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Improving Outcomes in Prostate Cancer Dr Clare Gilson MD(Res) Institute of Clinical Trials and Methodology University College

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Improving Outcomes in Prostate Cancer Dr Clare Gilson MD(Res) Institute of Clinical Trials and Methodology University College Improving Outcomes in Prostate Cancer Dr Clare Gilson MD(Res) Institute of Clinical Trials and Methodology University College London 1 Declaration I declare that the work presented in this thesis is my own. I have stated the contributions of others within the following acknowledgement section ………………………………………………………….. Dr Clare Gilson 2 Improving Outcomes in Prostate Cancer Acknowledgements I would like to thank my supervisors Ruth Langley, Duncan Gilbert, Simon Chowdhury and Matthew Sydes for all their support, guidance and encouragement which has enabled me to complete this thesis. The STAMPEDE trial is a large and complex project that started in 2003 and will continue for many years to come. I joined the trial team as a Clinical Research Fellow based at the MRC Clinical Trials Unit at UCL in June 2015. During my three year fellowship I wrote the translational protocol to permit sequencing analyses on tumour samples, secured funding and established the required academic and industry collaborations. With the help and support of the CTU team, I initiated sample retrieval from NHS sites. I am grateful for the support of Malcolm Mason and the Wales Cancer Bank team, particularly Alison Parry- Jones, Fiona Morgan and David Griffiths for all their help in facilitating and processing sample collection and histopathological review. I drafted the protocol amendment to permit docetaxel within STAMPEDE and have been closely involved in implementing this and subsequent changes, such as the addition of metformin and the biomarker-screening pilot. With the help of Matthew Nankivell, I undertook the PSA analyses and I am grateful for the encouragement and support of Robert Laing, Simon Chowdhury and Matthew Sydes in this. Melissa Gannon and Chris Brawley led on the statistical aspects of the proposed future trial design and generate the projected scenarios. I thank Fiona Ingleby for her help in graphically presenting the prevalence data. I thank Gert Attard, Marina Parry and Emily Grist at UCL for their support, advice and teaching. I also thank Sarah Burdett from the MRC UCL meta-analysis group for her guidance. I am grateful to Clovis Oncology for funding the sample analysis and fostering positive collaborations with Almac Diagnostics and Foundation Medicine who undertook all sequencing analyses. Finally, I would like to thank my colleagues past and present in the STAMPEDE trial team; Matthew Sydes, Claire Amos, Nafisah Atako, Max Parmar, Melissa Gannon, Fiona Ingleby, Chris Brawley, Chris Wanstall, Orla Prendiville, Mazna Anjum, Nour Merzouki, Dominic Hague and Francesca Schiavone. 3 Table of Contents Abbreviations and Glossary of terms ................................................................................... 8 Gene list ............................................................................................................................. 11 List of clinical trials ............................................................................................................. 12 Chapter 1 Introduction ....................................................................................................... 23 1.1 Clinical overview .................................................................................................... 23 1.1.1 Systemic treatment of metastatic prostate cancer ....................................... 23 1.1.2 Changes in up-front systemic therapy ........................................................... 27 1.2 Molecular basis of prostate cancer ........................................................................ 29 1.3 STAMPEDE clinical trial .......................................................................................... 32 1.3.1 Trial design ..................................................................................................... 32 1.3.2 Summary of STAMPEDE results to date ......................................................... 34 1.4 Identified research priorities ................................................................................. 40 1.5 How can STAMPEDE data inform treatment selection? ........................................ 40 1.5.1 Seek support and understanding of variable treatment effects .................... 41 1.5.2 Improved risk-stratification ........................................................................... 44 1.5.3 Identify potential predictors of response ...................................................... 45 1.6 Summary of research objectives ............................................................................ 46 Chapter 2 Contextualising the STAMPEDE celecoxib and zoledronic acid results ............. 48 2.1 Introduction ........................................................................................................... 48 2.1.1 Rationale to evaluate cox-2 inhibitors as anti-cancer agents ........................ 50 2.1.2 Impact of external safety data ....................................................................... 54 2.1.3 Rationale for evaluating in combination with zoledronic acid ...................... 56 2.1.4 Research aims ................................................................................................ 59 2.2 Methods ................................................................................................................. 59 2.2.1 Search strategy............................................................................................... 59 4 2.2.2 Outcomes ....................................................................................................... 59 2.2.3 Study selection ............................................................................................... 60 2.2.4 Eligibility criteria ............................................................................................. 60 2.2.5 Data items and collection .............................................................................. 61 2.2.6 Statistical analysis .......................................................................................... 61 2.3 Results .................................................................................................................... 62 2.3.1 Study selection ............................................................................................... 62 2.3.2 Study characteristics ...................................................................................... 65 2.3.3 Risk of bias ..................................................................................................... 72 2.3.4 Additional data on bisphosphonate use ........................................................ 75 2.3.5 Synthesis of results ........................................................................................ 78 2.3.6 Review of additional translational analyses .................................................. 86 2.3.7 Ongoing trials of interest ............................................................................... 87 2.4 Discussion ............................................................................................................... 89 2.4.1 Summary of evidence .................................................................................... 89 2.4.2 Limitations ...................................................................................................... 90 2.4.3 Exploring potential therapeutic mechanisms of action ................................. 90 2.4.4 Future work .................................................................................................... 92 2.5 Conclusions ............................................................................................................ 93 Chapter 3 Prostate-specific antigen kinetics as prognostic biomarkers ............................. 94 3.1 Introduction ........................................................................................................... 94 3.1.1 Research aims ................................................................................................ 98 3.2 Methods ................................................................................................................. 98 3.2.1 Outcome measures ........................................................................................ 99 3.2.2 Statistical approach ...................................................................................... 100 3.2.2.1 Analysis of PSA response ............................................................................. 100 3.2.2.2 Analysis of PSA nadir .................................................................................... 101 3.3 Results .................................................................................................................. 103 5 3.3.1 Patient cohorts for analysis of PSA response ............................................... 103 3.3.2 PSA response in ADT alone group ................................................................ 107 3.3.3 Impact of PSA response on overall survival ................................................. 112 3.3.4 Impact of PSA response on failure-free survival in ADT alone group .......... 116 3.3.5 Impact of PSA response in ADT+docetaxel treated group ........................... 117 3.4 Patient cohort for analysis of PSA nadir assessed following completion of docetaxel .......................................................................................................................... 119 3.4.1 Comparative baseline characteristics by PSA nadir category
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