Advanced prostate cancer - Non CRPC

Management of Advanced Prostate Cancer – Non 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:

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.

Prostate Cancer: The Story:

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

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

Prostate Cancer: Best Identity:

Natural History

Androgen Biosynthesis

Androgen Receptor Activity

Aggressiveness

AndrogenicDisease

HypothalamusLHRH

Pituitary

Testes Supra-renal

Testosterone

LH ACTH

Prostate Cancer is an Androgenic Disease:

LHRH Analogue

Bilateral Orchiectomy

+/- AR Blockers

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

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”

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.

Advanced Prostate Cancer:Definition:

• Contemporary Diagnosis:

+ M1

AJCC 2012

Advanced Prostate Cancer:Definition: Extended Criteria:

Risk Stratification

Localized Prostate Cancer

Very Low Risk

Low Risk

Intermediate Risk

High Risk

Very High Risk

Uptodate.com 2015

Advanced Disease=

+M1 Disease

• Very Low - Risk: “All Should be Present”1. Disease is detected only on biopsy (No Clinical or

radiologic suspicion).2. PSA < 10 ng/ml.3. Gleason Score < 64. < 3 positive biopsy cores.5. < 50% positivity within any core.6. PSA density less than 0.15 ng/mL/gram

Risk Stratification:

Uptodate.com 2015

• High Risk Disease: (T3) Peri-Prostatic and S.V. Involvement

• Very High Risk Disease: (T4) & (L.N. +ve)Fixation and Positive Lymph Nodes.

Risk Stratification:

Uptodate.com 2015

Prostate Cancer:Diagnostic Work up: Unmet Needs:• DRE: Personal Variability.• Conventional Grey Scale US:

– Isoechoic & Anterior lesions.– Multifocal Disease, Heterogonous Texture.– Capsular Infiltration & Peri-prostatic Extension.– SV involvement.

• Computed Tomographic Scans:– Limited value for local disease extent.– Superior in Bone Metastases.

• Original MRI < 1 t:– Variable Sensitivity and Specificity.

• Isotopic Bone Scan:– No direct imaging of Bone Metastases.– Difficult to quantify burden of disease.

• PET – CT Scan:– 18FDG: Glycolytic Activity and not Osteoblastic activity.

What is the Proper Staging?1. Multiparametric MRI1. Diffusion Weighted Imaging (DWI).2. Prostate T2 Weighted Imaging.3. Dynamic Contrast Enhanced Images (DCE).4. Magnetic Resonance Spectroscopy Imaging (MRSI).

mpMRI is Mandatory of patients with Intermediate and High Risk Prostate Cancer & to confirm the validity of Active Surveillance.

EUA Guidelines: Isotopic Bone Scanning is NOT Indicated in:1. Asymptomatic patients.2. Well to moderately differentiated disease.3. PSA < 20 ng/ml.

What is the Proper Staging?2. Isotopic Bone Scanning:

1. Radiation Therapy (External or Brachytherapy).2. Addition of Short Term ADT is advisable.3. Radical Prostatectomy with LNs Dissection.

Postoperative histo-pathology might indicate the need for adjuvant therapy.

4. Active Surveillance???

2. Management of Intermediate - Risk Disease:

Uptodate.com 2015

EORTC 22991:

Prostate CancercT1b-c & cT2a(819 Patients)

Radical Radiation Therapy

Treatment

RTH + AS(Short Term)

Biochemical Failure & DFS


EORTC 22991: 7 YEARS FOLLOW UP:


HR = 0.52 – P < .001 HR = 0.63 – P = .001

Biochemical Failure

Disease Freesurvival

1. External Beam Radiation Therapy with Long Term (2 – 3 Years) ADT.

2. Radical Prostatectomy with Lymph Node Dissection. Postoperative Irradiation +/- ADT are to be considered.

3. Management of High - Risk Disease:Extra-capsular Extension & SV Involvement:

Uptodate.com 2015

1. External Beam Radiation Therapy + Long Term ADT.

2. Radical Prostatectomy and Lymph Node Dissection might be a less appealing option.

3. Nodal Affection: Radiation Therapy with ADT.

4. Management of Very High - Risk Disease, Fixation and Nodal Affection:

Uptodate.com 2015

Long versus Short Term ADT:

Lancet Oncol 2015; 16: 320–27

Long versus Short Term ADT:355 Patients – 64 ms Median Follow up

Lancet Oncol 2015; 16: 320–27

Long Term ADT > Short Term ADT

Biochemical Failure Free Survival

P = .01

OASP = .009

Metastasis Free SurvivalP = .01

Long versus Short Term ADT:

Lancet Oncol 2015; 16: 320–27

Practice Changing Guidelines:

Salvage Treatment of Biochemical Failure following RP:

Lancet Oncology. Published online May,6, 2016.

Salvage Rth + STAS for biochemical Failure:

Lancet Oncology. Published online May,6, 2016.

ADT in Locoregional Disease:AD

TIntermediate Risk Short

High Risk Long

Very High Risk Long

Biochemical Failure after RP Short

Metastatic Sensitive Disease

1. Primary Hormonal Manipulation:1. Surgical Castration:

Bilateral Sub-Capsular

Orchiectomy

1 2 3 4 50

100

200

300

Serum Testosterone Fol-lowing Bilateral Or-

chiectomy

Days following Bilateral orchiectomySe

rum

Tes

tost

eron

e (n

g/m

l)

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 Castration Surgical Castration Items

GnRH Agonists Bilateral Sub-Capsular Orchiectomy

Procedure

Reversible Irreversible Castration

3-4 weeks Rapidly Achieved Castrate Level of Testosterone

Elective Emergency Application

Yes no Flare

May be Required Not Required Prior Anti-Androgens

More Less Cost

More Preferred Less Preferred Psychological Element

Discussion

Primary Hormonal Manipulation:2. LHRH Agonist versus Antagonist:

Hypothalamo-Pituitary AxisLHRH Agonist LHRH Antagonist

+ LH & FSH

+ Testes

+ Testosterone

Neg

ative

Fee

d Ba

ck M

echa

nism

+ Symptoms FLARE

3 –

4 W

eeks

Castrate Level

Castrate Level

72 –

96

Hour

s

Disease Control

GnRH Antagonist versus Agonist:Agonist Antagonist Item

3-4 weeks 96 Hours Castrate Level

Yes No Flare

14.1% 8.9% PSA Failure

1% 40% Local Injection Reaction

Similar Cardiovascular Complications

Every 3 Months Monthly Administration

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 in combined androgen blockade & to

prevent flare & manage non-satisfactory results after ADT only.

Presented By Maha Hussain at Genitourinary Cancers Symposium 2016

50%35%

15% No CABYes in Minority of PatientsYes in Majority of Patients

Practical Considerations:3. Intermittent Androgen Deprivation:

Prolonged ADT

CRPC

Side Effects

ADT Maximum Response

Treatment Withdrawal

ProgressionRestart ADTOutcome??

IDT ADT Item

5.1 y 5.8 y Median OAS

38% 42% 7 – Year OAS

1.09 HR

Practical Considerations:3. Intermittent Androgen Deprivation:

INT 0162 – Non-Inferiority Trial 3040 Patients - ASCO 2012

ADT IDT

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

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

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

Practical Considerations:4. Timing of ADT:

• Loss of libido.• Impotence.• Hepato-splenomegaly.• Hot flashes.• Gynecomastia.

Complications of Short Term ADT:

• Obesity.• DM & CVS.• Insulin resistance.• Osteoporosis and clinical fractures.

Complications of Long Term ADT:

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

androgen-dependent cell

CRPC

Intrinsic Resistance to ADT

Role of Cytotoxics in HSPC:

Role of Cytotoxic Therapy in HSPC:

Effect of Adding Docetaxel on OAS in M1 Disease:


Effect of Adding Docetaxel on FFS in M1 Disease:


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 Oligometastatic Disease:

Take Home Message:

• Management of advanced prostate cancer represents a definite oncologic burden.

• “Stick adherent to treatment guidelines” is the gold standard of practice.

• ADT has an increasing share in the management of non-metastatic disease, while Docetaxel has been moved earlier in the treatment course of mHSPC.

• Oligometastatic prostate cancer is a new terminology that should be dealt only within clinical trial in high volume centers with experienced MDT practice.

Thank You

Advanced prostate cancer - Non CRPC

Health & Medicine

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