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Sequencing Therapy for CRPC:A Practical Approach.
Mohamed Abdulla M.D.Prof. of Clinical Oncology
Kasr Al-Aini School of MedicineCairo University
SUN – Genitourinary Cancer MeetingRadisson Blue Hotel – Alexandria07/11/2014
Basic Facts & Figures:
• Increasing Incidence: Aging and Screening Programs.
• 2nd Most Common Cancer in Men.• 1/6 Men.• African Americans – Black Races,• Rare Before Age of 40 and then Readily Rises.• Prostate Cancer is an Androgenic Disease
Circulating Androgens & Androgen Receptors.
Uptodate.com 06/02/2014
HypothalamusLHRH
Pituitary
Testes Supra-renal
Testosterone
LH ACTH
Prostate Cancer is an Androgenic Disease: “Androgen Synthesis”
NTD DBD Hinge LBD
Nuclear & Steroid
Superfamily
Androgen
Estrogen
GlucocorticoidMineralocorticoid
Progesterone
Constitutively Active DNA
Promoter Gene
AndrogensN/C
HSP
Prostate Cancer is an Androgenic Disease: “Androgen Receptor Structure”
Prostate Cancer is an Androgenic Disease: “Androgen Receptor Activity”
Testosterone DHT5@ Reductase
DHT+AR+HSP Active AR
Active AR Active AR Active AR
Proliferation
Angiogenesis
Metastases
AREAR
Degraded
Genomic ActivityPSA, IGF, …
Testosterone 5 α Reductase DHT + AR (LBD)
PI3KCaveolae
RTKGPCR
AR Activation & Dimerization
HSP
AKTSrc
MAPKERK1/2
Nuclear Transcription Factors
• Proliferation, Angiogenesis, …• No AR Degradation.
Prostate Cancer is an Androgenic Disease: “Androgen Receptor Activity”
Non Genomic Activity
Androgen Androgen Receptors
Perfect Disease Control
• Surgical Castration.• Medical Castration.
• Blocking Receptors.
Androgen Synthesis
Receptor Activity
Androgen Receptor in Prostate Cancer:
Androgen Receptor is Sensitive & Addicted to Stimulation
Steroidogenesis & Prostate Cancer :
Cholesterol CYP 11A1 Pregnenolone CYP 17A1 Testosterone
ASS
Androgen Biosynthesis
Castrate Resistant Prostate Cancer:Prognostic Factors:
1. Site of Metastases: 5 RCTs:
Liver
Lungs
Bone
LNs
0 5 10 15 20 25 30
OAS
Months
Halabi et al. Journal of Clinical Oncology, 2014 ASCO Annual Meeting Abstracts. Vol 32, No 15_suppl (May 20 Supplement), 2014: 5002
Castrate Resistant Prostate Cancer:Prognostic Factors:
Halabi et al. J Clin Oncol 32:671-677. © 2014
1984-1989
...but this rapid change has left many unanswered questions, including the optimal selection and sequence of therapy
Mitoxantrone3 Docetaxel5,6*
Sipuleucel-T8*
LHRH agonists1*
1. The Leuprolide Study Group. N Engl J Med. 1984;311(20):1281-1286. 2. Crawford ED, et al. N Engl J Med. 1989;321(7):419-424. 3. Tannock I et al. J Clin Oncol. 1996;14(6):1756-1764. 4. Saad F, et al. J Natl Cancer Inst. 2002;94(19):1458-1468. 5. Petrylak DP, et al. N Engl J Med. 2004;351(15):1513-1520. 6. Tannock I, et al. N Engl J Med. 2004;351(15):1502-1512. 7. de Bono JS, et al. Lancet. 2010;376(9747):1147-1154. 8.Kantoff P, et al. N Engl J Med. 2010;363(5):411-422. 9. Fizazi K, et al. J Clin Oncol. 2009;27(10)1564-1571. 10. de Bono JS, et al. N Engl J Med.2011;364(21):1995-2005. 11. Scher HI, et al. N Engl J Med. 2012;367(13):1187-1197.
1996 2002 2004 .... 2010
Abiraterone10*
Reversible AR blockers2
Cabazitaxel7*
2011
Denosumab9
Radium 223?
Zoledronic Acid4
2012
Enzalutamide11*
• Pain
• Bone vs visceral metastases
• Performance status
• Neuropathy
• Comorbidity
• “Early or late” CRPC
• Prior therapy exposure and response
• Response biomarkers
• Tumor characteristics
CRPC, castration-resistant prostate cancer
Management of CRPC:
1. ADT should be continued.2. Choose between therapies associated with
survival benefit.
COU-AA-301 Study Design Phase III Post-Docetaxel
Abiraterone 1000 mg QD Prednisone 5 mg BID
n = 797
Primary endpoint:
• OS
Secondary endpoints:
• PSA response
• Time to PSA progression
• rPFS
Placebo QD Prednisone 5 mg BID
n = 398
R A N D O M I Z E D2:1
Phase 3, double-blind placebo-controlled trial of abiraterone + prednisone versus placebo + prednisone in mCRPC post- chemotherapy
de Bono JS, et al. N Engl J Med. 2011;346(21):1995-2005.
• 1195 patients with progressive mCRPC
• Failed 1 or 2 chemotherapy regimens, 1 of which contained docetaxel
Ove
rall
Su
rviv
al, %
0
20
40
60
80
100
12 18
Time to Death, months0 6 24 30
AA + P 797 657 473
Placebo + P 398 306 183273 15 0
100 6 0
AA + P:
AA, abiraterone acetate; CI, confidence interval; P, prednisone
Placebo + P:
HR = 0.74 (95% CI,0.638-0.859) P<.000126% reduction in risk of death
Median follow-up: 20.2 months
Fizazi K, et al. Lancet Oncol. 2012;13(10):983-992.
0.5 0.75 1 1.5
Favors abiraterone Favors placebo
de Bono JS, et al. N Engl J Med. 2011;364(21):1995-2005.
Variable Subgroup N HR 95% CI
All subjects All 1195 0.66 0.56-0.79
Baseline ECOG 0-1 1068 0.64 0.53-0.782 127 0.81 0.53-1.24
Baseline BPI < 4 659 0.64 0.50-0.82
≥ 4 536 0.68 0.53-0.85
No of prior chemotherapy regimens
1 833 0.63 0.51-0.78
2 362 0.74 0.55-0.99Type of progression PSA only 363 0.59 0.42-0.82
Radiographic 832 0.69 0.56-0.84
Age, years < 65 0.66 0.48-0.91
≥ 65 0.67 0.55-0.82Visceral disease at entry Yes 353 0.70 0.52-0.94
Baseline PSA above median
Yes 591 0.65 0.52-0.81
Baseline LDH above median
Yes 581 0.71 0.58-0.88
Baseline ALK-P above median
Yes 587 0.60 0.48-0.74
Region N America 652 0.64 0.51-0.80
Other 543 0.69 0.54-0.90
Abiraterone 1000 mg QD+ Prednisone 5 mg BID
n = 546Co-Primary endpoints:
• OS
• rPFSPlacebo BID
+ Prednisone 5 mg BIDn = 542
R A N D O M I Z E D1:1
COU-AA-302 Study Design Phase III Pre-Docetaxel
Phase 3, double-blind placebo-controlled trial of abiraterone + prednisone versus placebo + prednisone in mCRPC pre- chemotherapy
Ryan CJ, et al. N Engl J Med. 2013;368(2):138-148.
• 1088 progressive chemonaïve patients with mCRPC
• Asymptomatic or mildly symptomatic
COU-AA-302: rPFS
Abiraterone + prednisone, 16.5 months
Prednisone alone,8.3 months
Pro
gre
ssio
n-F
ree
Su
rviv
al, %
110 –
80 –
60 –
40 –
20 –
0 –0 3 6 9 12 15 18 21 24 27 30
HR = 0.53 (95% CI, 0.45-0.62) P<.00147% reduction in risk of progression
Ryan CJ, et al. N Engl J Med. 2013;368(2):138-148.
COU-AA-302: Updated OS
Placebo + prednisone,30.1
months
Months From Randomization
Second interim analysis: 43% death1
Third interim analysis: 56% death2
Su
bje
cts
Wit
ho
ut
Dea
th,
%
HR = 0.79 (95% CI, 0.66–0.95) P = .0151Prespecified P for significance: .0035100
80
60
40
20
00 3 6 9 12 15 18 21 24 27 30 33 36
Abiraterone + prednisone,35.3 months
1. Ryan CJ, et al. N Engl J Med. 2013;368(2):138-148. 2. Rathkopf DE, et al. J Clin Oncol. 2013;31(Suppl 6): Abstract 5.
Enzalutamide, an AR Signaling Inhibitor: Targets Multiple Steps in the (AR) Signaling
PathwayA
1. Competitively inhibitsandrogen binding to AR
2. Impairs AR nuclear translocation
3. Inhibits AR interaction with DNA
A
AR
Cell nucleus AR
Cell cytoplasm
Tran C, et al. Science. 2009;324(5928):787-790.
Enzalutamide 160 mg QD n = 800
Efficacy end points (ITT)
Primary endpoint:
• OS
Secondary endpoints:
• PSA response
• Time to PSA progression
• rPFS
• Time to first SRE
Placebo QD n = 399
R A N D O M I Z E D2:1
AFFIRM Study Design: Phase III Post-Docetaxel
Scher HI, et al. N Engl J Med. 2012;367(13):1187-1197
Phase 3, double-blind placebo-controlled trial of enzalutamideversus placebo in mCRPC post-chemotherapy
No corticosteroids required
• 1199 patients with progressive mCRPC
• Failed 1 or 2 chemotherapy regimens, 1 of which contained docetaxel
% O
AS
0 3 6 9 12 15 18 2124
AFFIRM Overall Survival: Median of 4.8 Months
Enzalutamide: 18.4 months(95% CI: 17.3, NYR)
Placebo: 13.6 months(95% CI: 11.3, 15.8)
100
90
80
70
60
50
40
30
20
10
0
Duration of Overall Survival, months
HR = 0.631 (95% CI: 0.529, 0.752) P < .000137% reduction in risk of death
Scher HI, et al. N Engl J Med. 2012;367(13):1187-1197.
Enzalutamide 800 775 701 627 400 211 72 7 0
Placebo 399 376 317 263 167 81 33 3 0
PREVAIL Phase III Trial: Enzalutamide Pre-Docetaxel CRPC:
1717 Patients
with CRPC
Enzalutamide160 mg/d
Placebo
• Radiographic PFS• OAS
NEJM, 01 JUNE 2014
PREVAIL Trial: Effect on Radiographic PFS:
Rate PFS at 12 months65% vs 14%
NEJM, 01 JUNE 2014
• Reduction of Risk of death by 29%.
• mOAS: 32.4 vs 30.2 months.
• CTH Delay by 17 months.
PREVAIL Trial: Effect on OAS:
NEJM, 01 JUNE 2014
ALLIANCE TRIAL: Co-Targeting Androgen Receptor & Biosynthesis:
• 1224 pts.• Progressive
Metastatic CRPC.• No Prior Taxanes
Enzalutamide 160 mg QD
Enzalutamide 160 mg QD
Aberaterone 1000 mg QD
Prednisone 5 mg bid
2
1
OAS
Clinicaltrials.gov:/01949337
Subsequent Hormonal Therapies Following ADT: Data From Last ASCO:
• Gleason Score: No• Duration of Response to Previous ADT:
Better Response to Subsequent Hormonal Therapy if: PSA Control > 12 months. Longer PFS.
• Aberaterone or Enzalutamide First?
Enz Abt Abt EnzPSA ↓ 50% 3% 29%
PSA ↓30% 11% 37%
Metastatic
Castration Resistant
Symptomatic First Line
Category 1• Docetaxel• Radium-223‡
Nonmetastatic
Local Therapy
Castration Hormone Therapy Asymptomatic or
Minimally Symptomatic
Category 1• Sipuleucel-T*• Abiraterone acetate
Category 2A• Sipuleucel-T*• Salvage chemotherapy• Docetaxel rechallenge• Mitoxantrone• Secondary hormonal
therapy• Clinical trial• Best supportive care
Bone Health: Denosumab, Zoledronic Acid
*For asymptomatic or minimally symptomatic mCRPC with ECOG PS 0/1, no hepatic metastases, and life expectancy≥6 months. †May be considered for rapid progression or hepatic metastases despite lack of symptoms. ‡For symptomatic mCRPC with bone metastases; not approved in combination with chemotherapy. §For patients who are not candidates fordocetaxel-based regimens. ׀׀ For symptomatic mCRPC with bone metastases.National Comprehensive Cancer Network Guidelines in Oncology (NCCN Guidelines®)—Prostate Cancer. V.2.2014. Available at: http://www.nccn.org. Accessed May 15, 2014.
Symptomatic Second
Line
Category 1: Post-Docetaxel
• Abiraterone acetate
• Enzalutamide• Cabazitaxel• Radium-223‡Category 2A
• Secondary hormonal therapy
• Docetaxel†
• Clinical trial
Category 2A• Mitoxantrone§
• Abiraterone acetate§
• Enzalutamide§
• Palliative radiotherapy׀׀
• Clinical trial• Best supportive care
Take Home Message:
• Unequivocal evidence of continued involvement of AR signaling axis.
• We need to better understand prostate cancer heterogeneity.
• Broad array of therapeutic options.• Non – Cytotoxic therapies are now of interest
before chemotherapy administration.• Evaluate for the best sequence Biomarker
Studies.
Thank You