Management of CRPC

Mohamed Abdulla M.D.Prof. of Clinical Oncology

Cairo UniversityDirector of Advisory Board KOSC

2nd KIOW Khartoum – CORENTHIA HotelSaturday, 26/11/2016

Member of Advisory Board, Consultant, and Speaker for:•Amgen, Astellas, AstraZeneca, Hoffman la Roche, Janssen Cilag, Merck Serono, Novartis, Pfizer, Mundipharma, MSD.•The content of this presentation does not relate to any product of a commercial interest. •No Financial Disclosures for this presentation

Speaker Disclosures:

Prostate Cancer: Best Identity

Androgenic Disease

Androgen Deprivation“Surgical or Medical”

Androgen Receptor Blocking

Perfect Disease Control

Prostate Cancer:Natural History:

Locoregional Disease

Biochemical Failure

Metastatic “Sensitive”

Metastatic “Refractory”

TIME

Tum

or B

urde

n

Risk Stratification

A.S.Local Therapy+/- Hormonal

Local Therapy+ Hormonal

Hormonal+/- Others

2nd HormonalOthers

HypothalamusLHRH

Pituitary

Testes Supra-renal

Testosterone

LH ACTH

Blocking Androgen Biosynthesis:

LHRH Analogue

Bilateral Orchiectomy

+/- AR Blockers

Androgen Biosynthesis: “More Clear Insight”

Cholesterol CYP 11A1 Pregnenolone CYP 17A1 Testosterone

AndrogenADT +/- AR Bocker

Androgen Receptor in Prostate Cancer:

CRPC: Therapeutic Strategy:

1. ADT: Should be maintained avoid re-evolution of hormone sensitive clones.

2. Tackling other targets: Biosynthesis; inhibition of CYP 17A1: Abiraterone

Acetate. Androgen Receptor Blocker: Enzalutamide. Induce Cytotoxicity: Docetaxel & Cabazitaxel. Bone Only Disease: Radium 223. Immunotherapy: Sipuleucel-T.

3. Bone Modifying Agents.

Prostate Cancer:The Story: New Chapters:

2004 2010 2011 2012 2013 2014

Docetaxel &

Zoladronic

CabazitaxelD-mabSip T.

Abi (Post) Abi (Pre) Enza (Post)Radium 223

Enza (Pre)

OAS = 18.9 ms

OAS = 35.3 ms

2015 & Beyond

ADT + Cytotoxic in HSPC:•Metastatic: CHAARTED & STAMPEDE•Locally Advanced: RTOG 0521

Taxanes Beyond Cytotoxicity:• Documented Effect:

Microtubule Stabilization Blocking or Delaying Mitosis at Metaphase – Anaphase of Cell Cycle Apoptosis.

• Anti-Androgen Effect:

de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 2011; 364:1995-2005. Watson PA, Chen YF, Balbas MD, et al. Constitutively active androgen receptor splice variants expressed in castration-resistant prostate cancer require full-length androgen receptor. Proc Natl Acad Sci U S A 2010; 107:16759-65.

Sartor AO, Oudard S, Sengelov L, et al. Cabazitaxel versus docetaxel in chemotherapy-naïve patients with metastatic castration-resistant prostate cancer: a three-armed phase III study (FIRSTANA). Abstract 5006, American Society of Clinical Oncology 2016 meeting

Cabazitaxel versus Docetaxel:FIRSTANA TRIAL

OAS

RRPFS = NS

COU-AA-301 Study Design Phase III Post-Docetaxel

Abiraterone 1000 mg QD Prednisone 5 mg BID

n = 797Primary 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

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.

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

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

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.

BTT and Abiraterone pre-chemo <br />

Abiraterone Acetate: Better Insight:• Abi 5β HSD D4A (Active Metabolite).• D4A:

1. More potent inhibitor of CYP17A1.2. Potent Inhibitor of 5@Reductase..3. 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:•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 21 24

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)

10090

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

Current Problems:

• Which drug or mechanism to start with?– Sipuleucel T: Asymptomatic with low tumor burden

patients.– R223: Bone only metastases.

• ARV7 Neither Abi nor Enza.• Sequential use (Abi Enza) or (Enza Abi).• The subsequent therapies:

– Abi and Enza are lacking activity after each other.– Docetaxel & Cabazitaxel are still active in subsequent

therapies following Abi & Enza.

• Pain• Bone vs visceral metastases• Performance status• Neuropathy & other Comorbidity• “Early or late” CRPC• Prior therapy exposure and response• Response biomarkers• Tumor characteristics

CRPC, castration-resistant prostate cancer

Met. CRPC: Treatment Allocations:

LancetOncology2015; 16: e279–92

Chemotherapy

2nd Hormonal

Take Home Message:

• CRPC is an increasing event in daily practice.• Median OAS had increased (doubled) since

2004 till now.• Proper assessment is crucial.• ADT should be continued• Proper sequence is not known but trials are

under way with increasing insight.

Thank You