Hormone sensitive prostate cancer To add abiraterone or docetaxel? Dr Lisa Pickering

Transcription

1 > Hormone sensitive prostate cancer To add abiraterone or docetaxel? Dr Lisa Pickering

2 Disclosures Institutional Research Support/P.I. Employee Consultant Major Stockholder Speakers Bureau Honoraria Scientific Advisory Board Novartis, Pfizer, Pierre Fabre N/A Astellas, BMS, EUSA Pharma, Ipsen, Janssen, MSD, Novartis, Pfizer N/A BMS, EUSA Pharma, Novartis, Pfizer Astellas, Ipsen, Janssen, MSD, Pfizer Astellas, EUSA Pharma, Ipsen, Janssen, MSD, Novartis, Pfizer, Sanofi

3 Initial systemic therapy in hormone sensitive locally advanced high risk or metastatic prostate cancer ADT. Docetaxel Abi + pred 1940s 1950s 2000s Historically ADT alone but in last 2-3 years, addition of upfront therapies: Docetaxel: CHAARTED; GETUG-15; STAMPEDE Abiraterone: STAMPEDE; LATITUDE

4 So which to add? Docetaxel or abiraterone? Potential considerations Efficacy for failure-free survival Efficacy for overall survival Tolerability / QoL Cost Comparative data Is it the same answer for all patients? N1M0 (ie node positive) patients? M1 (ie metastatic) patients Low volume High volume

5 Sweeney et al NEJM 2015, Sweeney et al ESMO 2016 CHAARTED (E3805): Upfront Docetaxel Improved survival with upfront docetaxel: mos improvement of 13.6m in overall population

6 GETUG 15: Overall survival Crosses indicate censoring. No survival benefit from the addition of docetaxel Gravis et al. Lancet Oncol 2013

7 STAMPEDE: Upfront docetaxel Overall survival benefit Docetaxel (+ADT) leads to a mos benefit of 10 months in metastatic & high risk localised prostate cancer James et al. Lancet 2016

8 Upfront docetaxel: Meta-analysis & summary Meta-alaysis: addition of docetaxel to ADT confers: OS benefit with HR 0.77 (95%CI , p<0.0001) 9% absolute improvement in 4YS FFS benefit with HR 0.64 (95%CI , p<0.0001) Conclusion Upfront ADT + docetaxel should be standard of care for advanced hormone sensitive prostate cancer providing adequate PS & comorbidities for docetaxel Question Vale et al. Lancet Oncol 2016 Should this include all patients; non-metastatic, nodepositive and metastatic low and high risk?

9 So which to add? Docetaxel or abiraterone? Potential considerations Efficacy for failure-free survival Efficacy for overall survival Tolerability / QoL Cost Comparative data Is it the same answer for all patients? N1M0 (ie node positive) patients? M1 (ie metastatic) patients Low volume High volume

10 Upfront docetaxel: questions 1. Should this include locally advanced patients? In my opinion This should be considered for all patients who meet criteria of STAMPEDE trial for node positive, 2 of: T3/4; Gleason 8-10; PSA 40 (if adequate PS) These patients did benefit according to the metaanalysis for failure-free survival However strength of receommendation is weaker as no data yet for OS (longer follow-up required)

11 Meta-analysis: M0 patients FFS favours docetaxel. OS HR crosses 1.00

12 Upfront docetaxel: questions 2. Should this include all metastatic patients or just high risk? In my opinion Considering STAMPEDE & meta-analysis this should now be offered to all patients providing they are of adequate PS and comorbidities allow docetaxel Or should it be restricted to high volume only? (ie those with 4 bone metastatic sites)

13 Meta-analysis: All M1 patients OS& FFS both clearly favour docetaxel

14 What are we learning from long term follow-up of CHAARTED? High volume Original data: Median follow-up 28.9 months R months / HR 0.6 Updated analysis: Median Follow-up 53.7 months Median Follow up 28.9 months Med 5 follow up of CHAARTED: Hig What are we learning from l 17 months / HR months / HR 0.6 Benefit exists in high volume disease & is maintained over time Sweeney et al NEJM 2015, Sweeney et al ESMO 2016

15 0 months / HR 1.0 ave aggressive disease and benefit from early docetaxel?) What are we learning from long term follow-up of CHAARTED? Low volume Original data: Median follow-up 28.9 months Median Follow up 28.9 months M Updated analysis: Median Follow-up 53.7 months follow up of CHAARTED: Lo What are we learning from NR / HR months / HR 1.0 Benefit less clear in low volume disease Sweeney et al NEJM 2015, Sweeney et al ESMO months

16 GETUG: why negative? More low risk patients? By their own criteria only 22% high risk Reclassified by CHAARTED criteria: 48% high volume (compared with 66% in CHAARTED) No OS advantage for docetaxel in these 52% Is it about subsequent therapies? Recruitment completed Dec 2008 compare 2012 / 13 for CHAARTED and STAMPEDE) Fewer GETUG pts accessed abi/enza/cabazi

17 STAMPEDE-Doc: OS benefit by subgroups Upfront docetaxel (+ADT) leads to a mos benefit in metastatic (&?high risk localised) prostate cancer James et al. Lancet 2016

18 So how to manage advanced HSPC? The all-in-one approach Organ Confined Low Risk Organ Confined - Risk of Mets Metastatic Disease HSPC Castration Resistant Prostate Cancer Prostate Cancer Risk of cancer Rising PSA no mets HSPC Rising PSA no mets CRPC M0 Within the red box, STAMPEDE reports no evidence of heterogeneity and suggests docetaxel for all who are eligible for long course ADT: High risk localised Rising PSA post localised therapy Low volume mhspc High volume mhspc

19 Or the splitting approach Organ Confined Low Risk Organ Confined - Risk of Mets Metastatic Disease HSPC Castration Resistant Prostate Cancer Prostate Cancer Risk of cancer Rising PSA no mets HSPC Rising PSA no mets CRPC M0 CHAARTED suggests that there are different disease states with different treatment considerations: High risk localised Rising PSA post localised therapy Low volume mhspc High volume mhspc Benefit in FFS with docetaxel with ADT + XRT No benefit from docetaxel yet demonstrated in 2 phase 3 trials; EMBARK pending One study has reported no benefit. Along spectrum from rising PSA Clear benefit from ADT plus docetaxel in FFS / rpfs and OS So evidence robust in HV mhspc but questions / gaps in others

20 The rationale for upfront abiraterone? Intracellular conversion of steroid precursors to androgenic steroids by prostate cancer cells is a mechanism of escape from ADT CYP17 inhibition results in androgen depletion Abiraterone is a selective, irreversible inhibitor of CYP17 COU-301 & COU-302 showed benefit of abiraterone + pred in CRPC 1.Attard G, et al J Clin Oncol. 2008;26(28): de Bono JS, et al NEJM 2011;364(21): Ryan CJ, et al, NEJM. 2013;368(2):

21 LATITUDE: Trial Design Double blind, placebo-controlled phase III RCT HSPC; N = 1199 Metastatic prostate cancer ADT for < 120 days No prior chemotherapy At least two of: Gleason or more bone mets 3 or more visceral mets ADT + placebos (N = ) ADT + Abiraterone + pred (N = ) Treated up to 24 mos or until CR, PD, unacceptable AE, or investigator decision* Primary endpoints: OS and rpfs Secondary endpoints: Time to clinical progression; time to CRPC; PSA CR at 6 & 12 months; QoL 1. Fizazi et al. ASCO 2017; 2. Fizazi et al. NEJM 2017

22 LATITUDE: clinical efficacy results at median follow-up 30.4 months OS rpfs ADT + Abi OS NR ADT + Abi PFS 33.0mo HR 0.62 (95% CI, ) P<0.001 ADT OS 34.7mo OS Rate at 3 years ADT + Abi: 66% ADT: 49% ADT PFS 14.8mo HR 0.47 (95% CI, ) P<0.001 Statistically significant 38% risk reduction of death Statistically significant 53% risk reduction of rpfs or death Patient Reported Outcomes Improved pain Improved HRQoL Median follow-up: 30.4 months 1. Fizazi et al. ASCO 2017; 2. Fizazi et al. NEJM 2017

23 STAMPEDE: Upfront abiraterone Newly-diagnosed Any of: Metastatic Node-Positive 2 of: Stage T3/4 PSA 40ng/ml Gleason 8-10 All patients Fit for all protocol treatment Fit for follow-up WHO performance status 0-2 Written informed consent Relapsing after previous RP or RT with 1 of: PSA 4ng/ml and rising with doubling time <6m PSA 20ng/ml Node-positive Metastatic Full criteria 1:1 control:research (Note: control was ADT ± RT if M0) Accrual: Nov 2011 Jan 2014, 1917 Primary EP: OS; Key secondary EPs: FFS, toxicity James et al. Lancet 2016

24 STAMPEDE: Upfront abiraterone Overall survival benefit 37% improvement in OS HR: % CI: p = James et al. ASCO 2017; 2. James et al. NEJM 2017

25 STAMPEDE: Upfront abiraterone Overall survival benefit 1. James et al. ASCO 2017; 2. James et al. NEJM 2017

26 STAMPEDE: Upfront abiraterone Failure-free survival benefit 71% improvement in FFS HR: % CI: p = x 10-61

27 Efficacy summary, upfront docetaxel 10% absolute improvement in OS which is practice changing Upfront ADT + docetaxel should be standard of care for advanced hormone sensitive prostate cancer Efficacy summary, upfront abiraterone Benefit has been shown in 2 studies: Overall survival by 37 38% Failure free survival by 55 71% Symptomatic skeletal events by 55% Abiraterone acetate + prednisolone increases OS and rpfs in newly diagnosed advanced HSPC & should be part of the standard of care

28 So which to add? Docetaxel or abiraterone? Potential considerations Efficacy for failure-free survival Efficacy for overall survival Tolerability / QoL Cost Comparative data Is it the same answer for all patients? N1M0 (ie node positive) patients? M1 (ie metastatic) patients Low volume High volume

29 Comparative toxicity between docetaxel & abi Grade 3 5 AEs in 2% of patients CHAARTED 1 LATITUDE 2 STAMPED ARM G 3 ADT + docetaxel (n=390) Abiraterone (n=597) ADT (n=602) Abiraterone (n=948) ADT (n=960) AE, % Grade 3 Grade 4 Grade 5 Grade 3 Grade 4 Grade 3 Grade 4 Grade 3 5 Grade 3 5 Any event Allergic reaction Fatigue Neutropenia Febrile neutropenia Hypertension <1 1 5 Hypokalaemia <1 <1 1 ALT increased 5 <1 1 0 <1 6 Hyperglycaemia 4 <1 3 0 AST increased 4 <1 1 0 <1 1 Bone pain Cardiac disorder Anaemia <1 Back pain Spinal-cord compression <1 Endocrine disorder Musculoskeletal disorder 7 5 Gastrointestinal disorder 5 4 General disorder Sweeney et al. N Engl J Med 2015; 2. Fizazi et al. NEJM 2017; 3. James et al. NEJM 2017

30 Comparative toxicity between docetaxel and abiraterone The toxicity profiles of these drugs differ We know that already from studies and clinical experience in CRPC In CHAARTED, STAMPEDE, LATITUDE the safety profiles were consistent with expectations There may be some patients for whom abiraterone is a more attractive option & others (fewer?) for whom docetaxel is preferred There is no reason on the basis of toxicity to routinely or exclusively select either agent

31 So which to add? Docetaxel or abiraterone? Potential considerations Efficacy for failure-free survival Efficacy for overall survival Tolerability / QoL Cost Comparative data Is it the same answer for all patients? N1M0 (ie node positive) patients? M1 (ie metastatic) patients Low volume High volume

32 Docetaxel or abiraterone: Does cost play a role? This will differ across different health economies and funding structures Sometimes YES, cost will play a role Is that a problem? I don t think so currently From that data both are appropriate, active options that improve survival for HSPC pts Although docetaxel has more toxicity for some patients it is tolerated by most

33 So which to add? Docetaxel or abiraterone? Potential considerations Efficacy for failure-free survival Efficacy for overall survival Tolerability / QoL Cost Comparative data Is it the same answer for all patients? N1M0 (ie node positive) patients? M1 (ie metastatic) patients Low volume High volume

34 Comparative efficacy across trials Trial N HR OS p HR FFS p CHAARTED ( ) < ( ) <0.001 GETUG ( ) n/s n/s STAMPEDE-D ( ) <0.006 LATITUDE ( ) < ( ) <0.001 STAMPEDE-A ( ) < ( ) <0.001 Benefits seen from both agents

35 STAMPEDE: Comparison between abiraterone & docetaxel arms Design Opportunistic comparison. Not fully powered. Looked at patients randomised within same time window Efficacy FFS HR in M1 population: 0.56 favouring abiraterone Clinical PFS (not PSA): HR 0.65 favouring abiraterone OS: no difference. 25% patients each arm have died Subequent treatments Progression after docetaxel: most start abi or enza Progression after abiraterone: most start docetaxel

36 STAMPEDE: Comparison between abiraterone & docetaxel arms Design Opportunistic comparison. Not fully powered. Looked at patients randomised within same time window Subequent treatments Progression after docetaxel: most start abi or enza Progression after abiraterone: most start docetaxel Accrual to both arms: Nov 11 March 13 N = 566; 189 docetaxel and 377 abiraterone 1. James et al. ASCO 2017; 2. James et al. NEJM 2017; 3. Sydes et al ESMO 2017

37 STAMPEDE: ADT + Doc vs ADT + Abi Progression free survival SOC + DocP SOC + AAP Events Pts Events Pts All M M HR (0.95% CI) P value Interaction test All 0.65 ( ) M ( ) M ( ) 0.02 Abiraterone prevented PSA rise for longer than docetaxel Sydes et al. ESMO 2017

38 STAMPEDE: ADT + Doc vs ADT + Abi Overall survival SOC + DocP SOC + AAP Events Pts Events Pts All M M HR (0.95% CI) P value Interaction test All 1.16 ( ) 0.40 M ( ) 0.40 M ( ) Docetaxel followed by subsequent therapy same OS as Abiraterone followed by subsequent therapy Sydes et al. ESMO 2017

39 STAMPEDE: ADT + Doc vs ADT + Abi Head-to-head data in 566 patients Failure-free survival Favours Favours SOC+AAP SOC+DocP Nov-2011 to Mar-2013 Progression-free survival Metastatic progression-free survival Symptomatic skeletal events Cause-specific survival Overall survival Hazard ratio Evidence favours AAP Weak evidence favouring AAP No good evidence of a difference Proportionately different time spent in each disease state Sydes et al. ESMO 2017 On this basis, possibly abiraterone preferred? Although we are aiming for more than just treating the PSA

40 Docetaxel and abiraterone: Efficacy FFS Some pros and cons Docetaxel Abiraterone Improved FFS? Efficacy OS Equally appropriate Equally appropriate Duration 4 months 2 years + Tolerability Occasionally preferred Often preferred Cost More affordable Less affordable Availability Increasingly available?? Issues to considering: 1. Potential toxicity of long term >5 yrs of abi & daily pred 2. And how does efficacy compare with sequential or intermittent approach?

41 So what will you do in practice? Docetaxel or abiraterone? N+M0 high risk: FFS / rpfs benefit from both & OS benefit not yet clear M1 low volume although many believe will be seen Different opinions exist currently I believe docetaxel is appropriate Toxicity important if both available M1 high volume Clear OS benefit from both FFS may favour abi. Not definitive

42 Important observation: Despite early docetaxel and abiraterone 20% of patients die by 24 months ollow up onths Median Follow up: 53.7 months are we learning from long term up of CHAARTED: High volume CHAARTED: HV LATITUDE STAMPEDE-Abi M1 1. Sweeney et al. N Engl J Med 2015; 2. Fizazi et al. NEJM 2017; 3. James et al. NEJM 2017

43 Triplet vs Doublet [ADT + D] vs [ADT + D + Enza or Abi] Recruiting trials Plan to combine the data from trials that stratified by docetaxel ENZAMET PEACE-1* Combined Overall N N N ADT+D ADT+Doc + Enz /Abi High Volume ADT+D ADT+D+E/A Plus: Some patients from STAMPEDE and TITAN (ADT +/- apalutamide) Hypothesis: Targeting both AR positive & AR negative clones could lead to incremental benefit with ADT + docetaxel + abiraterone + pred

44 Conclusions for 2017 Two drug strategy is better C Sternberg ESMO 2017 Both docetaxel & abiraterone lead to improved FFS compared with ADT alone in M0 and M1 patients Both docetaxel & abiraterone lead to improved OS compared with ADT alone in M1 patients Both have good tolerability. Some patients may be better suited to one or the other (toxicity/schedule) Magnitude of benefit from docetaxel may be greater in high volume disease. Some benefit is seen in all pts Suggestion that abiraterone better for FFS but not definitive (not formal RCT) & no OS signal currently Availability & cost will be important factors and may have regional variations

45 Thank you