Presentación de PowerPoint€¦ · Hussain M et al. Oral presentation, ASCO, Chicago, 3 June 2012...
Transcript of Presentación de PowerPoint€¦ · Hussain M et al. Oral presentation, ASCO, Chicago, 3 June 2012...
Prostate Cancer Standard of Practice in 2018
and future directions
Eleni Efstathiou MD PhD
Disclosures – Eleni Efstathiou
Research Support/P.I.Janssen-Cilag, Sanofi-Aventis,
Astellas/Medivation
Employee NA
ConsultantJanssen-Cilag, Sanofi-Aventis,
Astellas/Medivation. Oric
Major Stockholder NA
Speakers Bureau NA
Honoraria Janssen-Cilag, Sanofi-Aventis
Scientific Advisory BoardJanssen-Cilag, Sanofi-Aventis, MSD, Viamet,
Takeda, Tokai, Bayer
Presentation includes discussion of the off-label use of a drug or drugs(depending on country of origin)
‘Discovery is our Business’
Charles Huggins (1902-1997)
Nobel Prize in Medicine 1966
1.Local disease treatment
2.Biochemical Recurrence
3. Metastatic Diseasehormone naive (HNPC)
castrate resistant (CRPC)
A Medical Oncologist should be the “coordinator”
We care for the Man not the cancer :
keeping him healthy against the odds of ADT and other treatmentsProviding coaching for diet exercise well being Information Clarity are paramount .
M F. Berger et al. Nature 470, 214-220 (2011) doi:10.1038/nature09744
Graphical representation of seven prostate cancer genomes
Prostate Cancer Heterogeneityhas not been addressed
Pathology dictated by Morphology
Gleason Grade and Score
(STILL!!)
Tips to remember: Gleason Scoring differs Between biopsy and Prostatectomy specimen Gleason Scoring does notapply when Androgen
Deprivation is used Cribriform / intraductal spreadAssociated with more aggressive Disease
Hormone Naïve Prostate Cancer
Chemotherapy
Tum
or
volu
me
& a
ctiv
ity
1.De Novo Metastatic2. Biochemical Recurrence
3. Recurrent Metastatic Hormone Sensitive
Intermittent ADT (IAD) is non inferior to Continuous (CAD) in Biochemical Recurrence
Crook et al NEJM 2012
Causes of Death
Crook et al NEJM 2012More PCa related deaths in IAD arm
Hussain M et al. Oral presentation, ASCO, Chicago, 3 June 2012
Overall conclusion: in mHNPCIAD is NOT non inferior compared to CAD
Hussain et al NEJM 2014
Progress Report 2014-2017Three practice changing years in Hormone Naive Prostate Cancer
To date the biggest impact in survival
exhibited
1. The reemergence of Chemotherapy (2 positive / 1 negative trial)
2. Moving Androgen Biosynthesis Inhibition earlier in the disease spectrum (2 positive trials)
GETUG 15ADT-docetaxel: 60.9 m ADT alone: 46.5 m p = 0.44
Gravis, et al. Lancet Oncology 2015 12
Upfront Use of Chemo in Hormone Sensitive Metastatic Disease
Failed Attempt 1 : GETUG 15
GETUG15 The first trial in HSPC testing Docetaxel A negative Trial
Successful Attempt 2 :CHAARTED
Sweeney C J et al. Clin Oncol 32:5s, 2014 (suppl; abstr LBA2)Sweeney C J et al. N Engl J Med. 2015;373(8):737–46.
Patient Characteristics
• Diagnosis of prostate cancer with metastatic disease
• ECOG PS 0-2• Prior adjuvant ADT was allowed
if the duration o ≤24 months and progression >12 months after completion
• Patients receiving ADT for metastatic disease were eligible if no evidence of progression and treatment commenced ≤120 days before randomization
Stratification• Extent of metastasis: high volume vs low volume*• Age: ≥70 vs <70 years• ECOG: 0-1 vs 2• CAB > 30 days: yes vs no• SRE prevention: yes vs no• Prior adjuvant ADT: ≤12 vs >12 months
R
A
N
D
O
M
I
Z
E
D
1
:
1
ARM AADT + Docetaxel 75 mg/m2
21 days for maximum 6 cycles
ARM BADT (androgen deprivationtherapy alone)
Evaluate every 3 weeks whilereceivingdocetaxel and atweek 24 thenevery 12 weeks
Evaluate every 12 weeks
Follow up for time to progression andoverall survival
Chemotherapy atinvestigator’sdiscretion atprogression
Phase 3, multicenter, open label study
(N = 790)
• ADT allowed up to 120 days prior to randomization• Intermittent ADT dosing was not allowed• Standard dexamethasone premedication but no daily prednisone
*At study start only pts with high volume disease were to be enrolled. Study was amended to also include patients with low-volume disease.
CHAARTED Overall Survival
High Volume:
>=4 bone mets at least 1
Outside axial skeleton
Or /and visceral mets
All Patients
p=0.0006HR=0.60 (0.45-0.81)Median OS: ADT + D: 49.2 monthsADT alone: 32.2 months
Sweeney C J et al. Clin Oncol 32:5s, 2014 (suppl; abstr LBA2)Sweeney C J et al. N Engl J Med. 2015;373(8):737–46.
Hazard Ratios for Death in Subgroups.
Sweeney CJ et al. N Engl J Med 2015;373:737-746
Sweeney CJ et al. N Engl J Med 2015;373:737-746
CHAARTED: Overall QoL on FACT-P
Patrick-Miller al. J Clin Oncol 2016;34(suppl): abstract 5005
Of interest the final improvement of qol for ADT +Docetaxel: dual interpretation …
E-3805 CHAARTED UPDATEDSURVIVAL POINTS TO HETEROGENEITY
First data (NEJM 2015) Updated data (ESMO 2016)
HR=0.60 (95%CI 0.32-1.13)HR=1.04 (95%CI 0.70-1.55)
Hig
h v
olu
me d
isease
Low
volu
me d
isease
HR=0.60 (95%CI 0.45-0.81) HR=0.63 (95%CI 0.50-0.79)
Sweeney et al #720
Updated Survival Analysis :
Low Volume mHNPC
Does not derive benefit from
Addition of Docetaxel
Attempt 3 : STAMPEDE
Nicholas JamesUniversity of Warwick and Queen Elizabeth Hospital Birmingham on behalf of
Matthew Sydes, Malcolm Mason, Noel Clarke, David Dearnaley, Melissa Spears, Robin Millman, Chris Parker, Alastair Ritchie, J. Martin Russell, John Staffurth, Robert Jones, Shaun Tolan, John Wagstaff, Andrew Protheroe, Rajaguru Srinivasan, Alison Birtle, Joe O'Sullivan, Richard Cathomas, Mahesh Parmar and the STAMPEDE Investigators
Lancet dec 21 2015
Docetaxel & ZA comparisons: patients
Docetaxel: SurvivalSOC 405 deathsSOC+Doc 165 deaths
HR (95%CI) 0.76 (0.63, 0.91)P-value 0.003
Non-PH p-value 0.51
Median OS (95% CI)SOC 67m (60, 91m)SOC+Doc 77m (70, NR)
Restricted mean OS timeSOC 58.8m SOC+Doc 63.4mDiff (95%CI) 4.6m (1.8, 7.3m)
21
2015 Standard of care for men with mHNPCADT + Docetaxel
21
1. Gravis G, et al. Eur Urol. 2016:70:256-262. 2. Sweeney C, et al. N Engl J Med. 2015;373:737-746; Sweeney C, et al. Ann Oncol. 2016;27(Suppl 6):243-265. 3. James N, et al. Lancet. 2016;387:1163-1177. and Vale C, et al. Lancet Oncol2016;17:243-256.
62.1 48.60.88 (0.68-
1.14)0.3
57.6 47.20.73 (0.59-
0.89)0.0018
60 450.76 (0.62-
0.92)0.005
ADT + DOC
ADT
Median
(mos)
Median (mos)
HR (95% CI) P Value
GETUG-151
CHAARTED2
STAMPEDE3
Overall
Survival
Docetaxel in mHNPC
Conclusions & Questions
Conclusions : PRACTICE SHAPING
Docetaxel exhibits an overall survival benefit in hormone
sensitive metastatic disease in two studies and does not in one
Docetaxel added to ADT in hormone naïve metastatic disease
with “high volume” prolongs survival (CHAARTED)
De novo metastatic disease derives consistent benefit in both
positive studies
Marrow Toxicity remains a concern
Questions
• Is there meaningful benefit in low volume disease?
• How do we objectively select men who will benefit?
• Subsequent access to treatment important
• How do we address the ~20% of highly aggressive disease not
benefiting
Mechanisms of resistance to ADT may develop early1-3
ADT does not inhibit adrenal or intracrine/ paracrine androgen synthesis; inhibits testicular synthesis but less profoundly than abiraterone
A more robust ‘wild type’ androgen signaling driver of disease Abiraterone + Prednisone
improves OS in mCRPC4,5
reduces tumor burden in high-risk, localized PC6,7
These data suggest a potential role for inhibiting extragonadal androgen biosynthesis prior to the emergence of castration resistance
23
Rationale for Abiraterone added to ADT in mHNPC
1. Gravis G, et al. Eur Urol. 2016:70:256-262. 2. Sweeney C, et al. N Engl J Med. 2015;373:737-746. 3. James N, et al. Lancet. 2016;387:1163-1177. 4. de Bono JS, et al. N Engl J Med. 2011;364:1995-2005. 5. Ryan CJ, et al. Lancet Oncol. 2015;16:152-160. 6. Taplin ME, et al. J Clin Oncol. 2014;32:3705-3715. 7. Efstathiou E, et al. J Clin Oncol. 2015;33(suppl):15s. Abstract 5061.
Tumor Cell Density (%)
P < 0.0001 P < 0.0001
Tumor Epithelium Volume: Tumor Cell Density × Volume
Tumor Volume (cc)
P = 0.003
Efficacy end points
Co-primary:
• OS
• rPFS
Secondary: time to
• pain progression
• PSA progression
• next symptomatic
skeletal event
• chemotherapy
• subsequent PC therapy
ADT
+ Abiraterone acetate 1000
mg QD
+ Prednisone 5 mg QD
(n = 597)
ADT
+ placebos
(n = 602)
Patients
• Newly diagnosed adult
men with high-risk
mHNPC
Stratification factors• Presence of visceral
disease (yes/no)
• ECOG PS (0, 1 vs 2)
RANDOMIZED
1:1
• Conducted at 235 sites in 34 countries in Europe, Asia-Pacific, Latin America, and Canada
• Designed and fully enrolled prior to publication of CHAARTED/STAMPEDE results
LATITUDE Study Design
Fizazi et al NEJM 2017
Treatment arms: GS >=8 and bone lesions main criteria
ADT + AA + P(n = 597)
ADT + Placebos(n = 602)
Median age, years (range) 68.0 (38-89) 67.0 (33-92)
Gleason score ≥ 8 at initial diagnosis
98% 97%
Patients with ≥ 3 bone metastases at screening 98% 97%
Extent of diseaseBoneLiverLungsNode
97%5%
12%47%
98%5%
12%48%
Baseline pain score (BPI-SF Item 3)
0-12-3≥ 4
50%22%29%
50%24%27%
FFizazi et al NEJM 2017Fizazi et al NEJM 2017
Latitude: 38% risk reduction of death
0
0 6 12 18 24 30 36 42
20
40
60
80
100
Months
Ov
era
ll S
urv
ival (%
)
No. at risk
ADT + AA + P 597 565 529 479 388 233 93 9
602 564 504 432 332 172 57 2
Hazard ratio, 0.62 (95% CI, 0.51-0.76)
P<0.0001
ADT + AA + P, not reached
ADT + placebos, 34.7 mo
ADT + placebos
OS rate at 3 years:ADT + AA + P: 66%ADT + placebos: 49%
No. of events: 406 (48% of 852)
ADT + AA + P: 169
ADT + placebos: 237
Median follow-up: 30.4 months
Fizazi et al NEJM 2017
53% risk reduction of radiographic progression or death
0
20
40
60
80
100
Pro
gre
ssio
n-F
ree S
urv
ival (%
)
0 4 8 12 16 2420 28 32 36 40
Months
No. at risk
ADT + AA + P 597 533 464 400 353 316 251 177 102 51 21
602 488 367 289 214 168 127 81 41 17 7
No. of events
ADT + AA + P: 239
ADT + placebos: 354
Hazard ratio, 0.47 (95% CI, 0.39-0.55)
P<0.0001
ADT + AA + P, 33.0 mo
ADT + placebos, 14.8 mo
ADT + placebos
27Fizazi et al NEJM 2017
ADT + AA + P
(n = 597)
ADT + placebos(n = 602)
n (%) n (%)
Patients eligible*n = 314 (53%)
n = 469 (78%)
Patients who received life- prolonging therapy
125 (40) 246 (52)
Docetaxel 106 (34) 187 (40)
Enzalutamide 30 (10) 76 (16)
AA-P 10 (3) 53 (11)
Cabazitaxel 11 (4) 30 (6)
Radium-223 11 (4) 27 (6)
*Patients who discontinued treatment and were eligible for subsequent therapy.
Subsequent life-prolonging therapy for prostate cancerNot enough AA on control arm?
Fizazi et al NEJM 2017
Docetaxel & ZA comparisons: patients
Trial includes localised and M1 HSPCLocalised receive AA for 2years
STAMPEDE ARM G REPORT 2017
30
STAMPEDE Patient characteristics
1% WHO PS 2 [s]
21% WHO PS 1 [s]
67yr Median age [s](min 39, max 85)
52% Metastatic [s](88% Bony mets)
20% N+M0
28% N0M0
99% LHRH analogues [s]
41% Planned for RT [s](96% of N0M0 pts; 62% of N+M0 pts)
5% Previous local therapy
Balanced by arm
James N, et al. ASCO 2017. LBA5003 and Oral Abstract Session
James et al NEJM 2017
Events262 Control | 184 abiraterone plus prednisone
HR 0.6395% CI 0.52 to 0.76P-value 0.00000115
SOC
SOC+AAP
OS – STAMPEDE “abiraterone plus prednisone comparison”
James N, et al. ASCO 2017. LBA5003 and Oral Abstract Session
This represents a 37% improvement in survival
James et al NEJM 2017
HR 0.2995% CI 0.25 to 0.34P-value 0.377x10-61
Events535 Control | 248 abiraterone plus prednisone
SOC
SOC+AAP
Failure Free Survival – STAMPEDE
James N, et al. ASCO 2017. LBA5003 and Oral Abstract Session
This represents a 71% improvement in time to failure
James et al NEJM 2017
Subsequent TreatmentsMore Frequent use of Docetaxel post AA
and limited use of AA in ADT arm
James et al NEJM 2017
Abiraterone in 2017Conclusions : PRACTICE SHAPING
Abiraterone added to ADT in “high risk” hormone naïve
metastatic disease prolongs survival (LATITUDE)
Abiraterone exhibits an overall survival benefit in hormone
sensitive metastatic disease in two studies
De novo metastatic disease derives consistent benefit in both
positive studies
No new safety concerns with the use of Abiraterone
Questions
• Is the observed benefit based only on “biology” or “window of
opportunity?” as well : Consistently who gets more does better
• Is there meaningful benefit in ‘low risk’ and M0 disease?
• How do we objectively select men who will benefit from one of
the other agent?
• How do we address the ~20% of highly aggressive disease not
benefiting with either choice
Decision Making in mHNPCDocetaxel (6cs)
Low Cost
High Volume CHARTEED definition
Abiraterone acetate with consistent long term monitoring
androgen signaling driven biology is dominant
Fear of chemo frailty
The ‘Breast Cancer’ Model albeit without the molecular classification
Docetaxel 6cs followed by Abiraterone Acetate : TOO EARLY
BUT : Monitor Closely
Patients on both agents lived longer consistently on all trials
Different Mechanism of Action
Particularly High Volume disease may warrant more aggressive approach
High risk LATITUDE definition (majority) to be distinguished from High Volume CHARTEED definition: High volume is a subset of high risk
ADT
A minority of men with slowly progressive disease (eg gleason 7 but no tertiary 5)
Heart failure and comorbidities limiting survival
Strong evidence favouring AA+P
Toxicity profiles quite different and well known
Weak evidence favouring AA+P
No good evidence of a difference in OS
FavoursADT+AA+P
FavoursADT+DOC
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
STAMPEDE points to “Equivalence” Is it a loss vs gain – balance
AA+P = abiraterone acetate plus prednisone/prednisolone; ADT = androgen-deprivation therapy; DOC = docetaxel
Adapted from: Sydes M, et al. Abstract LBA31 presented at ESMO 2017 Sydes et al Annals of Oncology
Conclusions for now…HNPC treatment options
Intermittent ADT a valid option for biochemical recurrence of m0 HNPC
Continuous vs Intermittent ADT preferred for m HNPC
Six Cycles of Docetaxel 75mg/m2 or Abiraterone Acetate (continuously) combined with ADT recommended for m HNPC patients
Prostate Cancer Treatment Paradigm
in 2010
Local
therapy
Androgen deprivation
therapy (ADT)
Therapies after
ADT
Death
ADT
mCRPC
post-
docetaxel
mCRPC
symptomatic
mCRPC
mildly
symptomatic
mCRPC
asymptomatic
(failed ADT)
Hormone
sensitive
Docetaxel
A New Therapy landscape in ‘Advanced Prostate Cancer ‘
(2018)Death
ADT
supportive care
(denosumab/bisphosphonates)
Advanced metastatic Prostate Cancer
Hormone
Sensitive
Prostate Cancer
Localized / Metastatic
Sipuleucel-T
Abiraterone
Docetaxel Cabazitaxel
Radium 223
Enzalutamide
mHSPC
ADT +
Docetaxel
mHSPC
ADT +
Abiraterone
Apalutamide
Please see Important Safety Information throughout this presentation.Please see full Prescribing Information available at this presentation.
Non-Metastatic CRPC : Is this a real disease state?
40
Certain patients with prostate cancer receiving ADT will eventually develop
castration-resistant disease.1,2 Patients with CRPC who present with:
No evidence of detectable metastasis3
Non-metastatic3
or M0 CRPC4Rising PSA*
while on ADT3
Serumtestosterone levels
below 50 ng/dL3
No evidence of detectable metastases with convenitonal imagingnmCRPC includes local recurrence prostate bed + pelvic nodes
Please see Important Safety Information throughout this presentation.Please see full Prescribing Information available at this presentation.
• Apalutamide is an AR inhibitor that binds directly to the ligand-binding domain of the AR1
• Apalutamide inhibits AR nuclear translocation, inhibits DNA binding, and impedes AR-mediated transcription1
Apalutamide Mechanism of Action
41
Metastasis-Free Survival in nmCRPCimproved with Apalutamide
Apalutamide
Apalutamide+ ADT
FDA Approval on Valentine ‘s Day 2018
Proposed Treatment Algorithms for mCRPC reflective of lack of precision
NCCN Guidelines v2 2016; http://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf
Matthew R. SmithUS
Hideyuki AkazaJP
Gerhardt AttardUK
Tomasz M. BeerUS
Himisha BeltranUS
Arul M. ChinnaiyanUS
Johann De BonoUK
Charles G. DrakeUS
Rosalind A. EelesUK
Eleni EfstathiouUS
Stefano FantiIT
Karim FizaziFR
Silke GillessenCH
Susan HalabiUS
Axel HeidenreichDE
Maha H.A. HussainUS
Christopher J. Logothetis
US
Peter NelsonUS
William K. OhUS
Anwar PadhaniUK
Nicholas D. James
UK
Chris ParkerUK
Mark A. RubinUS
Oliver A. SartorUS
Jack A. SchalkenNL
Howard I. ScherUS
Avishay SellaIL
Neal ShoreUS
Eric SmallUS
Cora N. SternbergIT
Hiroyoshi SuzukiJP
Christopher SweeneyUS
Martin E. GleaveCA
Ian TannockCA
FrédéricLecouvetBE
Bertrand TombalBE
David OlmosES
Gedske DaugaardDK
Maria De SantisAT
Sten NilssonSE
Ian DavisAU
urologist medical oncologist othersradiation oncologist
APCCC St Gallen MeetingOffering Guidance
Therapeutic agents for “Advanced Prostate Cancer”/mCRPC
Trial Regimen Pts HR NSurvival
(months)Delta
(months)
IMPACT1 Sipuleucel-T CRPC 0.78 512 25.8 vs 21.7 4.1
TAX 3272 Docetaxel+Prednisonevs Mitoxantrone+Prednisone
CRPCChemonaive
0.76 1006 18.9 vs 16.5 2.4
TROPIC3 Cabazitaxel+Prednisonevs Mitoxantrone+Prednisone
CRPCPost-docetaxel
0.70 755 15.1 vs 12.7 2.4
COU-AA-3014 Abiraterone +Prednisone vs Prednisone
CRPCPost-docetaxel
0.74 1195 15.8 vs 11.2 4.6
ALSYMCA5 Alpharadin vs Placebo
CRPC 0.695 809 14.0 vs 11.2 3.6
AFFIRM6 Enzalutamidevs Placebo
CRPCPost-docetaxel
0.63 1199 18.4 vs 13.6 4.8
1. Kantoff PW et al. N Engl J Med 2010;363:411-22.2. Tannock IF et al. N Engl J Med 2004;351:1502-12.
3. de Bono JS et al. Lancet 2010;376:1147-54.
454. Fizazi K et al. Lancet Oncol 2012.5. Parker C et al. ASCO 2012 (LBA 4512).6. Scher H et al. N Engl J Med 2012;367:1187-97.
Survival prolongation on average 3.5 months!
Docetaxel in Metastatic Castrate Resistant Prostate Cancer
Tannock et al NEJM 2004
1Heinlein CA et al. Endocr Rev. 2004;25(2):276-308 2Hu R et al. Expert Rev Endocrinol Metab. 2010;5(5):753-764
PI3K/AKT/ERK/mTOR
PI3K/AKT/ERK/mTOR
NUCLEUS
AR
T/DHT
Androgen production by adrenal glands
and prostate tumor2
AR overexpression2
AR splice variants2
AR mutants2
Signaling cross-talk1,2
Upregulation of AR cofactors1,2
Up to 80% of CRPCs elevated AR gene copy number, 30% high-level amplification of the geneAR mutations common10-30% of the CRPC treated with antiandrogens
CRPC Remains Driven by Androgen Receptor Signaling – AR Alterations Selected During Therapy
Abiraterone Acetate: Androgen Biosynthesis Inhibitor
Μechanism of Action
Tip : Endocrine Side Effects
Low-dose steroid replacement minimizes mineralocorticoid-related
toxicity- NOT SUPRAPHYSIOLOGIC DOSING
Enzalutamide : Antiandrogenmechanism of action
Enzalutamide is an AR signalling inhibitor that inhibits AR signalling in three distinct ways:
DHT
1. Blocks AR binding 3. Blocks DNA binding and activation
EnzalutamideEnzalutamide AR
Cytoplasm Nucleus
2. Impairs nuclear translocation
Enzalutamide
Tran et al. Science 2009;324:787–90; Watson et al. Proc Natl Acad Sci USA 2010;107:16759–65.AR, androgen receptor; DHT, dihydrotestosterone
TIP: Crosses brain blood barrier
Centrally driven adverse event profile; fatigue
Steady State 28 day
COU-AA-301: Abiraterone Acetate Improves Overall Survival in Metastatic CRPC post docetaxel
De Bono et al. N Engl J Med.
21
HR = 0.646 (0.54-0.77) P < 0.0001
Placebo: 10.9 months (95% CI: 10.2-12.0)
Abiraterone acetate: 14.8 months (95% CI: 14.1-15.4)
100
80
60
40
20
Surv
ival
(%
)
00 3 6 9 12 15 18
Placebo
AA
Time to Death (Months)
CRPC, castrate resistant prostate cancer.
FDA Approved Apr 28, 2011EMEA Approved Sep 2011
Median age: 69 yrs≥ 75 years: 28%
Tip PSA increase should be a trigger for further evaluation but not discontinuation
AFFIRM Enzalutamide Improves Overall Survival in Metastatic CRPC post docetaxel
HR = 0.631 (0.529, 0.752) P < 0.000137% Reduction in Risk of Death
MDV3100: 18.4 months (95% CI: 17.3, NYR)
Placebo: 13.6 months (95% CI: 11.3, 15.8)
Surv
ival
(%
)100
80
60
Enzalutamide 800 775 701 627 400 211 72 7 0
Placebo 399 376 317 263 167 81 33 3 0
40
20
90
50
30
0
10
70
Scher et al NEJM 2012
FDA Approved Aug 2012EMA Dec 2012
Targeting Androgen Signaling Earlier Two large trials in line in chemo naïve
mCRPC : Both positive100
80
60
40
20
00
Ove
rall
Surv
ival
(%
)
9 21 30 48 6039Time to Death (Months)
24123 36 45 54
HR (95% CI): 0.81 (0.70-0.93)
p Value: 0.0033
Prednisone, 30.3 mos
Abiraterone, 34.7 mos
6 15 18 27 33 42 51 57
Ryan et al. NEJM 2014, Beer et al NEJM 2014
Su
rviv
al
(%)
60
50
40
30
20
10
0
90
80
70
100
0 3 6 9 12 15 18 21 24 27 30 33 36
Enzalutamide
Placebo
HR: 0.706 (95% CI: 0.60,0.84)P<0.0001
Placebo: 30.2 (95% CI 28.0, NYR)
Enzalutamide: 32.4
(95% CI 30.1, NYR)
Alpharadin Mechanism of action: microenvironment targeting?
Bonemarrow
Tumor
Range ofalpha particle(small volume)2-10 cell diameter
Minimal damage to surrounding bone marrowand tissue
BoneBone
surface
Radionuclide
Alpharadin increases Overall Survival in mCRPCpatients ineligible for or who refused chemo
Parker et al Lancet 2013Median Age
70
How to Train your Immune system…
Sipuleucel –T improves overall survival in mCRPC
Tips : No PSA response no rPFS improvement anticipatedSub-analysis in favor of prechemo – smaller volume disease with “stability”FYI two large ipilimumab trials negative in mCRPC Small et al 2010
Median age: 68 yrs≥ 75 years: 18%
TROPIC: Cabazitaxel improvesoverall survival vs Mitoxantrone in
post docetaxel mCRPC
De Bono et al. Lancet, 2010, 376:1147-54
Pro
po
rtio
n s
urv
ivin
g (%
)
100
80
60
40
20
0
Mitoxantrone
Cabazitaxel
0 6 12 18 24 30
28%
17%
Time (months)
HR 0.70 (95% CI 0.59–0.83)p <0.0001
FIRSTANA:
Overall survival no difference
Sartor et al. J Clin Oncol 2016
Conclusion : Cabazitaxel not superior to docetaxel in first line mCRPCCabazitaxel 20mg/m2 less toxic than 25mg/m2
FDA issued new dosing instruction : 20mg /m2 in 2017
Supportive Treatmentfor bone mCRPC
Bone HealthVit D (+Calcium) – a mandate for PCa patients
Zoledronic acid 4mg iv q 3-4 wks vsDenosumab 120mg /q 4wks
Both only approved for mCRPC in such regimen
Denosumab vs zoledronic acid in mCRPC
SIOG recommendations for senior men
Treatment recommendations for older men with prostate cancer should be based:
• health status (mainly driven by comorbidities)
• patient preferences
NOT on chronological age!!!
Droz JP et al, Lancet Oncology. 2015,
Treatment should be adapted tohealth status
Standard
treatment
Geriatric
intervention
• ‘Fit’: Same treatment as younger patients≈ 50% of men 70–75 years ≈ 25% of men 80–85 years
• ‘Vulnerable’: Geriatric intervention then standard treatment
• ‘Frail’: Geriatric intervention then adapted treatment or palliative treatment
• ‘Too sick’ Onlypalliative treatment
Treatment Selection for mCRPC
No available predictors of outcome No Clear selection Criteria between androgen signaling inhibitors
and docetaxel ....both abiraterone acetate and enzalutamide have proven survival benefit when given prior to docetaxel ..
• Alpharadin should be used only for bone metastases
• Sipuleucel –T is preferred pre chemo and on lower disease burden
• “ Vintage “ hormones are no longer recommended given lack of survival benefit data
Patient preference should be considered
Future Directions
Do not confuse motion with progress
Montalpert
Current Practice: Reactive Medicine
Regimen
+
+
Patient success
to
+
-+
Choice of TreatmentAccess to Treatment – Reimbursement status- Regulatory aspectsLevel I evidence : originating from randomised PhIII trials Personal Experience - Discipline
2015-17 Trial Progress ReportClinical Practice Change in mHNPC
The reemergence of Chemotherapy in advanced Prostate cancer
mHNPC data
Failure for microenvironment agents and immunotherapy in ALL mCRPC studies:
Orteronel ,Tasquinimod, Cabozantinib, Ipilimumab (2)
Moving Androgen Biosynthesis Inhibition earlier in the disease spectrum
mHSPC positive data ( 2 positive trial)
mCRPCSaturation?Lack of Selection
Design of prostate cancer studies largely rely on
uniform prognostication
Moving the Therapeutic Dilemma Earlier
Local
therapy
Death
ADT
supportive care (eg
denosumab/bisphosphonates)
mCRPC
post-
docetaxel
mCRPC
symptomatic
mCRPC
mildly
symptomatic
mCRPC
asymptomatic
(failed ADT)
Hormone
sensitive
Sipuleucel-T
Enzalutamide
Abiraterone Abiraterone
Docetaxel Cabazitaxel
Radium 223
EnzalutamidemHNPC
ADT +
Docetaxel
mHNPC
ADT +
Abiraterone
2017
Apalutamide
Agents• Docetaxel• Cabazitaxel• Sipeuleucel-T• Abiraterone• Enzalutamide• Rad 223
Giving Perspective :Pembrolizumab for MSI across solid tumors
Survival prolongation on average 3.5 months in mCRPCMost trials to date focused on drug development irrespective of risk category
Have we reached ‘Saturation’ in mCRPC ?
Registration Study Failures in mCRPC
Uniform Prognostication Approach
Cabozantinib, Tasquinimod and Ipilimumab (2),
And all Docetaxel + combinations (15)
Too many questions to be answered / lack of validation of companion
diagnostics
Galeterone
Too late Space taken / Saturation
Orteronel
Are we missing opportunities for our
patients and how can we rectify ?Ipilimumab in Post-Chemotherapy mCRPC
1.0
0.8
0.6
0.4
0.2
0.0
0 4 8 12 16 20 24 28 32 36
Pro
po
rtio
n A
live
IpilimumabCensored
PlaceboCensored
Months
Kwon, ED et al. Lancet Oncol. 2014.
HR 0·85, 95% 0·72–1·00; p=0·053
Steps in the right direction
Multi-institutional integrative clinical sequencing analysis- East Coast SU2C
Underscores Heterogeneity
~90% of mCRPC harbor clinically actionable molecular alterations
NEED FOR PROSPECTIVE VALIDATION TO PROVE A
POTENTIAL BENEFIT OF ANY ACTION
Robinson et al Cell 2015
A “feasibility” report paving the way for predictive biomarker identificationAnd a much needed classification
Somatic mutation landscape in far advanced mCRPC
Highly Burdened mutational landscape
A tall order to identify a driver ….
Cell. 2015 May 21;161(5)
DNA Repair Genes aberrations in mCRPC maybe ‘treatable’ with a PARP inhibitor :
A “retrospective” analysis providing insight – the path for a prospective validation
Mateo J et al. N Engl J Med 2015;373:1697-1708 Mateo et al 2015 NEJM
Pritchard, NEJM, 2016
GENETIC TESTING: SHOULD IT BE OFFERED
AND WILL IT AFFECT EARLY TREATMENT CHOICES ?
32
22 2 1 1 1 1 1 1
11 ATM
(13%)
10 CHEK2
(12%)
6 BRCA1
7%
RAD51D
ATR
GEN1NBN
PMS2
FAM175A
RAD51C
MSH6
MSH2BRP1
MRE11A
37 BRCA2
(45%)
12%
How to “Efficiently” target?
Would earlier treatment reduce “variables” that may be driving progression or resistance ?
What are the “variables” and how do they change over time and how do we track them?
Development of Biomarkers :Should a biomarker be ‘reflective’ of the
pathway of progression rather than a ‘by association’ event
Precision Medicine Requirements
National Research Council 2012
Precision Medicine Requirements Knowledge Network for
Biomedical Researchintegrating :
Molecular Characterisation& Clinical Data
New Taxonomy of Disease
Biomedical Research Clinical Medicine
Precision Medicine Delivered
Understand Anticipate
Cure/
Secondary
PreventionIntegrate KnowledgeIdentify / Classify findings
Enable Risk Assessment
Treat based on Taxonomy AND patient characteristics
Right treatment strategy at the right dose at the right time, with minimum ill consequences and
maximum efficacy
A need to acquire Knowledge to make most of information
Make the most of data – adapt to
your practice
Monitor patients diligently – details
matter
Listen to the need of the patient
For now : we can use available treatment strategy at the right dose, with minimum ill
consequences and strive for maximum efficacy
Working together to support ourPatients and their families
Questions
2016 question 1
An 80 yr old previously fit man with no comorbidities has recently started having back pain loss of weight and fatigue his PS is quickly deteriorating . Found to have de novo metastatic prostate cancer GS 8 with >20 bone lesions, PSA 800, LDH 1000 . What would be the preferred approach? a. Start Androgen Deprivationb. Start Androgen deprivation and bone modifying agentsc. Start Androgen deprivation and Docetaxeld. Start Androgen Deprivation and Abiraterone Acetate plus
low dose steroids e. C or D
2. Please propose the appropriate 1st line treatment for a gentleman of 78 yrswith no known comorbidities , who has mCRPC with multiple bone and lymphnode metastases . Patient remains fully active has no symptoms has a very busy social life. He is on treatment with lhrh analogue for 3 years and is now progressing by imaging and PSA criteria. Lymphnode size ranges from 2-3 cm . Novel agents are available and reimbursed or patient can afford
Pick all appropriate choicesa Novel Androgen Signaling Inhibitor : Abiraterone Acetate or Enzalutamideb 6-10 courses of Docetaxelc Alpharadind 6-10 courses of Cabazitaxele Sipuleucel – Td prednisone or dexamethasone low dose e Bicalutamide 50mg /qdf Denosumab or Zoledronic acid infusion added to one of choices of systemic treatment
3. A patient of 73 yrs old has received prior chemo with docetaxel and is now on treatment with a novel androgen signaling inihibitor ( abiraterone or enzalutamide) . For the past 12 months . He had initiated treatment because of a rising psa to 150 .
Initially his PSA regressed to 10 .His PSA is now progressing within the past 3 months ( 05/16 : 10 06/16: 12 07/16: 14)
Patient is feeling great and his imaging did not show any sign of progression Patient is concerned please advise regarding best option
a. Stop an androgen signaling inhibitor b continue the androgen signaling inhibitor and monitor closely imaging and clinical
symptoms while reassuring patient c continue androgen signaling inhibitor and add chemo with cabazitaxeld stop androgen signaling inhibitor and start treatment with cabazitaxel
e . Stop androgen signaling inhibitor and initiate alpharadinf change from one androgen signaling inhibitor to the other (abiraterone to
enzalutamide or vice versa depending on what he was on)g reassure patient nothing is wrong and send him home to continue monitoring only
psa every 3 months
4. A 68 yr old gentleman is diagnosed with a Gleason Score 7 (3+4) Prostate Cancer in 3/8 right lobe biopsy cores and none of 0 /6 left lobe biopsy cores . No comorbidities but hypertension. Please recommend treatmentoptions.Multiparametric Choose the most appropriate selectiona. Active Surveillanceb. XRT + ADT for 6 monthsc. XRT d. Radical Prostatectomy