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Beyond LHRH Analogues in Hormone Refractory Prostate Cancer.
Mohamed Abdulla M.D.Prof. of Clinical Oncology
Cairo UniversityJOS Meeting – GI. GU ConferenceLe Royal Hotel – Amman – Jordan Friday, 01/04/2016
Member of Advisory Board, Consultant, and Speaker for:• Amgen, Astellas, AstraZeneca, Hoffman la Roche, Janssen Cilag,
Merck Serono, Novartis, Pfizer, Mundipharma• The content of this presentation does not relate to any product of a
commercial interest
Speaker Disclosures:
HypothalamusLHRH
Pituitary
Testes Supra-renal
Testosterone
LH ACTH
Prostate Cancer is an Androgenic Disease:
LHRH Analogue
Bilateral Orchiectomy
Prostate Cancer:Natural History:
Locoregional Disease
Biochemical Failure
Metastatic “Sensitive”
Metastatic “Refractory”
Deat
h
TIME
Tum
or B
urde
n
Risk Stratification
A.S.Local Therapy+/- Hormonal
Local Therapy+/- Hormonal
Hormonal+/- Others
2nd HormonalOthers
Maintaining testosterone <32 ng/dL was associated with significantly longer mean survival free of CRPC compared with levels >32 ng/dL
Survival free of CRPC in 73 patients with non-metastatic prostate cancer receiving ADT.*Patients with three serum testosterone determinations <32 ng/dL; †Patients with breakthrough increases >32 ng/dL.Serum testosterone was measured every 6 months. ADT=androgen-deprivation therapy; CRPC=castration-resistant prostate cancer.Figure adapted from Morote J, et al. J Urol 2007;178:1290–5.
100
80
60
40
20
0
Cum
ulat
e su
rviv
al fr
ee o
f CRP
C (%
)
0 50 100 150 200 250
Follow up (months)
>32 ng/dL†
<32 ng/dL*
p=0.0258
Testosterone ≤30 ng/dL has been associated with longer overall survival versus >30 ng/dL
VariableTestosteroneContinuous variable*
Testosterone<50 ng/dL
(n=94)
Testosterone≤30 ng/dL
(n=56)
Testosterone<20 ng/dL
(n=25)Time to progressionHR (95% CI)p value
1.76 (0.62–5.01)0.29
0.84 (0.52–1.37)0.51
0.76 (0.46–1.26)0.30
0.58 (0.30–1.15)0.12
Overall survivalHR (95% CI)p value
2.47 (0.70–8.75)0.16
0.74 (0.42–1.33)0.32
0.45 (0.22–0.94)0.034
0.19 (0.04–0.76)0.020
*Testosterone was considered a continuous (values were measured on a continuous scale) not categorical variable in this analysis. CI=confidence interval; HR=hazard ratio.Bertaglia V, et al. Clin Genitourin Cancer 2013;11:325–30.
Slide 5
Presented By Maha Hussain at Genitourinary Cancers Symposium 2016
50%35%
15% No CABYes in Minority of PatientsYes in Majority of Patients
Disease Progression
Androgen Receptor Activity
Other Malignant
Cellular Clones
Androgen Biosynthesis
NTD DBDHingeLBD
Nuclear & Steroid
Superfamily
Androgen
EstrogenGlucocorticoidMineralocorticoid
Progesterone
Constitutively Active DNA
Promoter Gene
Androgen N/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 Receptor in Prostate Cancer:
Steroidogenesis & Prostate Cancer :
Cholesterol CYP 11A1 Pregnenolone CYP 17A1 Testosterone
Prostate = Androgen Self Sufficient Organ
androgen-dependent cell
CRPC
Intrinsic Resistance to ADT:
Management of CRPC:
1. ADT should be continued.2. Choose between therapies associated with
survival benefit.
• 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
Therapies Associated with Survival Benefit:
COU-AA-301 Study Design Phase III Post-Docetaxel
Abiraterone 1000 mg QD Prednisone 5 mg BID
n = 797Primary endpoint:• OSSecondary 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
Surv
ival
, %
0
20
40
60
80
100
12 18Time to Death, months
0 6 24 30
AA + P 797 657 473Placebo + P 398 306 183
273 15 0100 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 1.5Favors abiraterone Favors placebo
de Bono JS, et al. N Engl J Med. 2011;364(21):1995-2005.
Variable Subgroup N HR 95% CIAll subjects All 1195 0.66 0.56-0.79Baseline ECOG 0-1 1068 0.64 0.53-0.78
2 127 0.81 0.53-1.24Baseline BPI < 4 659 0.64 0.50-0.82
≥ 4 536 0.68 0.53-0.85No 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 0.56-0.84Age, years < 65 0.66 0.48-0.91
≥ 65 0.67 0.55-0.82Visceral disease at entry Yes 353 0.70 0.52-0.94Baseline 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 0.51-0.80Other 543 0.69 0.54-0.90
COU – AA 301: Exploratory Analysis:Pain Effect:
Lancet Oncol 2012; 13: 1210–17
COU – AA 301: Exploratory Analysis:Pain Effect:
Lancet Oncol 2012; 13: 1210–17
COU – AA 301: Exploratory Analysis:Pain Effect:
Lancet Oncol 2012; 13: 1210–17
Abiraterone 1000 mg QD+ Prednisone 5 mg BID
n = 546Co-Primary endpoints:• OS• rPFS
Placebo BID+ Prednisone 5 mg BID
n = 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
Prog
ress
ion-
Free
Sur
viva
l, %
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
Subj
ects
With
out D
eath
, %
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.
The Phase 3 COU-AA-302 Study of Abiraterone Acetate in Men With Chemotherapy-Naïve Metastatic Castration-Resistant
Prostate Cancer: Stratified Analysis Based on Pain, Prostate-Specific Antigen and Gleason Score
32
• Kurt Miller, Joan Carles, Jürgen E. Gschwend, Henrik Van Poppel, Joris Diels, Sabine D. Brookman-May
• Poster (#775) presented at the 31st Annual EAU Congress, 11-15 March 2016, Munich, Germany
33
Results: Stratification• PSA, Gleason score and pain (BPI-SF) identified as prostate cancer-related
and with significant independent prognostic impact on OS in multivariate analysis
Stratification into 2 groups:
• Group 1: asymptomatic/no pain (BPI-SF 0-1), PSA < 80 ng/mL and Gleason score < 8– AA + P: 124/546 subjects (23%)– P: 140/542 subjects (26%)
• Group 2: any of the following – mildly symptomatic mild pain (BPI-SF ≥ 2), PSA ≥ 80 ng/mL or Gleason score ≥ 8– AA + P: 422/546 subjects (77%)– P: 402/542 subjects (74%)
Miller K, et al. Poster (#775) presented at the 31st Annual EAU Congress, 11-15 March 2016, Munich, Germany
34
Results: AA + P Significantly Prolonged OS and rPFS versus P Alone in Groups 1 and 2
Median OS Group 1 AA + P: 53.6 monthsP: 41.8 monthsHR=0.61 (95% CI: 0.43-0.87)p=0.0055
Median OS Group 2 AA + P: 31.2 monthsP: 28.4 monthsHR=0.84 (95% CI: 0.72-0.99)p=0.0321
Median rPFS Group 1 AA + P: 27.6 monthsP: 11.1 monthsHR=0.41 (95% CI: 0.30-0.57)p<0.0001
Median rPFS Group 2 AA + P: 13.7 monthsP: 8.2 monthsHR=0.59 (95% CI: 0.50-0.70)p<0.0001
Miller K, et al. Poster (#775) presented at the 31st Annual EAU Congress, 11-15 March 2016, Munich, Germany
35
Results: Time to Chemotherapy use and Time to Opiate use versus P Alone in Groups
1 and 2
Median time to chemotherapy use Group 1 AA + P: 37.0 monthsP: 24.3 monthsHR=0.64 (95% CI: 0.46-0.89)p=0.0073
Median time to chemotherapy use Group 2 AA + P: 23.3 monthsP: 14.5 monthsHR=0.71 (95% CI: 0.60-0.85)p=0.0001
Median time to opiate use Group 1 AA + P: NRP: 41.0 monthsHR=0.69 (95% CI: 0.48-0.99)p=0.0409
Median time to opiate use Group 2 AA + P: 30.5 monthsP: 19.3 monthsHR=0.70 (95% CI: 0.59-0.84)p=0.0001
Miller K, et al. Poster (#775) presented at the 31st Annual EAU Congress, 11-15 March 2016, Munich, Germany
Abiraterone Acetate: Better Insight:• Abi 5β HSD D4A (Active Metabolite).• D4A:
1. More potent inhibitor of CYP17A1.2. Potent Inhibitor of [email protected]. Potent inhibitor of AR (= Enzalutamide).
• Structural similarity to testosterone Reduced by 5@ & β Reductase Agonist to AR.
Li et al. Nature, 2015; 523(7560):347. Nima Shariffi. ASCO GU 2016
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:• OSSecondary 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
5040
30
2010
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
PREVAIL: Extended analysis Radiographic PFS
<br />PREVAIL: Extended analysis Overall Survival Analysis
BTT and Abiraterone pre-chemo <br />
Progress in metastatic CRPC
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