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Current role of chemotherapy in hormone-naïve patients
Elena Castro
Spanish National Cancer Research Centre
Lugano, 17 October 2017
Siegel, Ca Cancer J Clin,2017
Buzzoni, Eur Urol, 2015
-Aprox 15-20% of new PrCa diagnosis present with advanced disease:
- 4-5% distant metastasis EU, USA
- Prevalence of metastasis at diagnosis varies geographically, depending
on screening programs, access to health system, etc
- 80-75% patients with metastatic disease will present it after recurrence
following treatment for localized disease.
Local DIsease
M0
Metastatic
Disease
M1
Recurrence
M1
CPRC_M1
CPRC_M1
20%
80%
-ADT may induce biochemical and clinical responses in 90% of patients
- After 24-36 months progression to Castration Resistance Prostate Cancer ocurrs
-ADT may induce adaptation of hormone-sensitive cells and/or selection of AR-
independent clones
Hellerstdet, CA Cancer J Clin, 2002
Zong, Nat Rev Urol, 2013
Metastatic
No Chemo
ECOG ≤2
n=1006
Docetaxel 75mg/m2 q3w +
Prednisone 5 mg /12h
Mitoxantrone 12mg/m2 q3w +
Prednisone 5 mg /12h
Docetaxel 30 mg/m2 1w +
Prednisone 5 mg /12h
Study end points:• Primary: OS• Secondary: Pain reduction, QoL, ≥50% decline, tumour response
Improved OS (18.9m vs 16.5 m, p<0.001)≥ 50% PSA decline (45% vs 32 %, p<0.001)
Reduction in pain: 35 % vs 22 % (p=0.01)
QoL:22% vs 13% (p=0.009)
DocetaxelTAX-327
Tannock, NEJM, 2004
N=335
N=334
N=337
Would the adition of docetaxel to ADT for M1 hormone-sensitive
PrCa delay the progression to mCRPC and improve survival?
M1 HSPC
Stratification
- Previous TT
-Glass risk group-Apendicular vs axial disese
-Performance status
-PSA < or > 65ng/dL
-Gleason <or >8
Docetaxel 75mg/m2 q3w
(No prednisone) up to 9 cycles
+
ADT
ADT alone
Study end points:• Primary: OS• Secondary: Clinical and PSA Progression Free Survival
GETUG 15 study
Gravis, Lancet Oncol, 2013
N=193
N=192
Median OS: 58.4 vs 52.2 months, p=0.955)
3y OS: 64.2% vs 62.9%
72% de novo M1 Median follow-up: 50 months
Median 8 cycles
bPFS: 22.9 vs 12.9, HR 0.72, p=0.005 cPFS: 20.5 vs 15.4, HR 0.75, p=0.015
M1 HSPC
Stratification-Low vs High volume
- Age <70 vs >70 yrs
-MAB <30 vs >30 days
-SER prevention
-Adjuvant ADT <12
vs<12 months
Docetaxel 75mg/m2 q3w
(No prednisone) up to 6 cycles
+
ADT
ADT alone
Study end points:• Primary: OS• Secondary: Time to CRPC and to clinical progression
CHAARTED study
Seeney,NEJMl, 2015
N=397
N=393
ADT allowed up to 120 days prior to randomization
Median follow-up: 28.9 months
73% de novo M1
27% recurrent disease
Improved OS: 57.6 vs 44 months (HR 0.61, p<0.001)
cPFS: 33 vs 19.8 monts (HR, 0.49 p<0.001)
Time to CRPC: 20.2 vs 11.7 months (HR
0.56,p<0.001)
ADT + docetaxel was beneficial in all subgroups
Seeney,NEJMl, 2015
STAMPEDE: Docetaxel +Pred + ADT vs ADT
Recruitment: Oct-2005 to Mar-2013 Patients: 1184 SOC
592 SOC+DocP
Allocation ratio:2:1
Courtesy of Dr Sydes
STAMPEDE
SOC (ADT+/-RT)
N=1184
Study end points:• Primary: OS• Secondary: PFS
61% M1 and 39% M0
Median follow-up: 43 months
Docetaxel 75mg/m2 q3w + Prednisone 5mg/12h
up to 6 cycles + SOC
N=592
Metastasis at presentation
OS: 60 vs 45 months
(HR 0.76, p=0.005)
OS: 81 vs 71 months, (HR 0.78, p=0.006)
SOC+DOC
SOC
Sweeney,NEJMl, 2015
Do all patients benefit the same?
HIGH volume disease
-Visceral metastasis or
-≥ 4 bone metastasis with ≥1 beyond vertebral bodies and pelvis
CHAARTED_update ESMO 2016
-Benefit on OS in High Volume
- Low Volume: Benefit on time to CRPC: 31 months (ADT+Doce) vs 27monts (ADT),
p=0.03
OS High Volume Disease
(48%)
OS Low Burden Disease
- 20% reduction in the risk of death in the HVD group (No significant)
- Patients with LVD did not benefit form early docetaxel.
GETUG-AFU15 post hoc analysis
Puente, Ther Adv Me Oncol, 2017
METAANALYSIS M1
2993 patients included
-Addition of Docetaxel to ADT improved OS.
-HR 0.77 and 9% absolute improvement in survival at 4 years.
-Addition of Docetaxel to ADT improved PFS.
-HR 0.64 and 15% absolute reduction in failure at 4 years.
Vale, Lancet Oncol, 2016
Overall Survival PFS
METAANALYSIS M0
2121patients included
-Addition of Docetaxel to ADT did not improved OS.
-HR 0.87, p=0.218.
-Addition of Docetaxel to ADT improved PFS.
-HR 0.70 and 8% absolute reduction in failure at 4 years.
Overall Survival PFS
CONCLUSIONS
-Addition of Docetaxel to ADT should be considered standard of care for M1 Hormone-
Sensitive Prostate Cancer.
- Further evidence on the impact of Docetaxel in survival is needed to recomend the
addition of docetaxel to ADT for M0 patients
The addition of abiraterone acetate to ADT significantly increases OS and rPFS in M1 HSPC
LATITUD trial
Fizazi, NEJM, 2017
Slide 30
Presented By Nicholas James at 2017 ASCO Annual Meeting
OK…….SO WHAT SHOULD WE USE?
Reference
STAMPEDE: SOC+AAP vs SOC+DocP
-Evidence about whether to
give both is pending
-566 patients randomised
contemporaneously to either
research arm:
ESMO2017
Patients: 189 SOC+DocP
377 SOC+AAP
Recruitment: Nov2011-Mar2013
Courtesy of Matt Sydes. ESMO 2017
Populations in each comparison
SOC+DocP vs SOC+AAP
M1 60%
Age 66 yr median
PSA 56 ng/ml median
Accrue Nov-2011 to Mar-2013
Freeze Mar-2017
SOC+DocP vs SOC
M1 61%
Age 65 yr median
PSA 68 ng/ml median
Accrue Oct-2005 to Mar-2013
Freeze May-2015
SOC+AAP vs SOC
M1 52%
Age 67 yr median
PSA 53 ng/ml median
Accrue Nov-2011 to Jan-2014
Freeze Mar-2017
Courtesy of Matt Sydes. ESMO 2017
HR (95%CI) P-valInteractn
test
All 1.16 (0.82 to 1.65) 0.40
M0 1.51 (0.58 to 3.93) 0.400.69
M1 1.13 (0.77 to 1.66) 0.53
Key:HR<1 favours SOC+AAPHR>1 favours SOC+DocP
Interactn = test for interaction (heterogeneity of treatment effect)
SOC+DocP SOC+AAP
Events Pts Events Pts
All 44 189 105 377
M0 6 74 16 150
M1 38 115 89 227
SOC+AAP
SOC+DocP
Overall Survival
Courtesy of Matt Sydes. ESMO 2017
Cause-specific survival
Sub-HR
(95%CI)P-val
All 1.02 (0.70 to 1.49) 0.92
Status SOC+DocP SOC+AAP
N % N %
Alive 145 77% 272 72%
Dead 44 23% 105 28%
PCa Death 40 21% 86 23%
Other cause 4 2% 19 5%
Competing risks approach
SOC+DocP death: 91% PCa and 9% otherSOC+AAP deaths: 82% PCa and 18% other
Key:HR<1 favours SOC+AAPHR>1 favours SOC+DocP
Courtesy of Matt Sydes. ESMO 2017
PSA Failure-free survival
HR (95%CI) P-valInteractn
test
All 0.51 (0.39 to 0.67) <0.001
M0 0.34 (0.16 to 0.69) 0.0030.17
M1 0.56 (0.42 to 0.75) <0.001
SOC+AAP
SOC+DocP
Key:HR<1 favours SOC+AAPHR>1 favours SOC+DocP
Interactn = test for interaction (heterogeneity of treatment effect)
SOC+DocP SOC+AAP
Events Pts Events Pts
All 97 189 122 377
M0 18 74 13 150
M1 79 115 109 227
Courtesy of Matt Sydes. ESMO 2017
Progression-free survival
HR (95%CI) P-valInteractn
test
All 0.65 (0.48 to 0.88) 0.005
M0 0.42 (0.17 to 1.05) 0.060.32
M1 0.69 (0.50 to 0.95) 0.02
Key:HR<1 favours SOC+AAPHR>1 favours SOC+DocP
Interactn = test for interaction (heterogeneity of treatment effect)
SOC+DocP SOC+AAP
Events Pts Events Pts
All 72 189 103 377
M0 10 74 9 150
M1 62 115 94 227
SOC+AAP
SOC+DocP
PFS = FFS ignoring PSA failure Courtesy of Matt Sydes. ESMO 2017
Metastatic progression-free survival
HR (95%CI) P-val
Interactn
test
All 0.77 (0.57 to 1.03) 0.08
M0 0.91 (0.42 to 2.01) 0.820.74
M1 0.76 (0.55 to 1.04) 0.09
Key:HR<1 favours SOC+AAPHR>1 favours SOC+DocP
Interactn = test for interaction (heterogeneity of treatment effect)
SOC+DocP SOC+AAP
Events Pts Events Pts
All 71 189 118 377
M0 10 74 18 150
M1 61 115 100 227
SOC+AAP
SOC+DocP
MPFS = new or progression of metastases
Symptomatic skeletal events
HR (95%CI) P-valInteractn
test
All 0.83 (0.55 to 1.25) 0.38
M0 1.28 (0.24 to 6.67) 0.770.65
M1 0.82 (0.53 to 1.25) 0.35
SOC+AAP
SOC+DocP
Key:HR<1 favours SOC+AAPHR>1 favours SOC+DocP
Interactn = test for interaction (heterogeneity of treatment effect)
SOC+DocP SOC+AAP
Events Pts Events Pts
All 36 189 63 377
M0 2 74 5 150
M1 34 115 58 227
Exposure to relapse treatments after FFS event
Note:
• Randomisation: Nov-2011 to Jan-2013
• Data freeze: Feb-2017
Docetaxel started after FFS event AR-targeted therapy started after FFS event
SOC+AAP
SOC+DocP
FFS event FFS event
Note:
• Relapse treatments at investigators’ discretion
• Access to relapse treatments may depend on:
• Metastatic status at event
• Calendar year of event
• Suspect under reporting of third-line therapies and onwards
SOC+AAP
SOC+DocP
Summary
Strong evidence favouring AAP
Toxicity profiles quite different and well known
Weak evidence favouring AAP
No good evidence of a difference
FavoursSOC+AAP
FavoursSOC+DocP
Hazard ratio
Metastatic progression-free
survival
Progression-free survival
PSA Failure-free survival
Symptomatic skeletal events
Cause-specific survival
Overall survival
Head-to-head data in 566 pts (Nov-2011 to Mar-2013)
Courtesy of Matt Sydes. ESMO 2017
Safety population SOC+DocP SOC+AAP
Patients included in adverse event analysis 172 (91%) 373 (>99%)
Grade 1+ AE 172 (100%) 370 (99%)
Grade 3+ AE 86 (50%) 180 (48%)
Grade 3+ AEs by category (incl. expected AEs)
Endocrine disorder (incl. hot flashes, impotence) 15 (9%) 49 (13%)
Febrile neutropenia 29 (17%) 3 (1%)
Neutropenia 22 (13%) 4 (1%)
Musculoskeletal disorder: 9 (5%) 33 (9%)
Cardiovascular (incl. hypertension, MI, cardiac dysrhythmia): 6 (3%) 32 (9%)
Gastrointestinal disorder: 9 (5%) 28 (8%)
Hepatic disorder (incl. increased AST, increased ALT): 1 (1%) 32 (9%)
General disorder (incl. fatigue, oedema): 18 (10%) 21 (6%)
Respiratory disorder (incl. breathlessness): 12 (7%) 11 (3%)
Renal disorder 5 (3%) 20 (5%)
Lab abnormalities (incl. hypokalaemia): 9 (5%) 11 (3%)
Adverse events – worst toxicity ever
Courtesy of Matt Sydes. ESMO 2017
1 year SOC+DocP SOC+AAP
Patients in safety dataset 136 323
Grade 3+ AE 15 (11%) 37 (11%)
2 years SOC+DocP SOC+AAP
Patients in safety dataset 104 271
Grade 3+ AE 11 (11%) 30 (11%)
Adverse events – prevalence at 1 year and 2 years
Safety dataset includes patients who::: started treatment:: with assessment in toxicity window :: without FFS event before window
Courtesy of Matt Sydes. ESMO 2017
Wallis, Eur Urol, 2017
6067 patients included (1921 events)
- 1181 (19.5%) Docetaxel + ADT (391 events)
- 1557 (25.7%) Abiraterone +ADT (353 events)
- 3329 (54.9%) ADT alone (1177 events)
Docetaxel +ADT vs ADT
Pooled HR for OS
HR 0.75 (95%CI 0.55-0.72)
Abiraterone + ADT vs ADT
Pooled HR for OS
HR 0.75 (95%CI 0.55-0.72)
Indirect comparision of Abi + ADT vs Docetaxel + ADT shows no significant difference on OS
Choice of Abiraterone or Docetaxel may be driven by factors beyond survival outcomes:
- Treatment-associated side effects
- Physician – patient preferences
- Availability
- Cost