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