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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

Abiraterone 1000 mg QD+ Prednisone 5 mg BID

n = 546Co-Primary endpoints:• OS• rPFS

Placebo BID+ Prednisone 5 mg BID

n = 542


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


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


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


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

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