Tackling Prostate Cancer:Can we go better?

Mohamed Abdulla M.D.Prof. of Clinical Oncology

Kasr Al-Aini School of MedicineCairo University

NEMROCK – Sanofi SymposiumWednesday 7th, 2015Sofitel Tower & Hotel

Basic Facts & Figures:

• Increasing Incidence: Aging and Screening Programs.

• 2nd Most Common Cancer in Men.• 1/6 Men.• Black Races.• Rare Before Age of 40 and then Readily Rises.• Prostate Cancer is an Androgenic Disease.

MJA 2008; 189: 315–318

Prostate Cancer: Best Identity:

Natural History

Androgen Biosynthesis

Androgen Receptor Activity

Aggressiveness

HypothalamusLHRH

Pituitary

Testes Supra-renal

Testosterone

LH ACTH

Prostate Cancer is an Androgenic Disease: “Androgen Synthesis”

LHRH Analogue

Bilateral Orchiectomy

Steroidogenesis & Prostate Cancer :

Cholesterol CYP 11A1 Pregnenolone CYP 17A1 Testosterone

Prostate = Androgen Self Sufficient Organ

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 Receptor in Prostate Cancer:

Natural History of Prostate Cancer:

Time

Tum

or V

olum

e &

Mor

talit

y

Pre-Treatment Assessment:Basics Factors:

Management of Newly Diagnosed Prostate Cancer

Risk of Local

Recurrence

Risk of Disseminated

Disease

PSA StagingGleason

Score

Prostate Cancer: Risk Stratification:

Long versus Short Term ADT:

Lancet Oncol 2015; 16: 320–27

Long versus Short Term ADT:

Lancet Oncol 2015; 16: 320–27

Long Term ADT > Short Term ADT

Biochemical Failure Free Survival

OAS

Metastasis Free Survival

Long versus Short Term ADT:

Lancet Oncol 2015; 16: 320–27

Long versus Short Term ADT:NCCN GUIDELINES

androgen-dependent cell

CRPC

Intrinsic Resistance to ADT

The Hypothesis

• Docetaxel added at the time of starting ADT in hormone-sensitive metastatic prostate cancer (mHSPC) will prolong overall survival (OS)

Metastatic HSPC: GETUG 15 Trial Design

n = 385 pts

2 ADT:- LHRH agonist- or maximum androgen blockade- or orchiectomy

3 75 mg/m2 q3 up to 9 cycles

Gravis G, et al. Lancet Oncol. 2013;14(2):149-158.

1 Glass TR, et al. J Urol.2003;169(1):164-169.

Median PFS:ADT + D: 23 mo [19.6-28.4]ADT: 13 mo [11.9-17.7]HR [95%CI]: 0.72 [0.57-0.91] P = .0052

ADT+ docetaxelADT

ADTADT+ docetaxel

Gravis G, et al. Lancet Oncol. 2013;14(2):149-158.

Biochemical Progression-Free Survival:

Median cPFS:ADT + D: 23 mo [20.5-32]ADT: 15 mo [12.5-20]HR [95%CI]: 0.75 [0.59-0.94] P = .0147

ADT+ docetaxelADT

Clinical Progression-Free Survival:

ADT

ADT+ docetaxel

Gravis G, et al. Lancet Oncol. 2013;14(2):149-158.

Median OS:ADT + D: 59 mo [51-69]ADT: 54 mo [42-NR]HR [95%CI]: 1.01 [0.75-1.36] P = .95

ADT + docetaxelADT

ADT

ADT + docetaxel

Median follow-up: 50 months [49 - 54]

Overall Survival

Gravis G, et al. Lancet Oncol. 2013;14(2):149-158.

E3805 – CHAARTED

STRATIFICATIONExtent of Mets-High vs LowAge≥70 vs < 70yoECOG PS- 0-1 vs 2CAB> 30 days-Yes vs NoSRE Prevention-Yes vs NoPrior Adjuvant ADT≤12 vs > 12 months

R A N D O M I Z E

ARM A:ADT + Docetaxel 75mg/m2 every 21 days for maximum 6 cycles

ARM B:ADT (androgen deprivation therapy alone)

Evaluate every 3 weeks while receiving docetaxel and at week 24then every 12 weeks

Evaluate every 12 weeks

Follow for time to progression and overall survivalChemotherapy at investigator’s discretion at progression

Presented by: Christopher J. Sweeney, MBBS ASCO Plenary 2014Sweeney C, et al. J Clin Oncol. 2014;32(Suppl): Abstract LBA2.

Primary Endpoint: Overall Survival

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

3648

OS (Months)

0 12

24

60

72

84

Pro

babi

lity

Sweeney C, et al. J Clin Oncol. 2014;3A2(Suppl): Abstract7A2.

HR = 0.61 (0.47-0.80) P = .0006Median OS:ADT + D: 57.6 months ADT:44.0 months

ADT + DADT

Causes of Death

Sweeney C, et al. J Clin Oncol. 2014;32(Suppl): Abstract LBA2.

ADT + D (N=397)

N

ADT (N=393)

N

Due to prostate cancer

83 112

Due to protocol treatment

1 0

Other cause 8 11

Unknown 8 9

Missing 1 4

Total 101 136

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

3648

OS (Months)

0 12

24

60

72

84

Arm

ALIV

E

115116

DEA

D 1926

MEDIAN..

TOTAL

A134High-voB lume dise25a1 se:11017 m141onth32.2 improvement in

Bmedian OS142

Pro

babi

lity

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

36 48

OS (Months)

0 12

24

60

72

84

Pro

bab

ility

49.2 versus 32.2 months

OS by Extent of Metastatic Disease atStart of ADT

High Volume

Low Volume

p=0.0006HR=0.60 (0.45-0.81)Median OS:ADT + D: 49.2 months ADT :

32.2 months

p=0.1398HR=0.63 (0.34-1.17)Median OS:ADT + D: Not reached ADT : Not reached

ADT + DADT

ADT + DADT

Sweeney C, et al. J Clin Oncol. 2014;32(Suppl): Abstract LBA2.

Upfront Docetaxel + ADT in Castrate Sensitive Disease: NCCN Guidelines:

Prostate Cancer: Clinical Scenarios:

Loco-Region

al

Metastatic

HRPC

Risk Stratification Risk Stratification

• Active Surveillance.

• L-R Treatment.• L-R Treatment

+ HM

• HM• Chemotherapy• L-R Treatment

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*

Management of CRPC:

1. ADT should be continued.2. Inhibition of bone resorption3. Risk Stratification.4. Choose between therapies associated with

survival benefit.

Castrate Resistant Prostate Cancer:Prognostic Factors:

Halabi et al. J Clin Oncol 32:671-677. © 2014

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

2. Circulating Tumor Cells:– < 5/7.5 mL: med. OAS 22.1 months.– > 5/7.5 mL: med. OAS 10.9 months.

3. Markers of Bone Metabolism:– 2 markers of bone resorption (N-Telopeptide &

Pyridinoline) and 2 markers of bone formation (C-Terminal Collagen Peptide & Bone Alkaline Phosphatase).

– Higher levels are correlated with poor med. OAS 5 versus 13 months.

4. Gene Expression Profiles: 6 &9 Gene Assays.

Castrate Resistant Prostate Cancer:Prognostic Factors:

Scher et al. J Clin Oncol. 2011;29:293s.Lara et al. J Natl Cancer Inst. 2014.Olmos et al. Lancet Oncol. 2012;13(11):1114

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

Abiraterone Doubled Time to rPFS1

1. Rathkopf DE et al. Eur Urol 2014; [Epub ]

Ryan C et al. ESMO 2014; Abstract 7530 (oral presentation)

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.

Significant Improvement in Time to Opiate Use for Cancer-Related Pain in the Final Analysis

• At the time of IA3, the median time to opiate use had not been reached for abiraterone• All secondary end points showed significant improvement with abiraterone

Ryan C et al. ESMO 2014; Abstract 7530 (oral presentation)

Enzalutamide, an AR Signaling Inhibitor: Targets Multiple Steps in the (AR) Signaling Pathway

A

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

Tannock IF, et al. N Engl J Med. 2004;35(15):1502-1512.

Docetaxel + Prednisone or Mitoxantrone + Prednisone for CRPC:

Overall Survival

Petrylak DP, et al. N Engl J Med. 2004;351(15):1513-1520.

100

80

60

40

20

0

Pro

bab

ilit

y O

vera

ll S

urv

ival

, % 0 3 6 9 12 15 18

21

Months

217

104

24 27 30 33

Docetaxel q3w

Weekly docetaxel

Mitoxantrone

100

80

60

40

20

0

P = .02

Docetaxel + estramustine (217 deaths; median: 17.5 months)

24

Months

480 12 36

Mitoxantrone+ prednisone

(235 deaths; median: 15.6 months)

No at Risk Docetaxel every 3 wkWkly docetaxel

334Mitoxantrone

337

335 296 37 5

297297

200192

10595

2929

43

Post Docetaxel: Cabazitaxel/Prednisone vs Mitoxantrone/Prednisone

Overall SurvivalMP CBZP

30 Time, Months

Pro

po

rtio

n o

f O

S,

%

377CBZP

378

299321

195241

94137

3160

919

0 6 12 18 24

Median OS (mos)

Hazard ratio

95% CI

P value

12.7 15.1

0.70

0.59-0.83

<.0001

Number MPat Risk

Censored MP CBZP

Combined median follow-up: 13.7 months

CBZP

MP

de Bono, et al. Lancet. 2010; 376: 1147

Sequence of Therapies in CRPC

• 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

AR-Targeted Agents1

• Retrospective analysis in173 patients with metastatic PCa

• Poor response to subsequent hormone therapies (including abiraterone, enzalutamide) if time to CRPC with first ADT ≤1 year

2. Huillard O, et al. J Clin Oncol. 2013;31(Suppl); Abstract 5075.

↓PSA ≥ 50%

Median TTP (months)

16% 41%

3.2 6.6

• 188 patients with mCRPC in 2 prospective databases

• High Gleason score and visceral mets more common if early CRPC (≤1 year)

• Good response to docetaxel irrespective of time to CRPC

↓PSA ≥ 50%

Median TTP (months)

67% 81%

6.1 7.1

Docetaxel2

1. Loriot Y, et al. J Clin Oncol. 2012;30(Suppl5): Abstract 213.

Duration of ≤1 >1 Duration of ≤1 >1

response yr. yr. response yr. yr.

Duration of Response According to Response to Primary ADT:

Docetaxel1

• Post hoc analysis of TAX327randomized trial (n = 1006 mCRPC)

• Marked survival benefit with docetaxel q3w in patients with high Gleason score

All

Median OS months

Gleason 7-10

Months

OS benefit vs mitoxantrone

2.9 mo 4.4 mo

Abiraterone2

• Post hoc analysis of COU-AA-302randomized trial (n = 1088)

Gleason <8 Significant OS benefitHR [95% CI]

0.72 [0.54-0.97] p=0.0295

Gleason 8-10 No OS benefit with ABI vs P

HR [95% CI]0.84 [0.64-1.09]P = .1789

1. van Soest R, et al. Eur Urol. 2013 Aug 11. [Epub ahead of print].2. Fizazi K, et al. J Clin Oncol. 2014;32(Suppl 4): Abstract 20.

HR [95% CI]0.72 [0.54-0.97]P = .0295

P, prednisone

Docetaxel + P 19.2 mo 18.9 mo

Mitoxantrone + P 16.3 mo 14.5 mo

Initial Gleason Score Might Help to Choose Therapy in Chemonaive Patients:

Poor response to Abiraterone in patients progressing on Enzalutamide?

Loriot1

(n=38)Noonan2

(n=30)COU-AA-3013

(n=797)

Prior Enzalutamide Yes Yes No

Median PFS, mths 2.7 3.6 5.6

Median OS, mths 7.2 11.8 14.8

↓PSA ≥ 50%* 8% 3% 29%

1. Loriot Y et al. Ann Oncol 2013; 24: 1907-12; 2. Noonan Kl et al. Ann Oncol 2013; 24: 1802-04; 3. Fizazi K et al. Lancet Oncol 2012; 13: 983-92 OS: Overall survival; PFS: progression-free survival

[1-2] trials are retrospective studies conducted in 38 and 30 patients, respectively*PSA response confirmed by a second value

Poor response to Enzalutamide in patients progressing on Abiraterone?

Schrader1

(n=35)Bianchini2

(n=39)Thomsen3

(n=24)Badrising4

(n=61)AFFIRM5 (n=800)

Prior ABI Yes Yes Yes Yes No

Partial response 2.9% 4.3% - - 29%

Median PFS, mths - 2.8 - 3.0 8.3

Median OS, mths 7.1** - 4.8 7.9 18.4

↓PSA ≥50% 28.6% 12.8%* 16.7% 21% 54%*

571. Schrader A et al. Eur Urol 2014; 65: 30-36; 2. Bianchini D et al. Eur J Cancer 2014; 50: 78-84; 3. Thomsen FB et al. Scand J

Urol Nephro 2014; 48: 268-75; 4. Badrising S et al. Cancer. 2014; 120: 968-75; 5. Scher HI et al. Lancet Oncol 2012; 13: 983-92ABI: Abiraterone actetate, PFS: Progression-free survival; OS: overall survival

*PSA response confirmed by a second value; [1-4] trials are retrospective studies

Antonarakis E, et al. Presented at: American Association for Cancer Research Annual Meeting; April 5-9, 2014; San Diego, California. Abstr 2910.

• 31 mCRPC patients treated with enzalutamide

• Detectable AR-V7 mRNA from CTCs in 12/31 (38.7%)

• Presence of AR-V7 associated with:– Worse PSA response (0% vs 52.6%, P = .004)– Shorter PSA-PFS (median 1.4 vs 5.9 months, HR 7.4 [2.7-20.6], P0.001)

– Shorter PFS (median: 2.1 vs 6.1 months, HR 8.5 [2.8-25.4], P<.001)– Multivariable analysis: presence of AR-V7 (HR 3.5 [1.2-10.5], P

= .027), baseline PSA (HR 1.01 [1.00-1.01], P = .042) and prior abiraterone(HR 5.4 [1.1-26.5], P = .039) were all independently predictive of PSA-PFS

• Conclusions: If confirmed by prospective studies, AR-V7 couldbe used as a biomarker to predict enzalutamide resistance

AR-V6 As a Predictor to Enzalutamide Effect

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; however upfront cyto-toxic agents might be of help in certain subset of patients.

• Evaluate for the best sequence Biomarker Studies.