Management of Metastatic Prostate Cancer

Mohamed Abdulla M.D.

Prof. of Clinical Oncology

Cairo University

Menia Cancer CenterAstra Zeneca Symposium09/07/2017

Member of Advisory Board, Consultant, and Speaker for:

• Amgen, Astellas, AstraZeneca, Hoffman la Roche, Janssen Cilag, Merck Serono, Novartis, Pfizer, Mundipharma, MSD, Ely Lilly

Speaker Disclosures:

Basic Facts:

• 2nd most common cancer in men (27%).

• 1/6 men prostate cancer.

• 2nd leading cause of cancer related death in men (10%).

• World Wide: > 1000000 new case annually.

• > 300000 death/year.

• Closely related to age & Androgens

• Wide geographic and ethnic variations.

• Pre- and post-PSA era.

MJA 2008; 189: 315–318

Geographic Variations:

MJA 2008; 189: 315–318

1. No National Registry.2. Lacking of Screening &

Early Detection.3. Delayed Diagnosis.

Jsamy et al. Journal of Cancer Epidemiology Volume 2014, Article ID 437971, 18 pages

Egypt Demographic Data:

Prostate Cancer: The Story:

Dr. Huggins(1941): Orchiectomy and DES Effective Disease ControlNoble Price 1966.

Dr. Shcally et al: (1977): LHRH Analogue Effective disease Noble Price

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”

De

ath

TIME

Tum

or

Bu

rde

n

Effective Castration & AR BlockingSerum Testosterone < 0.2 – 0.5 ng/ml

Prostate Cancer is an Androgenic Disease: “Androgen Receptor Activity”

5@ Reductase

Genomic ActivityPSA, IGF, …

Microtubule

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

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

Cu

mu

late

su

rviv

al f

ree

of

CR

PC

(%

)

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.

1. Primary Hormonal Manipulation:1. Surgical Castration:

Bilateral Sub-Capsular

Orchiectomy

0

100

200

300

1 2 3 4 5

Seru

m T

est

ost

ero

ne

(n

g/m

l)Days following Bilateral orchiectomy

Serum Testosterone Following Bilateral

Orchiectomy

Surgical versus Medical Castration?

Seidenfeld J, Samson DJ, Hasselblad V, et al. Single-therapy androgen suppression in men with advanced prostate cancer: a systematic review and meta-analysis. Ann Intern Med 2000; 132:566.

Meta-AnalysisOf 1908 Patients

Surgical Castration

Medical Castration

EquivalentOASPFSTTF

Primary Hormonal Manipulation:

Medical CastrationSurgical CastrationItems

GnRH AgonistsBilateral Sub-Capsular Orchiectomy

Procedure

ReversibleIrreversibleCastration

3-4 weeksRapidly AchievedCastrate Level of Testosterone

ElectiveEmergencyApplication

YesnoFlare

May be RequiredNot RequiredPrior Anti-Androgens

MoreLessCost

More PreferredLess PreferredPsychological Element

Discussion

Primary Hormonal Manipulation:2. LHRH Agonist versus Antagonist:

Hypothalamo-Pituitary Axis

LHRH Agonist LHRH Antagonist

+ LH & FSH

+ Testes

+ Testosterone

Ne

gati

ve F

ee

d B

ack

Me

chan

ism

+ Symptoms FLARE

3 –

4 W

ee

ks

Castrate Level

Castrate Level

72

–9

6 H

ou

rs

Disease Control

GnRH Antagonist versus Agonist:

AgonistAntagonistItem

3-4 weeks96 HoursCastrate Level

YesNoFlare

14.1%8.9%PSA Failure

1%40%Local Injection Reaction

SimilarCardiovascular Complications

Every 3 MonthsMonthlyAdministration

Schroder FH, Tombal B, Miller K, et al. Changes in alkaline phosphatase levels in patients with prostate cancer receiving degarelix or leuprolide: results from a 12-month, comparative, phase III study. BJU Int 2010; 106:182.Tombal B, Miller K, Boccon-Gibod L, et al. Additional analysis of the secondary end point of biochemical recurrence rate in a phase 3 trial (CS21) comparing degarelix 80 mg versus leuprolide in prostate cancer patients segmented by baseline characteristics. Eur Urol 2010; 57:836.

Smith MR, Klotz L, Persson BE, et al. Cardiovascular safety of degarelix: results from a 12-month, comparative, randomized, open label, parallel group phase III trial in patients with prostate cancer. J Urol 2010; 184:2313.

ADT: Results of TreatmentFinal Statement:

2. When Do We Need CAB?

Surgical Castration

Serum Testosterone >

20 ng/dL

Medical Castration

Serum Testosterone >

50 ng/dL

Anti-Androgen

Antiandrogens:

• Competitive inhibition of peripheral androgen receptors.

• No action on hypothalamic receptors.

• Inferior to ADT in phase III trials.

• Not suitable in hormone naive patients as a mono-therapy.

• Used prior ADT to prevent flare & to manage non-satisfactory results after ADT only.

Slide 5

Presented By Maha Hussain at Genitourinary Cancers Symposium 2016

Practical Considerations:3. Intermittent Androgen Deprivation:

Prolonged ADT

CRPC

Side Effects

ADTMaximum Response

Treatment Withdrawal

ProgressionRestart ADTOutcome??

Continuous (CAD) vs Intermittent Androgen Deprivation (IAD): Trials in mHNPC Patients & Survival End Point

Slide 7

• A 2007 meta-analysis combined the resultsfrom 3065 patients in four randomized trials.

• Early ADT was associated with a statisticallysignificant decrease in prostate cancer-relateddeaths (relative risk [RR] 0.84; 95% CI 0.77-0.92.

• Although there was no significant benefit inoverall survival (RR 0.98; 95% CI 0.95-1.01).

Practical Considerations:4. Timing of ADT:

• Loss of libido.

• Impotence.

• Hepato-splenomegaly.

• Hot flushes.

• Gynecomastia.

Complications of Short Term ADT:

• Obesity.

• DM & CVS.

• Insulin resistance.

• Osteoporosis and clinical fractures.

Complications of Long Term ADT:

ADT: Key points from EAU guidelines 2014:“Oncologist & Urologist are Besides & Not A Side”

ADT=androgen-deprivation therapy; EAU=European Association of Urologists; mCRPC=metastatic castration-resistant prostate cancer.Mottet N, et al. EAU Guidelines on Prostate Cancer 2014. Available at: http://www.uroweb.org. Last accessed January 2015.

Optimal castration testosterone level is defined as <20 ng/dL

In high-risk localised and locally advanced prostate cancer, the combination of radiotherapy and ADT is recommended because it improves survival

First-line ADT is the standard of care for metastatic prostate cancer

Testosterone suppression should be continued indefinitely even when the disease becomes castration resistant

Second-line therapies for mCRPC should not be started unless patient testosterone levels are <50 ng/dL

Monitoring testosterone levels should be considered as part of routine clinical practice

androgen-dependent cell

CRPC

Intrinsic Resistance to ADT

Slide 10

Slide 12

Role of Cytotoxics in HSPC:

Role of Cytotoxic Therapy in HSPC:

Effect of Adding Docetaxel on OAS in M1 Disease:

Role of Cytotoxic Therapy in HSPC:

Effect of Adding Docetaxel on FFS in M1 Disease:

Role of Cytotoxic Therapy in HSPC:

Effect of Adding Docetaxel on OAS in M0 Disease:

Role of Cytotoxic Therapy in HSPC:

Effect of Adding Docetaxel on FFS in M0 Disease:

Management of OligometastaticDisease:

NTD DBDHingeLBD

Nuclear & Steroid

Superfamily

Androgen

Estrogen

Glucocorticoid

Mineralocorticoid

Progesterone

Constitutively Active DNA

Promoter Gene

Androgen N/C

HSP

Prostate Cancer is an Androgenic Disease: “Androgen Receptor Structure”

Androgen Receptor in Prostate Cancer:

AR Splice Variants:

Ciccarese et al. Cancer Treatment Reviews 43 (2016) 27–35

Androgen Biosynthesis: “More Clear Insight”

Cholesterol CYP 11A1 Pregnenolone CYP 17A1 Testosterone

An

dro

gen

ADT +/- AR Bocker

CRPC: Current Definition:

Castrate Serum Testosterone = < 50 ng/dL

or 1.7 nmol/L

Biochemical progression: 3 consecutive rises in PSA 1 wk apart, resulting in two

50% increases over the nadir, and PSA >2 ng/ml

Radiologic progression: The appearance of new lesions: either two or more new

bone lesions on bone scan or a soft tissue lesion

Symptomaticor Subjective Progression

Therapeutic Strategies Against CRPC:

• More effective Blocking of Androgen Biosynthesis:

CYP 17A1 Abiraterone Acetate.

• More Effective AR Blocking: Triple Inhibition Enzalutamide.

• Direct Cell Killing: Chemotherapeutics Anti-Microtubule Docetaxel & Cabazitaxel.

• Bone Only Disease “Symptomatic”: Radium 223.

• Immunotherapy: Sipuleucel T

Maintain Androgen Deprivation Therapy

Summary of Clinical Trials Outcome:

Discussion Points: Current Practice

• What drives current sequencing decisions in

patients with mCRPC ?

Patient/doctor preference?

Cost/reimbursement? Other reasons?

Evidenced based data?

• What criteria would you use to determine a change

in the current therapy? Disease extent and anticipated survival?

Symptomatology?

Chemotherapy in Advanced Prostate Cancer:

EARLY

M.C. Markowski, M.A. Carducci / Cancer Treatment Reviews 55 (2017) 218–224

LATE

Choice of Therapy:Special Considerations:

• Heavy Tumor Burden, Highly Symptomatic, Short PSA DT, Visceral Disease: Chemotherapy.

• Compromised Cardiac Functions, HTN, Compromised Liver Functions: ? Abiraterone.

• Possibility of Seizures: No Enzalutamide.

• Drug Resistance: Androgen Receptor Splice Variants and Cross Drug Resistance:

? Abiraterone/Enzalutamide.

Antonarakis E. Clinical Advances in Hematology & Oncology. 2016, 14(5)

Prostate Cancer:The Story:

1940 - 1950 1970 - 1980 1980 - 1990 1990 - 2000

Bilateral Orchiectomy + DES

LHRH Agonist

FDA APPROVAL

FLUTAMIDE + ADT

CRPC

Mitoxantrone + Prednisone

OAS < 6 ms

OAS > 24 ms

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

Current & Future Paradigm

• Sequencing of Available Therapeutics.

• To Overcome Resistance.

Thank You