Addition of AR pathway inhibitors vs. docetaxel: Statisticians - - PowerPoint PPT Presentation

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Addition of AR pathway inhibitors vs. docetaxel: Statisticians - - PowerPoint PPT Presentation

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Addition of AR pathway inhibitors vs. docetaxel: Statisticians perspective Matthew Sydes MRC Clinical Trials Unit at UCL London 30-Aug-2019 Version 1.00, 29-Aug-2019 MRC Clinical Trials Unit at UCL What data are available? How to

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MRC Clinical Trials Unit at UCL

Addition of AR pathway inhibitors vs. docetaxel: Statisticians’ perspective

Matthew Sydes MRC Clinical Trials Unit at UCL London 30-Aug-2019

Version 1.00, 29-Aug-2019

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What data are available? How to compare? → Indirect → Direct Cautionary tales

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Disclosures

Relevant research funding to institute:

  • Astellas
  • Clovis Oncology
  • Janssen
  • Novartis
  • Pfizer
  • Sanofi-Genzyme

Honoraria and travel:

  • Eli Lilly
  • Janssen

Statistician on:

  • PR04
  • PR05
  • PR07
  • RADICALS-RT
  • RADICALS-HT
  • RT01
  • STAMPEDE:doc
  • STAMPEDE:doc+ZA
  • STAMPEDE:ZA
  • STAMPEDE:cel
  • STAMPEDE:cel+ZA
  • STAMPEDE:abi
  • STAMPEDE:M1-RT
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STOPCAP network meta-analysis (2018) – indirect comparison

Overall survival

Published data network meta-analysis

Vale et al Abridged version of Figure 2 from doi:10.1093/annonc/mdy071

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STOPCAP network meta-analysis (2018) – indirect comparison

Vale et al Abridged version of Figure 2 from doi:10.1093/annonc/mdy071

Overall survival

Published data network meta-analysis

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STOPCAP network meta-analysis (2018) – indirect comparison

Network = 6204 patients

Vale et al doi:10.1093/annonc/mdy071

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Vale et al doi:10.1093/annonc/mdy071

STOPCAP network meta-analysis (2018) – indirect comparison

Network = 6204 patients Effect of ADT+Doc vs ADT+AAP trigulated through ADT alone

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doi:10.1093/annonc/mdy071

STOPCAP network meta-analysis (2018) – indirect comparison

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Network of selected published results in mHSPC

Network of trials tending towards moving forward

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Network of selected published results in mHSPC

Network of trials tending towards moving forward Comparison of “Adding Docetaxel”

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Network of selected published results in mHSPC

Network of trials tending towards moving forward Comparison of “Adding Abiraterone”

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Network of selected published results in mHSPC

Network of trials tending towards moving forward Comparison of “Adding Radiotherapy”

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Network of selected published results in mHSPC

Network of trials tending towards moving forward Comparison of “Adding Docetaxel” OR “Adding abiraterone” Only directly comparative data of adding docetaxel or AR pathway inhibitor

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Data from STAMPEDE leading to direct comparison

SOC+DocP vs SOC (n=1776) [2:1] M1 61% Age 65 yr

median

PSA 68 ng/ml

median

Accrue Oct-2005 to Mar-2013 Freeze May-2015

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SOC+DocP vs SOC (n=1776) [2:1] M1 61% Age 65 yr

median

PSA 68 ng/ml

median

Accrue Oct-2005 to Mar-2013 Freeze May-2015 SOC+AAP vs SOC (n=1917) [1:1] M1 52% Age 67 yr

median

PSA 53 ng/ml

median

Accrue Nov-2011 to Jan-2014 Freeze Mar-2017

Data from STAMPEDE leading to direct comparison

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SOC+DocP vs SOC (n=1776) [2:1] M1 61% Age 65 yr

median

PSA 68 ng/ml

median

Accrue Oct-2005 to Mar-2013 Freeze May-2015 SOC+AAP vs SOC (n=1917) [1:1] M1 52% Age 67 yr

median

PSA 53 ng/ml

median

Accrue Nov-2011 to Jan-2014 Freeze Mar-2017

SOC+DocP vs SOC+AAP (n=566) [1:2] M1 60% Age 66 yr

median

PSA 56 ng/ml

median

Accrue Nov-2011 to Mar-2013 Freeze Mar-2017

Data from STAMPEDE leading to direct comparison

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SOC+DocP vs SOC (n=1776) [2:1] M1 61% Age 65 yr

median

PSA 68 ng/ml

median

Accrue Oct-2005 to Mar-2013 Freeze May-2015 SOC+AAP vs SOC (n=1917) [1:1] M1 52% Age 67 yr

median

PSA 53 ng/ml

median

Accrue Nov-2011 to Jan-2014 Freeze Mar-2017

doi: 10.1016/S0140-6736(15)01037-5

HR (95%CI) 0.78 (0.66, 0.93) P-value 0.006

SOC+DocP vs SOC+AAP (n=566) [1:2] M1 60% Age 66 yr

median

PSA 56 ng/ml

median

Accrue Nov-2011 to Mar-2013 Freeze Mar-2017

SURVIVAL

Data from STAMPEDE leading to direct comparison

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SOC+DocP vs SOC (n=1776) [2:1] M1 61% Age 65 yr

median

PSA 68 ng/ml

median

Accrue Oct-2005 to Mar-2013 Freeze May-2015 SOC+AAP vs SOC (n=1917) [1:1] M1 52% Age 67 yr

median

PSA 53 ng/ml

median

Accrue Nov-2011 to Jan-2014 Freeze Mar-2017

doi: 10.1016/S0140-6736(15)01037-5

HR (95%CI) 0.78 (0.66, 0.93) P-value 0.006 HR (95%CI) 0.63 (0.52, 0.76) P-value 0.00000115

doi: 10.1056/NEJMoa1702900

SOC+DocP vs SOC+AAP (n=566) [1:2] M1 60% Age 66 yr

median

PSA 56 ng/ml

median

Accrue Nov-2011 to Mar-2013 Freeze Mar-2017

SURVIVAL SURVIVAL

Data from STAMPEDE leading to direct comparison

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SOC+DocP vs SOC (n=1776) [2:1] M1 61% Age 65 yr

median

PSA 68 ng/ml

median

Accrue Oct-2005 to Mar-2013 Freeze May-2015 SOC+AAP vs SOC (n=1917) [1:1] M1 52% Age 67 yr

median

PSA 53 ng/ml

median

Accrue Nov-2011 to Jan-2014 Freeze Mar-2017

doi: 10.1016/S0140-6736(15)01037-5

HR (95%CI) 0.78 (0.66, 0.93) P-value 0.006 HR (95%CI) 0.63 (0.52, 0.76) P-value 0.00000115

doi: 10.1056/NEJMoa1702900

SOC+DocP vs SOC+AAP (n=566) [1:2] M1 60% Age 66 yr

median

PSA 56 ng/ml

median

Accrue Nov-2011 to Mar-2013 Freeze Mar-2017

doi: 10.1093/annonc/mdy072

SURVIVAL SURVIVAL

Data from STAMPEDE leading to direct comparison

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SOC+DocP vs SOC+AAP (n=566) [1:2] M1 60% Age 66 yr

median

PSA 56 ng/ml

median

Accrue Nov-2011 to Mar-2013 Freeze Mar-2017

doi: 10.1093/annonc/mdy072

Data from STAMPEDE leading to direct comparison

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Summary

Strong evidence favouring AAP Toxicity profiles quite different and well known Weak evidence favouring AAP No good evidence of a difference

Favours SOC+AAP Favours SOC+DocP Hazard ratio Metastatic progression-free survival Progression-free survival Failure-free survival Symptomatic skeletal events Cause-specific survival Overall survival

Head-to-head data in 566 M0 and M1 pts

(Recruited Nov-2011 to Mar-2013)

→ Proportionately different time spent in each disease state

doi: 10.1093/annonc/mdy072

HR<1 favours adding abiraterone HR>1 favours adding docetaxel

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A note of caution

‡ Key eligibility criteria in STAMPEDE unchanged in 15 years ‡ Subtle shifts over time in patients joining any trial ‡ Some shifts in standard practice and management,

especially relating to second-line care

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A note of caution

‡ Key eligibility criteria in STAMPEDE unchanged in 15 years ‡ Subtle shifts over time in patients joining any trial ‡ Some shifts in standard practice and management,

especially relating to second-line care KEY MESSAGE: If must be careful within 1 consistent protocol, must be really careful trying to understand differences across protocols!

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STAMPEDE: M1 – all outcome measures

STAMPEDE & STOPCAP

STOPCAP: M1 –Failure-free survival STOPCAP: M1 –Overall survival All graphs: HR<1 favours adding abiraterone HR>1 favours adding docetaxel

doi: 10.1093/annonc/mdy071 doi: 10.1093/annonc/mdy072

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STAMPEDE & STOPCAP: 2 ways to estimate same problem

‡ STAMPEDE direct comparison: ‡ 566 patients ‡ Short time window: Nov-2011 to Mar-2013 ‡ Consistent assessment methods ‡ STOPCAP indirect comparison: ‡ ~6000 patient network ‡ Long time window: Oct-2005 to Jan-2014 ‡ Data from multiple trials

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Future networks and interpreting published data

‡ Timing to recruitment

(proxy for many things including access to treatment at relapse)

‡ Geography of recruitment ‡ Use of docetaxel in standard-of-care

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Future networks and interpreting published data

‡ Timing to recruitment

(proxy for many things including access to treatment at relapse)

‡ Geography of recruitment ‡ Use of docetaxel in standard-of-care

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Future networks and interpreting published data

‡ Timing to recruitment

(proxy for many things including access to treatment at relapse)

‡ Geography of recruitment ‡ Use of docetaxel in standard-of-care

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Future networks and interpreting published data

‡ Timing to recruitment

(proxy for many things including access to treatment at relapse)

‡ Geography of recruitment ‡ Use of docetaxel in standard-of-care ‡ Use of previous local therapy ‡ Use of metastatic volume or burden

as stratifier (entry or analyses)

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Future networks and interpreting published data

‡ Timing to recruitment

(proxy for many things including access to treatment at relapse)

‡ Geography of recruitment ‡ Use of docetaxel in standard-of-care ‡ Use of previous local therapy ‡ Use of metastatic volume or burden

as stratifier (entry or analyses)

10 20 30 40 50 60 70 80 90 100 Adt ADT + Abi ADT ADT + docetaxel Primary Previous Rx 10 20 30 40 50 60 70 80 90 100 ADT ADT + Apa ADT ADT + enza TITAN ENZAMET STAMPEDE-abi STAMPEDE-doc

Graphs courtesy of Nick James

Reported prior therapy in TITAN, ENZAMET and STAMPEDE

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Future networks and interpreting published data

‡ Timing to recruitment

(proxy for many things including access to treatment at relapse)

‡ Geography of recruitment ‡ Use of docetaxel in standard-of-care ‡ Use of previous local therapy ‡ Use of metastatic volume or burden

as stratifier (entry or analyses)

GETUG-15 CHAARTED

Graphs courtesy of Nick James

Reported prior therapy and metastatic volume in GETUG-15 and CHAARTED 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% De-novo Prior local therapy 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% De-novo Prior local therapy High volume Low volume

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Future networks and interpreting published data

‡ Timing to recruitment

(proxy for many things including access to treatment at relapse)

‡ Geography of recruitment ‡ Use of docetaxel in standard-of-care ‡ Use of previous local therapy ‡ Use of metastatic volume or burden

as stratifier (entry or analyses)

All data

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Future networks and interpreting published data - burden

‡ Timing to recruitment

(proxy for many things including access to treatment at relapse)

‡ Geography of recruitment ‡ Use of docetaxel in standard-of-care ‡ Use of previous local therapy ‡ Use of metastatic volume/burden as

stratifier (entry or analyses)

Data available by volume

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Future networks and interpreting published data - burden

‡ Timing to recruitment

(proxy for many things including access to treatment at relapse)

‡ Geography of recruitment ‡ Use of docetaxel in standard-of-care ‡ Use of previous local therapy ‡ Use of metastatic volume/burden as

stratifier (entry or analyses)

Data available by volume

doi: 10.1016/j.eururo.2019.08.006

STAMPEDE-abi by volume now online at Eur Urol

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Future networks and interpreting published data – more…

‡ Timing to recruitment

(proxy for many things including access to treatment at relapse)

‡ Geography of recruitment ‡ Use of docetaxel in standard-of-care ‡ Use of previous local therapy ‡ Use of metastatic volume or burden

as stratifier (entry or analyses)

‡ Use of AA in control ‡ Timing of randomisation ‡ Outcome measure definition ‡ Timing and method of assessments ‡ Timing of reporting ‡ Length of follow-up ‡ Utility of reporting

All data

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Very very few patients No patients No information about censoring or events :: Results of 1,000 person survey due out shortly :: Included oncologists, surgeons & editors :: Email for results

Interpreting published data: follow-up and reporting

TITAN

TITAN doi: 10.1056/NEJMoa1903307

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Interpreting published data: follow-up and reporting

TITAN

TITAN doi: 10.1056/NEJMoa1903307

Reading across from y-axis = bad

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Interpreting published data: follow-up and reporting

TITAN

TITAN doi: 10.1056/NEJMoa1903307

Reading up from x-axis = good

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Need: individual patient data (IPD) network meta-analysis

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International Clinical Trials and Methodology Conference 2019 – Brighton, UK ICTMC2019.org

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Independent Data Monitoring Committee course

Course aimed at:

  • new IDMC members
  • new CIs
  • people likely to be on or report to future

IDMCs (clinical, statistical, operational) Next dates: 29-Oct-2019 + Spring 2020 (Date TBC) Booking open at: https://www.ucl.ac.uk/clinical-trials-and-

methodology/education/short-courses/idmc

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CONCLUSIONS Increasing number of positive trials in mHSPC Very little direct head-to-head data comparing new treatments Be cautious in comparing results from papers Consider: characteristics of trials and patients all outcome measures, including efficacy and safety available and cost of treatments Help each other with: consistent outcome measures and assessments clear presentations of results

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CONTACT DETAILS Matthew Sydes MRC Clinical Trials Unit at UCL London, UK Email: m.sydes@ucl.ac.uk Twitter: @mattsydes

Email for mailing list for KMunicate results

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International Clinical Trials and Methodology Conference 2019 – Brighton, UK ICTMC2019.org

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Independent Data Monitoring Committee course

Course aimed at:

  • new IDMC members
  • new CIs
  • people likely to be on or report to future

IDMCs (clinical, statistical, operational) Next dates: 29-Oct-2019 + Spring 2020 (Date TBC) Booking open at: https://www.ucl.ac.uk/clinical-trials-and-

methodology/education/short-courses/idmc

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CONTACT DETAILS Matthew Sydes MRC Clinical Trials Unit at UCL London, UK Email: m.sydes@ucl.ac.uk Twitter: @mattsydes

Email for mailing list for KMunicate results

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International Clinical Trials and Methodology Conference 2019 – Brighton, UK ICTMC2019.org

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Independent Data Monitoring Committee course

Course aimed at:

  • new IDMC members
  • new CIs
  • people likely to be on or report to future

IDMCs (clinical, statistical, operational) Next dates: 29-Oct-2019 + Spring 2020 (Date TBC) Booking open at: https://www.ucl.ac.uk/clinical-trials-and-

methodology/education/short-courses/idmc

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CONTACT DETAILS Matthew Sydes MRC Clinical Trials Unit at UCL London, UK Email: m.sydes@ucl.ac.uk Twitter: @mattsydes

Email for mailing list for KMunicate results