Showing papers by "Cora N. Sternberg published in 2016"
Memorial Sloan Kettering Cancer Center1, University of Chicago2, University of Washington3, University of North Carolina at Chapel Hill4, Université Paris-Saclay5, Johns Hopkins University6, Oregon Health & Science University7, University of British Columbia8, University of Texas MD Anderson Cancer Center9, University of Virginia10, Duke University11, Wayne State University12, University of Michigan13, Thomas Jefferson University14, University of Wisconsin-Madison15, Cornell University16, Rutgers University17, University of California, San Francisco18, Tulane University19, Harvard University20, Columbia University21
TL;DR: The concept of no longer clinically benefiting is introduced to underscore the distinction between first evidence of progression and the clinical need to terminate or change treatment, and the importance of documenting progression in existing lesions as distinct from the development of new lesions.
Abstract: PurposeEvolving treatments, disease phenotypes, and biology, together with a changing drug development environment, have created the need to revise castration-resistant prostate cancer (CRPC) clinical trial recommendations to succeed those from prior Prostate Cancer Clinical Trials Working Groups.MethodsAn international expert committee of prostate cancer clinical investigators (the Prostate Cancer Clinical Trials Working Group 3 [PCWG3]) was reconvened and expanded and met in 2012-2015 to formulate updated criteria on the basis of emerging trial data and validation studies of the Prostate Cancer Clinical Trials Working Group 2 recommendations.ResultsPCWG3 recommends that baseline patient assessment include tumor histology, detailed records of prior systemic treatments and responses, and a detailed reporting of disease subtypes based on an anatomic pattern of metastatic spread. New recommendations for trial outcome measures include the time to event end point of symptomatic skeletal events, as well as tim...
938 citations
Harvard University1, Institut Gustave Roussy2, Queen Mary University of London3, University of Texas MD Anderson Cancer Center4, Cleveland Clinic5, Johns Hopkins University6, Aarhus University Hospital7, Washington University in St. Louis8, Helsinki University Central Hospital9, University of Ulsan10, Tom Baker Cancer Centre11, Medical University of Vienna12, University of Utah13, Beth Israel Deaconess Medical Center14, Exelixis15, Texas Oncology16, City of Hope National Medical Center17, Memorial Sloan Kettering Cancer Center18
TL;DR: The randomised phase 3 METEOR trial compared the efficacy and safety of cabozantinib versus the mTOR inhibitor everolimus in patients with advanced renal cell carcinoma who progressed after previous VEGFR tyrosine-kinase inhibitor treatment.
Abstract: Summary Background Cabozantinib is an oral inhibitor of tyrosine kinases including MET, VEGFR, and AXL. The randomised phase 3 METEOR trial compared the efficacy and safety of cabozantinib versus the mTOR inhibitor everolimus in patients with advanced renal cell carcinoma who progressed after previous VEGFR tyrosine-kinase inhibitor treatment. Here, we report the final overall survival results from this study based on an unplanned second interim analysis. Methods In this open-label, randomised phase 3 trial, we randomly assigned (1:1) patients aged 18 years and older with advanced or metastatic clear-cell renal cell carcinoma, measurable disease, and previous treatment with one or more VEGFR tyrosine-kinase inhibitors to receive 60 mg cabozantinib once a day or 10 mg everolimus once a day. Randomisation was done with an interactive voice and web response system. Stratification factors were Memorial Sloan Kettering Cancer Center risk group and the number of previous treatments with VEGFR tyrosine-kinase inhibitors. The primary endpoint was progression-free survival as assessed by an independent radiology review committee in the first 375 randomly assigned patients and has been previously reported. Secondary endpoints were overall survival and objective response in all randomly assigned patients assessed by intention-to-treat. Safety was assessed per protocol in all patients who received at least one dose of study drug. The study is closed for enrolment but treatment and follow-up of patients is ongoing for long-term safety evaluation. This trial is registered with ClinicalTrials.gov, number NCT01865747. Findings Between Aug 8, 2013, and Nov 24, 2014, 658 patients were randomly assigned to receive cabozantinib (n=330) or everolimus (n=328). The median duration of follow-up for overall survival and safety was 18·7 months (IQR 16·1–21·1) in the cabozantinib group and 18·8 months (16·0–21·2) in the everolimus group. Median overall survival was 21·4 months (95% CI 18·7–not estimable) with cabozantinib and 16·5 months (14·7–18·8) with everolimus (hazard ratio [HR] 0·66 [95% CI 0·53–0·83]; p=0·00026). Cabozantinib treatment also resulted in improved progression-free survival (HR 0·51 [95% CI 0·41–0·62]; p vs 3% [2–6] with everolimus; p vs 12 [4%] in the everolimus group), diarrhoea (43 [13%] vs 7 [2%]), fatigue (36 [11%] vs 24 [7%]), palmar-plantar erythrodysaesthesia syndrome (27 [8%] vs 3 [1%]), anaemia (19 [6%] vs 53 [17%]), hyperglycaemia (3 [1%] vs 16 [5%]), and hypomagnesaemia (16 [5%] vs none). Serious adverse events grade 3 or worse occurred in 130 (39%) patients in the cabozantinib group and in 129 (40%) in the everolimus group. One treatment-related death occurred in the cabozantinib group (death; not otherwise specified) and two occurred in the everolimus group (one aspergillus infection and one pneumonia aspiration). Interpretation Treatment with cabozantinib increased overall survival, delayed disease progression, and improved the objective response compared with everolimus. Based on these results, cabozantinib should be considered as a new standard-of-care treatment option for previously treated patients with advanced renal cell carcinoma. Patients should be monitored for adverse events that might require dose modifications. Funding Exelixis Inc.
716 citations
TL;DR: This work performed whole-exome sequencing and clonality analysis of 72 urothelial carcinoma samples, including 16 matched sets of primary and advanced tumors prospectively collected before and after chemotherapy, to provide insights into how selective pressure from chemotherapy directs the evolution of uroclinical carcinoma and shapes its clonal architecture.
Abstract: Chemotherapy-resistant urothelial carcinoma has no uniformly curative therapy. Understanding how selective pressure from chemotherapy directs the evolution of urothelial carcinoma and shapes its clonal architecture is a central biological question with clinical implications. To address this question, we performed whole-exome sequencing and clonality analysis of 72 urothelial carcinoma samples, including 16 matched sets of primary and advanced tumors prospectively collected before and after chemotherapy. Our analysis provided several insights: (i) chemotherapy-treated urothelial carcinoma is characterized by intra-patient mutational heterogeneity, and the majority of mutations are not shared; (ii) both branching evolution and metastatic spread are very early events in the natural history of urothelial carcinoma; (iii) chemotherapy-treated urothelial carcinoma is enriched with clonal mutations involving L1 cell adhesion molecule (L1CAM) and integrin signaling pathways; and (iv) APOBEC-induced mutagenesis is clonally enriched in chemotherapy-treated urothelial carcinoma and continues to shape the evolution of urothelial carcinoma throughout its lifetime.
224 citations
Harvard University1, The Royal Marsden NHS Foundation Trust2, Paris Descartes University3, Medical University of Vienna4, Netherlands Cancer Institute5, Praxis6, Erasmus University Rotterdam7, University of Münster8, Université de Montréal9, Charité10, University of Liverpool11, University of Colorado Denver12, Kaiser Permanente13, University of Tübingen14, Exelixis15, University of Paris-Sud16
TL;DR: Cabozantinib did not significantly improve OS compared with prednisone in heavily treated patients with mCRPC and progressive disease after docetaxel and abiraterone and/or enzalutamide and had some activity in improving BSR, rPFS, SSEs, CTC conversions, and bone biomarkers but not PSA outcomes.
Abstract: PURPOSE: Cabozantinib is an inhibitor of kinases, including MET and vascular endothelial growth factor receptors, and has shown activity in men with previously treated metastatic castration-resistant prostate cancer (mCRPC). This blinded phase III trial compared cabozantinib with prednisone in patients with mCRPC.
PATIENTS AND METHODS: Men with progressive mCRPC after docetaxel and abiraterone and/or enzalutamide were randomly assigned at a two-to-one ratio to cabozantinib 60 mg once per day or prednisone 5 mg twice per day. The primary end point was overall survival (OS). Bone scan response (BSR) at week 12 as assessed by independent review committee was the secondary end point; radiographic progression-free survival (rPFS) and effects on circulating tumor cells (CTCs), bone biomarkers, serum prostate-specific antigen (PSA), and symptomatic skeletal events (SSEs) were exploratory assessments.
RESULTS: A total of 1,028 patients were randomly assigned to cabozantinib (n = 682) or prednisone (n = 346). Median OS was 11.0 months with cabozantinib and 9.8 months with prednisone (hazard ratio, 0.90; 95% CI, 0.76 to 1.06; stratified log-rank P = .213). BSR at week 12 favored cabozantinib (42% v 3%; stratified Cochran-Mantel-Haenszel P < .001). rPFS was improved in the cabozantinib group (median, 5.6 v 2.8 months; hazard ratio, 0.48; 95% CI, 0.40 to 0.57; stratified log-rank P < .001). Cabozantinib was associated with improvements in CTC conversion, bone biomarkers, and post-random assignment incidence of SSEs but not PSA outcomes. Grade 3 to 4 adverse events and discontinuations because of adverse events were higher with cabozantinib than with prednisone (71% v 56% and 33% v 12%, respectively).
CONCLUSION: Cabozantinib did not significantly improve OS compared with prednisone in heavily treated patients with mCRPC and progressive disease after docetaxel and abiraterone and/or enzalutamide. Cabozantinib had some activity in improving BSR, rPFS, SSEs, CTC conversions, and bone biomarkers but not PSA outcomes.
TRIAL REGISTRATION: ClinicalTrials.gov NCT01605227.
194 citations
TL;DR: Elderly men benefited from treatment with enzalutamide in terms of OS and rPFS and were well tolerated in the elderly subgroup and those aged <75 years, and age and enzyme treatment were associated with a higher incidence of falls.
91 citations
Scripps Health1, European Society for Medical Oncology2, American Society of Clinical Oncology3, Marche Polytechnic University4, Karolinska Institutet5, American University of Beirut6, Helsinki University Central Hospital7, University of Ioannina8, Université libre de Bruxelles9, The Royal Marsden NHS Foundation Trust10, University of Alabama at Birmingham11, European Organisation for Research and Treatment of Cancer12, Mayo Clinic13, University of Pittsburgh14, Veterans Health Administration15, Johns Hopkins University16, University of Liverpool17, University of Warwick18, University Medical Center Groningen19, Harvard University20, University of Florida21, University of Virginia22, Roswell Park Cancer Institute23, Hebron University24, University Hospital of Bern25, Vanderbilt University26, University of Texas MD Anderson Cancer Center27, University of Southern California28, Vienna General Hospital29, University of Southern Denmark30, Charité31, University of Texas Southwestern Medical Center32, University Hospital of Basel33, Memorial Sloan Kettering Cancer Center34, Community College of Rhode Island35, Indiana University36, Medical University of Vienna37, University Hospital of Lausanne38, Champalimaud Foundation39, National and Kapodistrian University of Athens40, University of British Columbia41, Uppsala University Hospital42, University of Turin43, European Institute of Oncology44, Brigham and Women's Hospital45, Maine Medical Center46, Institut Gustave Roussy47, Martin Luther University of Halle-Wittenberg48, Beth Israel Deaconess Medical Center49, Mount Sinai Health System50, University of St. Gallen51, University of Zurich52, Netherlands Cancer Institute53, University of Chicago54, New York University55, Katholieke Universiteit Leuven56
TL;DR: The European Society for Medical Oncology (ESMO) and the American Society of Clinical Oncologists (ASCO) published a new edition of the ESMO/ASCO Global Curriculum (GC) thanks to contribution of 64 ESMO-appointed and 32 ASCO-appointed authors as mentioned in this paper.
88 citations
Duke University1, Indiana University2, The Royal Marsden NHS Foundation Trust3, University of Utah4, University Hospitals Birmingham NHS Foundation Trust5, University of Münster6, Texas Oncology7, Guy's and St Thomas' NHS Foundation Trust8, Autonomous University of Barcelona9, Universidade Federal do Rio Grande do Sul10, Ipsen11, Johns Hopkins University12
TL;DR: In chemotherapy-naïve men with mCRPC, tasquinimod significantly improved rPFS compared with placebo, however, no OS benefit was observed.
Abstract: PurposeTasquinimod, a novel oral therapy targeting the tumor microenvironment, significantly improved progression-free survival (PFS) in a randomized, placebo-controlled phase II trial in men with metastatic castration-resistant prostate cancer (mCRPC). This phase III study was conducted to confirm the phase II results and to detect an overall survival (OS) benefit.Patients and MethodsMen with chemotherapy-naive mCRPC and evidence of bone metastases were assigned (2:1) to receive tasquinimod once per day or placebo until progression or toxicity. The primary end point was radiographic PFS (rPFS; time from random assignment to radiologic progression or death) per Prostate Cancer Working Group 2 criteria and RECIST 1.1. The study had 99.9% power to detect an rPFS hazard ratio (HR) of 0.6 with a two-sided alpha error of .05 and 80% power to detect a target HR of 0.8 for OS, the key secondary end point.ResultsIn all, 1,245 patients were randomly assigned to either tasquinimod (n = 832) or placebo (n = 413) bet...
78 citations
Scripps Health1, European Society for Medical Oncology2, American Society of Clinical Oncology3, Marche Polytechnic University4, Karolinska Institutet5, American University of Beirut6, Helsinki University Central Hospital7, University of Ioannina8, Université libre de Bruxelles9, The Royal Marsden NHS Foundation Trust10, University of Alabama at Birmingham11, European Organisation for Research and Treatment of Cancer12, Mayo Clinic13, University of Pittsburgh14, Veterans Health Administration15, Johns Hopkins University16, University of Liverpool17, University of Warwick18, University Medical Center Groningen19, Harvard University20, University of Florida21, University of Virginia22, Roswell Park Cancer Institute23, Hebron University24, University Hospital of Bern25, Vanderbilt University26, University of Texas MD Anderson Cancer Center27, University of Southern California28, Vienna General Hospital29, University of Southern Denmark30, Charité31, University of Texas Southwestern Medical Center32, University Hospital of Basel33, Memorial Sloan Kettering Cancer Center34, Community College of Rhode Island35, Indiana University36, Medical University of Vienna37, University Hospital of Lausanne38, Champalimaud Foundation39, National and Kapodistrian University of Athens40, University of British Columbia41, Uppsala University Hospital42, University of Turin43, European Institute of Oncology44, Brigham and Women's Hospital45, Maine Medical Center46, Institut Gustave Roussy47, Martin Luther University of Halle-Wittenberg48, Beth Israel Deaconess Medical Center49, Mount Sinai Health System50, University of St. Gallen51, University of Zurich52, Netherlands Cancer Institute53, University of Chicago54, New York University55, Katholieke Universiteit Leuven56
TL;DR: A new edition of the ESMO/ASCO Global Curriculum with several new chapters on technical contents such as molecular pathology, translational research or molecular imaging and on conceptual attitudes towards human principles like genetic counselling or survivorship have been integrated in the GC.
Abstract: The European Society for Medical Oncology (ESMO) and the American Society of Clinical Oncology (ASCO) are publishing a new edition of the ESMO/ASCO Global Curriculum (GC) thanks to contribution of 64 ESMO-appointed and 32 ASCO-appointed authors. First published in 2004 and updated in 2010, the GC edition 2016 answers to the need for updated recommendations for the training of physicians in medical oncology by defining the standard to be fulfilled to qualify as medical oncologists. At times of internationalisation of healthcare and increased mobility of patients and physicians, the GC aims to provide state-of-the-art cancer care to all patients wherever they live. Recent progress in the field of cancer research has indeed resulted in diagnostic and therapeutic innovations such as targeted therapies as a standard therapeutic approach or personalised cancer medicine apart from the revival of immunotherapy, requiring specialised training for medical oncology trainees. Thus, several new chapters on technical contents such as molecular pathology, translational research or molecular imaging and on conceptual attitudes towards human principles like genetic counselling or survivorship have been integrated in the GC. The GC edition 2016 consists of 12 sections with 17 subsections, 44 chapters and 35 subchapters, respectively. Besides renewal in its contents, the GC underwent a principal formal change taking into consideration modern didactic principles. It is presented in a template-based format that subcategorises the detailed outcome requirements into learning objectives, awareness, knowledge and skills. Consecutive steps will be those of harmonising and implementing teaching and assessment strategies.
71 citations
University of California, Davis1, University of Washington2, Medical University of South Carolina3, Washington University in St. Louis4, Université de Montréal5, University of Copenhagen6, Charité7, Asan Medical Center8, Nippon Medical School9, Durham University10, Institut Gustave Roussy11, The Royal Marsden NHS Foundation Trust12, Medivation13, Astellas Pharma14, Oregon Health & Science University15, Cliniques Universitaires Saint-Luc16
TL;DR: Enzalutamide provided clinically significant benefits in men with chemotherapy-naïve metastatic castration-resistant prostate cancer, with or without visceral disease, low- or high-volume bone disease, or lymph node only disease.
66 citations
TL;DR: This study confirmed the efficacy and safety of the novel androgen receptor pathway targeted agents in improving outcome of CRPC patients.
53 citations
01 Aug 2016
TL;DR: The tumour–non-tumour (TNT) ratio of 8 lesions, monitored by six 99mTc-MDP bone scans over a period of about 10 months, evidenced a TNT reduction in two lesions, evidencing that 223Ra-dichloride therapy tends to prevent further progression of osseous disease, leading to chronicity of the metastatic status.
Abstract: A 70-year-old man affected by bone metastases from castration resistant prostate cancer underwent Alpharadin ((223)Ra-dichloride) therapy (6 administrations of 50 kBq per kg i.v., once every 4 weeks). The inter-fraction variability of the absorbed dose to lesions was evaluated for four injections. Dosimetric assessments were performed following the MIRD approach and a recently published methodology. The mean absorbed dose and standard deviation for 4 lesions [mean (σ %)] were: 434 mGy (15%) and 516 mGy (21%) for the right and left humeral head, 1205 mGy (14%) and 781 mGy (8%) for the right and left glenoid. The estimated total absorbed dose after the whole treatment, considering also the relative-biological effectiveness of alpha particles (RBE = 5), yielded a D RBE range of 13-36 Gy. A good correlation between (99m)Tc and (223)Ra uptake was obtained (R (2) = 0.7613). The tumour-non-tumour (TNT) ratio of 8 lesions (those above, plus 4 additional), monitored by six (99m)Tc-MDP bone scans over a period of about 10 months, evidenced a TNT reduction in two lesions (-42 and -48 %), but in most lesions the TNT remained fairly constant, evidencing that (223)Ra-dichloride therapy tends to prevent further progression of osseous disease, leading to chronicity of the metastatic status.
TL;DR: A deeper knowledge of the pathogenesis of BC will derive from gene expression profiling (GEP), and this will give us new prognostic and predictive tools to develop more targeted treatments, including immunotherapy, which will become a pivotal treatment for BC in the very near future.
Abstract: In the last 25 years, there has been an improved understanding of the pathogenesis of muscle-invasive bladder cancer (BC). Development of new treatment strategies has followed. We have progressed from the awareness of the efficacy of platinum compounds, especially cisplatin, as single agents to the development of effective drug combinations with greater attention in improving safety profiles while impacting on survival. Peri-operative chemotherapy (CHT) is the standard of care for non-metastatic disease. The most evidence in terms of a survival advantage is derived from neoadjuvant chemotherapy (NC) trials, but adjuvant medical treatment should be strongly considered when NC has not been utilized. Patient selection and a multidisciplinary approach are essential. Platinum-based CHT is still the standard of care for both early and advanced disease. A deeper knowledge of the pathogenesis of BC will derive from gene expression profiling (GEP), and this will give us new prognostic and predictive tools to develop more targeted treatments. A high mutational rate has been observed in BC, which can generate neoantigens that initiate cancer immunity. Immunotherapy will become a pivotal treatment for BC, in the very near future. Emerging data are encouraging, and these treatments may well revolutionize the medical approach to this disease while CHT will play a less important role.
TL;DR: Determination of AR-V7 in CTCs is a big step towards a more personalized treatment approach in mCRPC, and several biomarkers are currently under investigation that may predict which patients will respond to specific therapies in the future of metastatic castration-resistant prostate cancer treatment.
Abstract: Context Biomarkers for the treatment of metastatic castration-resistant prostate cancer (mCRPC) are urgently needed by clinicians to facilitate treatment decisions. Objective To review current prognostic and predictive biomarkers in mCRPC. Evidence acquisition We performed a nonsystematic review of the literature from 2004 to August 2016 by searching in Medline. Cross-matching references were used to search for additional articles. We reviewed clinical research and review articles written in the English language. Evidence synthesis Nomograms of prognostic factors (eg, albumin, lactate dehydrogenase) enable clinicians to estimate the prognosis of men with mCRPC. These prognostic tools may aid with when to trigger treatment, therapeutic monitoring, and follow-up. However, validated predictive biomarkers in mCRPC are still lacking. Androgen receptor (AR) splice variants (ie, AR-V7), gene fusions, and point mutations determined using liquid biopsies such as circulating tumor cells (CTCs) or cell-free DNA (cfDNA) are promising biomarkers that are the subject of ongoing research. Patient biomarkers (eg, neutrophil-to-lymphocyte ratio) are readily available and come with no extra cost but need further validation before their implementation in clinical practice. Conclusions Determination of AR-V7 in CTCs is a big step towards a more personalized treatment approach in mCRPC. Genomic characterization of liquid biopsies such as CTCs, cfDNA, and circulating RNA are noninvasive tools to further personalize treatment in prostate cancer. Clinical parameters are readily available, but are derived from retrospective studies and should be interpreted with care. Only by conducting biomarker-driven studies, rather than large one-size-fits-all trials, will we be able to improve prostate cancer treatment. Patient summary Several biomarkers are currently under investigation that may predict which patients will respond to specific therapies in the future of metastatic castration-resistant prostate cancer treatment.
TL;DR: This analysis further evaluates PFS and ORR across pt subgroups and Safety profiles of C and E in this trial were similar to prior experience with each drug in this pt population.
Abstract: 499 Background: Cabozantinib (C) inhibits tyrosine kinases including VEGFRs, MET, and AXL. The METEOR phase 3 trial (NCT01865747) met its primary endpoint of significant improvement in PFS with C versus everolimus (E) in pts with advanced clear cell RCC and prior exposure to VEGFR TKIs (7.4 mo median PFS [C] vs 3.8 mo [E], HR = 0.58, 95% CI, 0.45 to 0.75; p < 0.001). The improvement in PFS was accompanied by a significant improvement in ORR and a trend for improved OS at an interim analysis. Safety profiles of C and E in this trial were similar to prior experience with each drug in this pt population. This analysis further evaluates PFS and ORR across pt subgroups. Methods: Pts had advanced RCC with clear cell component, measurable disease per RECIST 1.1, KPS ≥ 70%, and were stratified by MSKCC prognostic criteria and number of prior VEGFR TKIs. Pts must have progressed during treatment or within 6 months of the last dose of their most recent VEGFR TKI. 658 pts were randomized 1:1 to receive C (60 mg QD) ...
TL;DR: O1 Combinatorial CD8+ and PD-L1+ cell densities correlate with response and improved survival in non-small cell lung cancer patients treated with durvalumab.
Abstract: ### O1 Combinatorial CD8+ and PD-L1+ cell densities correlate with response and improved survival in non-small cell lung cancer (NSCLC) patients treated with durvalumab
#### Sonja Althammer1, Keith Steele2, Marlon Rebelatto2, Tze Heng Tan1, Tobias Wiestler1, Guenter Schmidt1, Brandon Higgs2, Xia
TL;DR: Concern and disagreement are expressed with the (grade 1A) recommendation in the ESMO clinical practice guidelines for prostate cancer that: ‘androgen deprivation therapy (ADT) plus docetaxel is recommended as first-line treatment of metastatic, hormone-naïve disease in men fit enough for chemotherapy’.
TL;DR: This case study supports the need to adjust for confounded OS due to crossover, which enables trials to meet ethical standards and provides decision makers with a more accurate estimate of treatment benefit.
Abstract: Objective: To identify the issues of using overall survival (OS) as a primary endpoint in the presence of crossover and the statistical analyses available to adjust for confounded OS due to crossover in oncology clinical trials. Methods: An indirect comparison was conducted between pazopanib and sunitinib in advanced renal cell carcinoma. Statistical adjustment methods were used to estimate the true comparative effectiveness of these treatments. Recently, a head-to-head trial comparing pazopanib and sunitinib was completed. This provided the opportunity to compare the OS treatment effect estimated for pazopanib versus sunitinib using indirect comparison and statistical adjustment techniques with that observed in the head-to-head trial. Results: Using a rank-preserving structural failure time model to adjust for crossover in the pazopanib registration trial, the indirect comparison of pazopanib versus sunitinib resulted in an OS hazard ratio (HR) of 0.97, while an unadjusted analysis resulted in an OS HR of 1.96. The head-to-head trial reported a final OS HR of 0.92 for pazopanib versus sunitinib. Conclusion: This case study supports the need to adjust for confounded OS due to crossover, which enables trials to meet ethical standards and provides decision makers with a more accurate estimate of treatment benefit.
TL;DR: Future strategies involving enzalutamide should account for previous exposure to taxanes or antiandrogen therapies and the presence of AR variants that could affect efficacy, as recent findings have suggested cross-resistance occurs between and within drug classes.
Abstract: Prostate cancer is initially responsive to androgen deprivation therapy, but most patients eventually develop castration-resistant disease. Enzalutamide is an androgen receptor (AR) inhibitor that targets several steps in the AR signaling pathway and has shown significant efficacy in the treatment of metastatic castration-resistant prostate cancer in patients with or without prior chemotherapy. To provide optimal treatment, it is important to understand the implications of enzalutamide use in the context of other therapies, as recent findings have suggested cross-resistance occurs between and within drug classes. Mutations and splice variants of AR also impact the course of prostate cancer. Future strategies involving enzalutamide should account for previous exposure to taxanes or antiandrogen therapies and the presence of AR variants that could affect efficacy.
TL;DR: The secondary efficacy endpoints discussed here include a panel of radiological, PSA based and symptomatically assessed measures that targets the tumor microenvironment.
Abstract: 239 Background: TASQ is an oral agent with immunomodulatory, anti-angiogenic and anti-metastatic properties that targets the tumor microenvironment. It was recently reported from this study that in chemotherapy-naive men with mCRPC, single-agent TASQ statistically significantly improved rPFS, by both central (HR (95% CI) 0.64 (0.54-0.75)) and local review, as compared to PBO but no OS benefit was demonstrated (HR (95% CI) 1.10 (0.94-1.28)). In this abstract the results of secondary efficacy endpoint analyses are presented. Methods: Men with asymptomatic to mildly symptomatic chemotherapy-naive mCRPC and evidence of bone metastases were assigned (2:1) to receive TASQ or PBO once daily until progression or toxicity. Randomization was stratified by KPS ( ≥ 90% vs < 90%), presence/absence of visceral disease, and geographic region. The secondary efficacy endpoints discussed here include a panel of radiological, PSA based and symptomatically assessed measures. Results: 1245 pts were randomized (TASQ, n = 832; ...
TL;DR: Preclinical studies suggest that in addition to blocking cell division, taxanes impair the AR signaling axis by inhibiting intracellular AR activity, which may explain and contribute to its efficacy in prostate cancer.
National and Kapodistrian University of Athens1, Alexandra Hospital2, University of Southampton3, Harvard University4, Fox Chase Cancer Center5, City of Hope National Medical Center6, St Bartholomew's Hospital7, University of Washington8, University of Milan9, Huntsman Cancer Institute10, Memorial Sloan Kettering Cancer Center11, Mount Sinai Hospital12
National and Kapodistrian University of Athens1, Alexandra Hospital2, Harvard University3, University of Southampton4, Fox Chase Cancer Center5, City of Hope National Medical Center6, St Bartholomew's Hospital7, Huntsman Cancer Institute8, University of Washington9, University of Michigan10, Stanford University11, Memorial Sloan Kettering Cancer Center12, Mount Sinai Hospital13
TL;DR: The primary end point was no ME, and secondary end points included additional safety, as well as response rate in the first 24 weeks, defined as a decline in prostate-specific antigen (PSA) ≥ 50% confirmed after 4 weeks.
Abstract: 261 Background: AA is approved for mCRPC, coadministered with prednisone (P) (5 mg BID) to prevent adverse events (AEs) associated with mineralocorticoid excess (ME). Lower GC doses had not previously been formally evaluated in combination with AA. Methods: This was an open-label, multicenter, phase 2 trial (NCT01867710) of asymptomatic chemotherapy-naive mCRPC pts randomized 1:1:1:1 to AA (1000 mg QD) plus P 5 mg BID or P 5 mg QD or P 2.5 mg BID or dexamethasone (DEX) 0.5 mg QD. Pts who had previously received GC or ketoconazole were excluded. The primary end point was no ME (% of pts experiencing neither hypokalemia nor hypertension during the first 24 weeks of treatment).Secondary end points included additional safety, as well as response rate in the first 24 weeks, defined as a decline in prostate-specific antigen (PSA) ≥ 50% confirmed after 4 weeks. Results: 164 pts were randomized; 133 (81.6%) completed 24 weeks’ treatment. Median age: 70 years. Table 1 shows the rates of ME, hypertension, hypokalem...
TL;DR: In all patients, addition of docetaxel chemotherapy improved failure-free survival (FFS) and addition of zoledronic acid (ZA) to ADT, and ZA alone did not affect FFS or overall survival (OS).
TL;DR: This study assessed whether TASQ maintenance therapy improved disease control duration in mCRPC pts with response or stabilization on first-line docetaxel (NCT01732549) and found that it did not.
Abstract: 201 Background: TASQ is an oral immunomodulatory, antiangiogenic and antimetastatic agent that targets the tumor microenvironment. In a phase 2 trial in mCRPC, TASQ increased PFS in chemotherapy-naive pts vs placebo (PBO) (Pili et al. JCO 2011), but there was no OS benefit in a recent phase 3 trial (NCT01234311). This study assessed whether TASQ maintenance therapy improved disease control duration in mCRPC pts with response or stabilization on first-line docetaxel (NCT01732549). Methods: Pts with mCRPC not progressing after docetaxel (min. 6 cycles; RECIST criteria; no PSA rise for last 3 tests) were assigned (1:1) to receive within 6 wks of last docetaxel administration: oral TASQ qd (0.25 mg/d rising to 1.0 mg/d over 4 wks, if tolerated) or PBO, until progression or toxicity. Randomization was stratified by visceral metastases and opioid analgesic use. Primary endpoint: radiographic PFS (rPFS) per RECIST 1.1 and PCWG 2 criteria, assessed locally. Planned sample size: 140 pts to achieve 80% power to det...
TL;DR: Using data from the final analysis at 439 rPFS events, a strong correlation between investigator and central review is shown and the association between investigator-assessed rP FS and OS is reported.
Abstract: 182 Background: In PREVAIL, enzalutamide (ENZA) significantly improved OS (hazard ratio [HR] 0.71; P < 0.0001) and rPFS (HR 0.19; P < 0.0001) compared with placebo in chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC). Using data from the final analysis at 439 rPFS events we showed a strong correlation between investigator and central review. Here we report sensitivity analyses (SAs) from the final analysis of investigator-assessed rPFS and the association between investigator-assessed rPFS and OS. Methods: The coprimary endpoint of rPFS was defined as time from randomization to the earliest objective evidence of centrally assessed radiographic progression, defined by PCWG2 guidelines for bone disease and RECIST v1.1 for soft-tissue disease, or death within 168 days of treatment discontinuation. Bone progression was captured using a validated bone scan data capture assay. Four SAs were performed on investigator-assessed rPFS to evaluate the impact of: (1) progression in bone, (2) c...
University of Milan1, UAB Hospital2, National and Kapodistrian University of Athens3, University of Southampton4, Harvard University5, Fox Chase Cancer Center6, University of Washington7, St Thomas' Hospital8, Stanford University9, City of Hope National Medical Center10, Memorial Sloan Kettering Cancer Center11, Icahn School of Medicine at Mount Sinai12
01 Jan 2016
TL;DR: The current standard of care and available hormonal strategies in advanced PCa and future therapeutic perspectives that could change treatment paradigms in the coming years are summarized.
Abstract: Prostate cancer (PCa) is the second most common cancer in men, comprising 15% of new cancer cases. While most cases are diagnosed at an early stage and can be managed conservatively or by local treatment alone, up to 30% of patients will receive androgen deprivation therapy (ADT). Indeed, high-risk localised and locally advanced PCa require either surgery or ADT in combination with radiation as a local strategy. On the other hand, metastatic patients are treated upfront with ADT, eventually combined with docetaxel, as suggested by recent studies. ADT has been in use for more than 60 years and during this time it has undergone considerable evolution. Gonadotropin-releasing hormone (GnRH) agonists have supplanted surgical castration and oestrogens, and are now challenged by GnRH antagonists. ADT induces profound but often short-lasting responses. In a low serum testosterone environment, the androgen receptor (AR) pathway may be reactivated either by overexpression, by mutation of the AR itself, or by adrenal or intracrine production of androgens. These mechanisms underlie the development of the majority of castration-resistant prostate cancers (CRPCs). In addition to AR adaptation, several AR-independent mechanisms may also underlie progression of these cancers on ADT. A new generation of AR-pathway inhibitors have succeeded first-generation anti-androgens and steroids, and are proven to extend survival in patients with metastatic CRPC. This review aims to summarise the current standard of care and available hormonal strategies in advanced PCa and future therapeutic perspectives that could change treatment paradigms in the coming years.