in Arm C (HR, 0.82 [95% CI: 0.70, 0.96]; P = 0.007). The comparison of OS did not cross the prespecified interim efficacy boundary, with a median of 16.0 mo in Arm A and 13.4 mo in Arm C (HR, 0.83 [95% CI: 0.69, 1.00]; P = 0.027; Table). For Arm B vs C, the median OS was 15.7 and 13.1 mo, respectively (HR, 1.02 [95% CI: 0.83, 1.24]), for ITT pts and not estimable and 17.8 mo, respectively (HR, 0.68 [95% CI: 0.43, 1.08]), for PD-L1 IC2/3 pts. ORRs were 47%, 23% and 44% and CR rates were 13%, 6% and 7% for Arms A, B and C, respectively. AEs that led to tx withdrawal occurred in 34%, 6% and 34% of pts in Arms A, B and C, respectively.Table:

LBA14_PR

Conclusions

Adding atezo to PBC for 1L mUC tx prolonged PFS vs PBC alone in pts with untreated mUC. The combination safety profile was consistent with that observed for the individual agents.

Clinical trial identification

NCT02807636.

Editorial acknowledgement

Medical writing assistance was provided by Paige Davies, PhD, of Health Interactions, and funded by F. Hoffmann-La Roche, Ltd.

Legal entity responsible for the study

F. Hoffmann-La Roche, Ltd.

Funding

F. Hoffmann-La Roche, Ltd.

Disclosure

E. Grande: Speaker Bureau / Expert testimony, Research grant / Funding (self): Pfizer; Speaker Bureau / Expert testimony, Research grant / Funding (self): Ipsen; Speaker Bureau / Expert testimony: BMS; Speaker Bureau / Expert testimony: Eisai; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Roche; Speaker Bureau / Expert testimony, Research grant / Funding (institution): MSD; Speaker Bureau / Expert testimony: Sanofi-Genzyme; Speaker Bureau / Expert testimony: Adacap; Speaker Bureau / Expert testimony: Novartis; Speaker Bureau / Expert testimony: EUSA Pharma; Speaker Bureau / Expert testimony: Pierre Fabre; Speaker Bureau / Expert testimony, Research grant / Funding (self): Lexicon; Speaker Bureau / Expert testimony: Celgene; Research grant / Funding (self): AstraZeneca; Research grant / Funding (self): MTEM/Threshold; Advisory / Consultancy: Enets; Officer / Board of Directors: Getne; Officer / Board of Directors: Gethi. M. Galsky: Advisory / Consultancy, Research grant / Funding (institution): Janssen; Advisory / Consultancy, Research grant / Funding (institution): Dendreon; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant / Funding (institution): Genentech; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy: BioMotiv; Advisory / Consultancy: Glaxo Smith Kline; Advisory / Consultancy: Lilly; Advisory / Consultancy: Astellas; Advisory / Consultancy: Novartis; Advisory / Consultancy: Pfizer; Advisory / Consultancy: EMD-Serono; Advisory / Consultancy: Seattle Genetics; Advisory / Consultancy: Incyte; Advisory / Consultancy: Aileron; Advisory / Consultancy: Dracen; Advisory / Consultancy: Inovio; Advisory / Consultancy: Dragonfly. J.A. Arranz Arija: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: BMS; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Pierre Fabre Oncology; Advisory / Consultancy: Astellas; Honoraria (self), Advisory / Consultancy: Ipsen; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Janssen; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Advisory / Consultancy: Merck; Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Honoraria (self): Roche; Honoraria (self): Cilag; Travel / Accommodation / Expenses: Essa; Travel / Accommodation / Expenses: Ferring. M. De Santis: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Amgen, Astellas, AstraZeneca, Bayer, Bioclin; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: BMS, EISAI, Roche; Honoraria (self), Travel / Accommodation / Expenses: Clovis, Incyte; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: ESSA; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Ferring; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Ipsen; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Janssen; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Merck; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Novartis; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: OncoGenex; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Pierre Fabre Oncology; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Sandoz; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Sanofi; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: SeaGen; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Shionogi, Synthon, Takeda; Non-remunerated activity/ies: EAU Prostrate Cancer Guidelines; Non-remunerated activity/ies: ESMO Bladder Cancer Practice Guidelines; Non-remunerated activity/ies: S3 Blasenkarzinom Leitlinien. I.D. Davis: Honoraria (institution), Advisory / Consultancy: Amrad; Honoraria (institution), Advisory / Consultancy: Sanofi (and Sanofi-aventis); Honoraria (institution), Advisory / Consultancy: NovoNordisk; Honoraria (institution), Advisory / Consultancy: Bayer; Honoraria (institution), Advisory / Consultancy: Pharmion ; Honoraria (institution), Advisory / Consultancy: Wyeth; Honoraria (institution), Advisory / Consultancy: Schering-Plough; Honoraria (institution), Advisory / Consultancy: Novartis; Honoraria (institution), Advisory / Consultancy: GSK; Honoraria (institution), Advisory / Consultancy: Medivation; Honoraria (institution), Advisory / Consultancy: Janssen; Honoraria (institution), Advisory / Consultancy: Dendreon; Honoraria (institution), Advisory / Consultancy: Ipsen; Honoraria (institution), Advisory / Consultancy: Astellas; Honoraria (institution), Advisory / Consultancy: Roche; Honoraria (institution), Advisory / Consultancy: Eisai; Honoraria (institution), Advisory / Consultancy: Pfizer; Honoraria (institution), Advisory / Consultancy: BMS, AstraZeneca; Research grant / Funding (institution): NHMRC Practitioner Fellowship; Officer / Board of Directors: Anzup. U.F.F. De Giorgi: Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Roche; Advisory / Consultancy, Research grant / Funding (institution): Sanofi; Advisory / Consultancy: Astellas; Advisory / Consultancy: Bayer; Advisory / Consultancy, Travel / Accommodation / Expenses: BMS; Advisory / Consultancy, Travel / Accommodation / Expenses: Ipsen; Advisory / Consultancy, Travel / Accommodation / Expenses: Janssen; Advisory / Consultancy: Merck; Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer. M. Mencinger: Advisory / Consultancy: Sanofi; Speaker Bureau / Expert testimony: BMS; Advisory / Consultancy: Merck; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Honoraria (self), Speaker Bureau / Expert testimony: Bayer; Honoraria (self), Speaker Bureau / Expert testimony: roche; Honoraria (self), Speaker Bureau / Expert testimony: Janssen; Honoraria (self), Speaker Bureau / Expert testimony: Astellas. E. Kikuchi: Honoraria (self), Research grant / Funding (institution): MSD; Honoraria (self), Research grant / Funding (institution): Nippon; Research grant / Funding (institution): Kayaku; Honoraria (self), Research grant / Funding (institution): Astellas; Honoraria (self), Research grant / Funding (institution): ONO; Honoraria (self), Research grant / Funding (institution): Chugai; Honoraria (self), Research grant / Funding (institution): Takeda; Honoraria (self), Research grant / Funding (institution): Taiho; Honoraria (self), Research grant / Funding (institution): AstraZeneca; Honoraria (self): Kissei; Honoraria (self): ASKA; Honoraria (self): Shinyaku; Honoraria (self): Pfizer. X. Garcia del Muro: Research grant / Funding (institution): AstraZeneca; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy, Travel / Accommodation / Expenses: BMS; Advisory / Consultancy, Travel / Accommodation / Expenses: Ipsen; Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy: Lilly; Advisory / Consultancy: Pharmamar; Advisory / Consultancy: Eusapharma; Honoraria (self), As a speaker or moderator in Scientific Meeting: Astellas. M. Gumus: Honoraria (self), Advisory / Consultancy: Lilly; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (institution), Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Honoraria (self), Advisory / Consultancy: Astellas; Honoraria (self), Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Amgen. M. Özgüroğlu: Honoraria (self), Honoraria (institution), Advisory / Consultancy, Travel / Accommodation / Expenses: Janssen; Honoraria (self), Honoraria (institution), Advisory / Consultancy: Sanofi; Honoraria (self), Honoraria (institution), Advisory / Consultancy: Astellas; Honoraria (self), Honoraria (institution): Novartis; Honoraria (self), Honoraria (institution): Roche; Travel / Accommodation / Expenses: BMS. A. Rezazadeh Kalebasty: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Genentech, Inc./Roche; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Exelixis; Honoraria (self), Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Janssen; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Bayer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): BMS; Honoraria (self), Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Eisai; Research grant / Funding (institution): Macrogenics; Honoraria (self), Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Astellas; Research grant / Funding (institution): beyond spring; Research grant / Funding (institution): Bioclin; Research grant / Funding (institution): Clovis; Research grant / Funding (institution): Bavarian Nordic; Research grant / Funding (institution): Seattle Genetics; Honoraria (self), Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Pfizer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Novartis; Honoraria (self), Speaker Bureau / Expert testimony: Amgen; Shareholder / Stockholder / Stock options: ECOM; Honoraria (self), Speaker Bureau / Expert testimony: Sanofi; Travel / Accommodation / Expenses: Prometheus Labs. B.Y. Alekseev: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Astellas; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Bayer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: BMS; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: MSD; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Sanofi; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Janssen; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Ferring. F.A.B. Schutz: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: MSD; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Bayer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: BMS; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Janssen; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Astellas; Advisory / Consultancy, Spouse / Financial dependant: Ipsen. A. Mecke: Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment: F. Hoffmann-La Roche. S. Mariathasan: Shareholder / Stockholder / Stock options, Full / Part-time employment: Roche/GNE. A. Thastrom: Shareholder / Stockholder / Stock options, Full / Part-time employment: Genentech, Inc.. A. Bamias: Honoraria (self), Research grant / Funding (institution): Roche; Honoraria (self), Research grant / Funding (institution): BMS; Honoraria (self), Research grant / Funding (institution): AstraZeneca. All other authors have declared no conflicts of interest.