Treatment of M1 hormone sensitive prostate cancer – Does ... Christoph… · Treatment of M1...
Transcript of Treatment of M1 hormone sensitive prostate cancer – Does ... Christoph… · Treatment of M1...
Treatment of M1 hormone sensitive prostate cancer – Does volume matter?
Christopher Sweeney, MBBSMedical Oncologist, Dana Farber Cancer Institute
Professor, Harvard Medical School
11:35 – 11:55
Disclosures
Consultant with compensation
Research Funding
Amgen XAstellas X XBayer X X
Genentech/Roche XJanssen X XPfizer X
Celgene XSanofi X X
Dendreon XLilly X
Tolmar X
• The answer is “YES” if you consider prostate cancer is a disease that
• 1) is biologically heterogeneous• 2) is clinically heterogeneous • 3) requires individual treatment plans
Does volume matter for upfront chemotherapy for castration naïve metastatic prostate cancer?
Early Low Volume: - Biochemical recurrence M0 after RP, XRT- No disease on CT or Tc-Bone Scan (many PSMA PET positive)- ADT 18 months +/- docetaxel for 6 cycles
Morris et al ASCO, 2015
N=412 patients;
Early Low Volume FrenchM0 HSPC ADT +/- docetaxel: N=250
Oudard et al JAMA Onc 2019
• On ADT alone• Patients with high volume disease have a poorer outcome
than low volume • High volume is 1 risk factor
• Patients with de novo metastatic disease have a poorer outcome than those who relapse after local therapy
• De Novo metastatic disease is 1 risk factor• What is OS if have 0 or 1 or 2 risk factors?
• Time and volume of metastases = destiny
Reproducibility of 0, 1, 2 risk factors for mHSPC:GETUG15 and CHAARTED
Reproducibility of prognostic factors in GETUG15, CHAARTED and Hospital-based Registry at DFCI
Francini et al Prostate 2018; Gravis et al Eur Urol 2018
CHAARTEDGETUG15
Median OS(years)
PLT and LV ~8
PLT and HV 4.5
De Novo and LV 4.5
DeNovo and HV 3
What are we learning from long term follow-up of CHAARTED: Overall Population
Median Follow-up: 53.7 months
Median Follow-up 28.9 months
13 months / HR 0.61 10 months / HR 0.73Sweeney et al NEJM 2015, Kyriakopolous et al JCO Jan 2018;
What are we learning from long term follow-up of CHAARTED: High volume
17 months / HR 0.6 17 months / HR 0.6
Median Follow-up: 53.7 months
Median Follow-up 28.9 months
Sweeney et al NEJM 2015, Kyriakopolous et al JCO Jan 2018;
(few low volume pts have aggressive disease and benefit from early docetaxel?)
What are we learning from long term follow-up of CHAARTED: Low volume
NR / HR 0.6 0 months / HR 1.0
Median Follow-up: 53.7 months
Median Follow-up 28.9 months
Sweeney et al NEJM 2015, Kyriakopolous et al JCO Jan 2018;
With long term follow-up low volume and high volume had a differential effect with early docetaxel
What are we learning from long term follow-up of CHAARTED: Test for Heterogeneity
High volume
Low volume
HR Weight0.63 75.12
1.04 24.88
0.71 100
Kyriakopolous et al JCO Jan 2018;
ADT alone (red curves) in low volume had no change in QOL over 12 months in low volume but decline in high volume (progression of disease – symptoms and progression)ADT plus docetaxel (blue curves) decline in QOL in low vol on chemoBut no decline and better 12 month QOL in high volume
QOL FACT-P: CHAARTEDLow Volume High Volume
Morgans et al J. Clin Oncol 2018
HV-High volume: ≥ 4 bone mets with one beyond vert bodies and pelvic bones and/or visceral mets (Merged SWOG and MDACC definitions to minimize misclassifying pts with e.g. isolated rib met who with SWOG definition would have been “extensive”)
High level summary of docetaxel treatment effect on OS as measured by Hazard Ratio (HR)
1Gravis et al Lancet Oncology 2015; 2Kyriakopolous et al JCO 2018; 3Gravis et al Eur Urol 2018; 4James et al Lancet 2015;
Trial All M1 High Volume/High risk
Low Volume Median Follow-up (mos)
GETUG151 HR(OS): 0.88 HR(OS)-HV: 0.78N=183
HR (OS): 1.02N=202
83.9
CHAARTED2 HR(OS): 0.72 HR(OS)-HV: 0.63N=513
HR (OS): 1.04N=277
57.6
CHAARTED/GETUG15 pooled3
HR(OS)-HV: 0.68N=696
HR(OS): 1.03N=479
Test for heterogeneityHV but not LV benefit (p=0.017)
Test for heterogeneity CHAARTED/GETUG15= “homogeneous”
CHAARTED/GETUG15= “homogeneous”
STAMPEDE-Doc3
(+/-Zolendronic acid)HR(OS): 0.76 N/A
N~720N/AN~720
43Update at ESMO 2019
STAMPEDE: Test for heterogeneity – M0 vs M1
• M0 combines• High risk localized treated with ADT + XRT• Rising PSA post local therapy
• M1 combines• Low and High Volume
• Authors conclude LV benefit based on inference because no difference on test of heterogeneity bwn M0 and M1
• Clear direct OS benefit in high volume in 2 studies that looked at the outcome by volume of disease and documented improvement in QOL
• Two studies provide DIRECT evidence of NO BENEFIT in low volume disease• I feel this outweighs indirect conclusions based on statistical inferences assessing
patient groups (M0 and M1) with vastly different outcomes
• Await the results of long term follow-up of STAMPEDE-docetaxel arm which RETROSPECTIVELY analyzed their patients by volume of disease
• If there is a modest benefit • 1) will this translate into routine care (treatment benefit less and toxicity worse than in trials)?• 2) why is the STAMPEDE an outlier?• 3) better tolerated abiraterone arm: completed later and does show modest benefit
My take about docetaxel added to ADT in M1 HSPC by volume of disease
Final Analysis: Overall Survival
Presented By Karim Fizazi at 2019 Genitourinary Cancers Symposium
Final overall survival(Median Follow-up 51.8 months)
LATITUDE: ADT +/- Abi in “poor risk” mHSPC(poor risk: de novo plus 2 of >2 bone mets / Gl > 7 / visceral mets)
LATITUDE: QOL results
Chi et al Lancet Onc 2018
Early Abi: Slower time to decline in QOL measured by FACT-P
LATITUDE: Overall Survival in High and Low Volume<br />(CHAARTED definition*)
Presented By Kim Chi at 2019 Genitourinary Cancers Symposium
(De Novo)
STAMPEDE OVERALL SURVIVAL:0
0.2
0.4
0.6
0.8
1.0
Prob
abilit
y of
ove
rall
surv
ival
220 210(6) 186(21) 125(19) 43(7)ADT alone208 205(2) 186(17) 131(16) 45(5)AAP
No. of patients(Events)
0 6 12 18 24 30 36 42 48 54
Months since randomisation
00.
20.
40.
60.
81.
0
Prob
abilit
y of
ove
rall
surv
ival
232 204(25) 148(51) 71(44) 13(15)ADT alone241 220(17) 190(29) 106(35) 28(12)AAP
No. of patients(Events)
0 6 12 18 24 30 36 42 48 54
Months since randomisation
ADT +AAP
ADT
ADT + AAPADT
82.4%
78% 64.7 %
45 %
OS - 4.4%HR 0.66 (0.44-0.98) p=0.041
OS – 19.7%HR 0.54 (0.41-0.70) p<0.001
Low Risk (ie: not LATITUDE High Risk) High Risk per LATITUDE
Hoyle et al ESMO 2018
Grade 3–5 AEs in ≥2% of patients
1. Sweeney et al. N Engl J Med 2015; 2. Fizazi et al. NEJM 2017; 3. James et al. NEJM 2017
The overall safety profile of ADT + abiraterone was consistent with prior studies in mCRPC and favorable in both STAMPEDE and LATITUDE
CHAARTED1 LATITUDE2 STAMPED ARM G3
ADT + Docetaxel(n=390)
ADT + Abiraterone(n=597)
ADT + Abiraterone(n=948)
AE, % Grade 3 Grade 4 Grade 5 Grade 3 Grade 4 Grade 3–5Allergic reaction 1.8 0.3 0 – – –Fatigue 4.1 0 0 2 0 2Neutropenia 3.1 9.0 0 – – –Febrile neutropenia 3.8 2.3 0 – – –Pulmonary disorder – – 0.3 – – –Hypertension – – – 20 0 1Hypokalaemia – – – 10 1 <1ALT increased – – – 5 <1 <1Hyperglycaemia – – – 4 <1 –AST increased – – – 4 <1 <1Bone pain – – – 3 0 –Cardiac disorder – – – 3 1 10Endocrine disorder – – – – – 14Gastrointestinal disorder – – – – – 5General disorder – – – – – 5
STAMPEDEADT + Doc vs ADT + Abi
Strong evidence favouring AAP
Weak evidence favouring AAP
No good evidence of a difference
FavoursSOC+AAP
FavoursSOC+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 pts (Nov-2011 to Mar-2013)
Proportionately different time spent in each disease state because targeting AR more intensely and longer with abiraterone
Sydes et al Annals of Onc 2018
ARCHES study design
Presented By Andrew Armstrong at 2019 Genitourinary Cancers Symposium
Primary endpoint: rPFS
Presented By Andrew Armstrong at 2019 Genitourinary Cancers Symposium
Overall survival: interim analysis (84 deaths)
Presented By Andrew Armstrong at 2019 Genitourinary Cancers Symposium
EligibilityMetastatic prostate cancerAdequate organ functionStarting 1st line ADT
StratificationVolume of diseaseAnti-resorptive therapyComorbiditiesStudy SiteDocetaxel use
ENZAMET will soon provide some guidance on role of new generation anti-AR therapy in mHSPC in presence of docetaxel and in high vs low volume
EndpointsOverall survival (primary)PSA progression free survivalClinical progression free survivalHealth related quality of lifeAdverse eventsIncremental cost-effectiveness
1,125 participants (March 2017)• CHAARTED Definition:• N=533 with Low volume: ~ 30% with docetaxel• N=592 with High volume: ~60% with docetaxel
1:1
Enzalutamide 160mg/daily + LHRHA (or orchidectomy) until progression
Non-Steroidal Anti-Androgen* + LHRHA (or orchidectomy) until progression
R
Yes - it is “unfashionable” to propose the more “toxic” therapy upfront
• But for the patient with high volume disease and fit for chemotherapy• Although docetaxel has short term adverse events it is done in 18 weeks
• And abiraterone is more “insidious” for some .. Esp when at risk for poor blood sugar control and tenuous cardiac and fluid volume status
• Abiraterone requires more clinic visits / long term monitoring
• We need to get docetaxel in before too frail • Abiraterone can be added on later more easily than docetaxel if patient becomes frail• Aim is to get in as many therapies as possible• “One-shot, One opportunity”1
• Less overall long term treatment and cost burden with upfront docetaxel• With similar OS efficacy
1Eminem, 8 Mile, 2002
Vintage vs Current Era of CRPC TherapyMore Effective therapies = Better Outcomes
• mCRPC Pts at DFCI not on trial• PCWG3 criteria of CRPC
• PSA > 1 and castrate• Uniform
• Docetaxel alone era N=317• 2004-2007
• Current era N=266• 2010 – 2013
• Sipuleucil-T, Abiraterone, Enzalutamide, Radium, Docetaxel, Cabazitaxel
• 5 yr OS for both groups
Covariates HR (95% CI) P-value
Cohort B (2010 – 2013) vs. Cohort A (2004 – 2007) (ref.)
0.66 (0.53 – 0.82) 0.0002
De-novo vs. Prior local therapy (ref.)
1.04 (0.58 – 1.84) 0.9
ECOG PS ≥ 1 vs. = 0 (ref.) 2.15 (1.58 – 2.93) < 0.0001
Francini accepted 2018Prostate Cancer and Prostatic Diseases
Ongoing randomized mHSPC trialsControl Arm Experimental Arm Acronyms Sponsor
ADT + NSAA* ADT + Enzalutamide EnzaMet(concurrent docetaxel)
ARCHES(post docetaxel)
ANZUP (ASCO 2019)
Astellas (GUASCO 2019)
ADT (No docet) Control + TAK700 SWOG (awaited)
ADT* ADT + abi + Enza STAMPEDE Arm J MRC (awaited)
ADT* ADT + Apalutamide TITAN(post docetaxel)
Janssen (ASCO 2019)(positive in HV and LV press release)
ADT + Docet ADT + Darolutamide +Docet ARASENS Bayer (awaited)
ADT * ADT + metformin STAMPEDE Arm K MRC (ongoing)
*Stratify by docetaxel
European Urol 2019 on line
For patients with 4 or less bone metastasis there was a 7% improvement in 3-year OS
Ongoing randomized mHSPC trials with treatment of the primary in M1 HSPC
Control Arm Experimental Arm Acronyms SponsorTreatment of the primary in patients with de novo metastatic prostate cancerADT ADT + Prostate Radiation HORRAD NetherlandsADT ADT + Prostate rads STAMPEDE Arm H MRCBest systemic therapy BST + RP or RT after 6 months MDACC / SWOG ADT +/- abiraterone* ADT + Prostate rad +/- abi PEACE 1 Unicancer
*Docetaxel added laterBST: best systemic therapy
Is the SWOG Study of Best Systemic Therapy +/-Radiation or RP at 6 months in mHSPCresponding to therapy still relevant?
I think “YES”
• 1) Will more effective systemic therapy extend the benefit to more patients than just low volume?
• 2) Will more effective systemic therapy negate the benefit for low volume (compare with nephrectomy in interferon vs VEGF TKI era)
Summary of mHSPC treatment choicesPatient Disease setting Treatment optionChemofit High volume Docetaxel or abiraterone
(consider docetaxel first to maximize chance of giving it at some stage)
Not chemofit High volume AbirateroneChemofit Low volume Abiraterone (?intermittent)
Consider radiate primary if de novoNot chemofit Low volume Abiraterone (?intermittent)
Consider radiate primary if de novoCaveats:1) In de novo LV: Unknown if radiation to primary adds to abiraterone or abiraterone adds to radiation
(PEACE-1 may provide guidance soon)2) Magnitude of 3 yr absolute OS benefit ~20% in HV and ~ 5% with either rads or abiraterone in LV