Castrate Resistant Prostate Cancer: Optimizing Outcomes Canil... · Learning Objectives • Discuss the evolving treatment in metastatic Castrate Resistant Prostate Cancer (CRPC)

Castrate Resistant Prostate Cancer: Evolving TherapiesOctober 2nd,2015

Dr. Christina CanilMedical Oncologist

The Ottawa Hospital Cancer CentreOttawa Hospital Research Institute

Assistant Professor of Medicine, University of Ottawa

Disclosures

• Attended Advisory Boards and Faculty Training with Astellas, Amgen, Bayer, Janssen, Novartis, and Sanofi-Oncology

• Educational travel grant from Janssen and Novartis

• Participated in clinical trials Astellas, Bayer, Bristol-Myer Squibb, Janssen, Novartis, Roche, and Sanofi-Oncology

Learning Objectives

• Discuss the evolving treatment in metastatic Castrate Resistant Prostate Cancer (CRPC)

• Review the evidence for the different lines of therapies

• Discuss the common and some of the rare, but important, toxicities of these new therapies

Castrate Resistant Prostate Cancer (CRPC) ?

Background

After local therapy, prostate cancer may recur

ORSome patients present de novo with metastatic prostate cancer*

Androgen Deprivaton Therapy

Orchiectomy orLHRH therapy -Leuprolide-Goserelin-Buserelin-Degarelix

Anti-Androgens-Bicalutamide-Nilutamide-Flutamide

Hoimes CJ, et al. Ther Adv Med Oncol. 2010;2:107-123.

Prostate

Cancer

Androgen Deprivation Therapy

7




Prostate

Cancer





Prostate

Cancer


Castrate Resistant Prostate Cancer (CRPC)

• Progressive prostate cancer despite castrate (ie VERY LOW) levels of serum testosterone

1. Rise in serum PSA2. Progression of radiological disease3. Progression of symptoms – fatigue,

anorexia, weight loss, bone pain

Management of CRPC…

1. Live Longer

2. Improve Quality of Life

Natural History of CRPC

CRPC Mets

asymptomatic symptomatic

Death

3-5 years

Chemo for Prostate Cancer Pts

• Older population

• Multiple co-morbidies

• Toxicity chemotherapy

• Potential benefits

Chemotherapy in mCRPCA Brief Review

• Prior to 1990’s – nothing

• Mid 1990s – Mitoxantrone + Prednisone– Improve quality of life, but no survival benefit

• Early 2000’s – IV Docetaxel (75 mg/m2 q 3 w) + Prednisone– Compared to Mitoxantrone

– improved overall quality of life–overall survival by 3 months

Docetaxel and Prednisone 1st line chemotherapy for mCRPC


CRPC Mets


Death

3-5 years


CRPC Mets


Death

3-5 years

D

O

C

E

T

A

X

E

L


CRPC Mets


Death

3-5 years

D

O

C

E

T

A

X

E

L


CRPC Mets


Death

3-5 years

D

O

C

E

T

A

X

E

L

Cabazitaxel

Abiraterone

Enzalutamide

Cabazitaxel (Jevtana)

• IV Chemotherapy

• Semi-synthetic taxane

• Selected to overcome emergence of taxaneresistance

• q 3 weeks, dose 25 mg/m2

• Given with prednisone 5 mg bid

R

Treatment A:Cabazitaxel 25mg/m2

IV q 3wPrednisone 10mg/dN=378

Treatment B:Mitoxantrone 12mg/m2

IV q3wPrednisone 10mg/dN=377

Docetaxel Refractory

Castrate ResistantMetastatic

Prostate CancerECOG 0-2

Adequate organ FunctionN=755

Primary Endpoint:

Overall Survival

Secondary Endpoints:

PSA response

Pain response

TROPIC Study: CABAZITAXEL

RESULTS

Cabazitaxel Mitoxantrone p-value

OS

(median, mos)15.1 12.7 <0.0001

PSA Response 39.2% 17.8% p=0.0002

Pain Response 7.8% 9.2% p=0.63

Toxicity

• Neutropenia, diarrhea, and fatigue

• 4.9% pts on cabazitaxel died of AE (vs 1.9% on mitoxantrone) – infection, renal failure

Cabazitaxel – Bottom Line

• Survival Benefit2.4 month increase in median survival

• Quality of LifeNo pain benefit

• ToxicityWatch out for diarrhea and neutropenia!

Lessons Learned• Choose patients wisely

• Low threshold for dose reduction (20 vs 25 mg/m2)

• Script for Imodium

• Organize prn IV hydration

• Neulasta if pt has private coverage

• Follow up phone call in 1 week


CRPC Mets


Death

3-5 years

D

O

C

E

T

A

X

E

L

Cabazitaxel

Abiraterone

Enzalutamide


Anti-AndrogensBicalutamideNilutamideFlutamide


Prostate

Cancer

Androgens Drive Prostatic Cancer Growth

2nd Generation

Hormonal Tx

Abiraterone Acetate (Zytiga)• Blocks testosterone production in

the testes, adrenal glands, and prostatic tumour tissues

• Irreversible and specific inhibitor of CYP17 (P450c17)

• 250mg tablet formulation

• 1000 mg (ie 4 pills all at once) podaily on empty stomach

• Must be given with Prednisone 5 mg po bid

Steroidogenesis Pathway1,2

*Schematic depicts androgen biosynthesis in the adrenal glands.1. Mostaghel E, et al. Best Pract Res Clin Endocrinol Metab. 2008;22:243-2582. Locke JA, et al. Cancer Res. 2008;68:6407-6415



HypokalemiaHypertensionFluid retention



HypokalemiaHypertensionFluid retention

Prednisone

COU-AA-301 Study Design• Phase III, multicenter, randomized, double-blind,

placebo-controlled study

31de Bono et al. NEJM. 2011; 364(21): 1995-2005.

COU-AA-301 Overall Survival:

ABI 797 736 657 520 282 68 2 0

Placebo 398 355 306 210 105 30 3 0

21

Hazard ratio = 0.646 (0.54-0.77) P < 0.0001

Placebo:

10.9 months (95% CI,10.2-12.0)

Abiraterone acetate: 14.8 months (95% CI, 14.1-15.4)

100

80

60

40

20

Surv

ival

(%

)

00 3 6 9 12 15 18

Placebo

ABI

Time to Death (Months)

3.9

months

32de Bono et al. NEJM. 2011; 364(21): 1995-2005.

COU-AA-301 Abiraterone Acetate and Pain:

33Morris M (Oral presentation at ASCO annual meeting: Chicago, IL; June 3-7, 2011)

Proportion of patients

experiencing palliation

44% vs. 27%

Most Common Adverse Reactions

• Hypertension

• Hypokalemia

• Fluid retention

• Hepatotoxicity

• Cardiac toxicity

• arrythmias

ZYTIGA™ Product Monograph. Janssen Inc. 2011

Abiraterone – Bottom Line

• Survival benefit

– 4 months

• Symptom benefit

– Improvement in pain

• Minimal toxicity

Lessons Learned

• Make sure pts are taking their prednisone

• Ask patients to monitor BP

• Monitor for leg edema, K+, liver enzymes

• Review medication history with (oncology) pharmacist

• Cautious with pts with cardiac history – arrhythmias or CAD (consider Echo to check LV)

Enzalutamide (Xtandi)

• Oral – 40 mg tablets – take 4 tablets daily (160 mg total)

• “Super-casodex”

Enzalutamide Has Several Unique Mechanisms of Action and No Known Agonist Effects

Enzalutamide

T

AR

T

Cell nucleus AR

Cell cytoplasm

Enzalutamide

Enzalutamide

Inhibits Nuclear

Translocation of AR

And Uniquely

Inhibits AR-Mediated

DNA Binding

Inhibits Binding of

Androgens to AR

Similar to Casodex

2

3

1

38

AFFIRM: A Phase 3 Trial of Enzalutamide vs. Placebo in Post-Chemotherapy Treated Castration-Resistant Prostate Cancer (CRPC)

Co- Principal Investigators: H. Scher & J. De Bono

Clinicaltrials.gov identifier:NCT00974311

RANDOMIZED

2:1

Primary Endpoint:

Overall Survival

Enzalutamide160 mg daily

n = 800

Placebon = 399

Note: Glucocorticoids were not required but allowed

Patient Population:

1199 patients with

progressive CRPC

* Previous docetaxel

chemotherapy

ASCO-GU 2012, LBA 1 & Oral Presentation.Scher HI et al. J Clin Oncol 30, 2012 (suppl 5; abstr LBA1). 39

Enzalutamide Prolonged Survival by a Median of 4.8 Months in the Phase 3 AFFIRM Trial

Enzalutamide: 18.4 months

(95% CI: 17.3, NYR)

HR = 0.631 (0.529, 0.752) P < 0.000137% Reduction in Risk of Death

Placebo: 13.6 months (95% CI: 11.3, 15.8)

ASCO-GU 2012, LBA 1 & Oral Presentation.Scher HI et al. J Clin Oncol 30, 2012 (suppl 5; abstr LBA1). 40

Most Common Adverse Reactions

• Fatigue

• Hot Flushes

• Headache

• Hypertension

• Seizures (<1%)

Drug Interactions with Enzalutamide

• Clarithromycin

• Diazepam, Haloperidol, Midazolam

• Colchicine

• Atorvastatin

• Bispropolol, Diltizem, Nifedipine

• Warfarin, Dabigatran

• Fenanyl, Tramadol

• Levothyroxine

Enzalutamide – Bottom Line

• Survival benefit

– 4.8 months

• Symptom benefit

– improvement in pain

• Minimal toxicity

– Avoid in patients with “seizure risk” – epilepsy, prior seizure, head trauma, stroke, syncope

Lessons Learned

• Fatigue can be a big issues

• Avoid in pts with high “seizure risk”

• Review medication history with (oncology) pharmacist


CRPC Mets


Death

3-5 years

D

O

C

E

T

A

X

E

L

Cabazitaxel

Abiraterone

Enzalutamide


CRPC Mets


Death

3-5 years

D

O

C

E

T

A

X

E

L

Cabazitaxel

Abiraterone

Enzalutamide

Abiraterone in mCRPC chemo-naïve pts - COU-AA-302

• Phase 3 multicenter, randomized, double-blind, placebo-controlled study conducted at 151 sites in 12 countries; USA, Europe, Australia, Canada

• Stratification by ECOG performance status 0 vs. 1

AA 1000 mg daily

Prednisone 5 mg BID

(Actual n = 546)

Co-Primary:

• rPFS by central review

• OS

Secondary:

• Time to opiate use

(cancer-related pain)

• Time to initiation of

chemotherapy

• Time to ECOG-PS

deterioration

• TTPP

Efficacy end points

Placebo daily

Prednisone 5 mg BID

(Actual n = 542)

RANDOMIZED

1:1

• Progressive chemo-

naïve mCRPC

patients

(Planned N = 1088)

• Asymptomatic or

mildly symptomatic

Patients

Ryan et al. ASCO 2012; Abstract LBA4518 (Oral Presentation)

Abiraterone Doubled Time to rPFS1

Third interim analysis data. rPFS assessed by investigator review at prespecified IA.

100

80

60

40

20

0

0

Pro

gre

ss

ion

-Fre

e S

urv

iva

l (%

)

6 12 18 30 3624

546

542

389

244

240

133

157

78

20

7

0

0

Abiraterone

Prednisone

117

45

Time to Progression or Death (Months)

1593 21 27 33

485

406

311

176

195

99

131

62

66

20

4

0

HR (95% CI): 0.52 (0.45-0.61)

p Value: < 0.0001

Prednisone, 8.2 mos

Abiraterone, 16.5 mos

1. Rathkopf DE, et al. Eur Urol. 2014 March 6 [Epub ahead of print].

Final OS Analysis

• Median follow-up of 49.2 mos

• Abiraterone treatment effect more pronounced when adjusting for 44% of prednisone patients who received subsequent abiraterone (HR = 0.74)

100

80

60

40

20

0

0

Ove

rall

Su

rviv

al (%

)

9 21 30 48 6039

546

542

525

509

422

401

296

261

59

42

0

0

Abiraterone

Prednisone

202

148

Time to Death (Months)24123 36 45 54

538

534

453

438

359

322

189

132

15

10

HR (95% CI): 0.81 (0.70-0.93)

p Value: 0.0033

Prednisone, 30.3 mos

Abiraterone, 34.7 mos

6 15 18 27 33 42 51 57

0

1

118

84

218

176

504

493

483

466

394

363

330

292

273

227

235

201

Safety Profile Remains Favorable

Abiraterone(n = 542)

%

Prednisone(n = 540)

%

All Grades Grade 3/4 All Grades Grade 3/4

Fluid retention/edema 31 1 24 2

Hypokalemia 19 3 13 2

Hypertension 24 5 14 3

Cardiac disorders 23 8 18 4

Atrial fibrillation 6 2 5 1

ALT increased 13 6 5 1

AST increased 12 3 5 1

ALT, alanine aminotransferase; AST, aspartate aminotransferase.

Abiraterone in Chemo-naïve mCRPC

• Delays radiological disease progression

• Increases survival

• Extends time with minimal or no symptoms

• No new important safety signals

PREVAIL: A Phase 3 Trial of Enzalutamide After Progression on Androgen Deprivation Therapy in Men with Metastatic Prostate Cancer

Presented By Andrew Armstrong at 2014 ASCO Annual Meeting

Enzalutamide Prolonged Radiographic <br />Progression-Free Survival


Enzalutamide Reduced Risk of Death by 29%


<br />Review of Specific Adverse Events<br />


Conclusions



CRPC Mets


Death

3-5 years

D

O

C

E

T

A

X

E

L

Cabazitaxel

Abiraterone

Enzalutamide

Abiraterone

Enzalutamide

Bone Health

Bone Metastases

• Bony Pain

– Anti-inflammatories

– Narcotics

– Palliative radiation

• At risk for fracture, cord compression

• Calcium and Vit D (1000/1000)

• Bone targeted agents

Bone Targeted Agents

• Decrease rate of skeletal related events

• Denosumab (XGEVA)

– 120 mg SC q 4 weeks

• Zolendronic Acid (Zometa)

– 4 mg IV q 4 weeks

• S/E – hypocalcemia and osteonecrosis of the jaw (<5%)

Osteonecrosis of the Jaw (ONJ)

Lessons Learned

• Oral calcium and vitamin D supplementation

• Patients should have an oral exam by a dentist and any dental work should be done prior to starting BTA

• Monitor calcium (check prior to injection), if low, hold until serum calcium is up

Ra-223:Alpharadin

• Radiopharmaceutical agent

• Radium

– A natural bone seeker because it is a ‘calcium mimic’1

• Radium-223

– An emitter of radioactive high energy densely ionizing α-particles2

• double-strand DNA breaks in adjacent tumor cells in the bone

• α-particles have a short track (2–10 cell diameters) 2

1. Henriksen et al. Can Res. 2002;62:3120.

2. McDevitt et al. Eur J Nucl Med

1998;25(9):1341

Ra88

20

Ca

TREATMENT

6 injections at 4-week intervals

Radium-223 (50 kBq/kg)

+ Best standard of care

Placebo (saline)

+ Best standard of care

R

A

N

D

O

M

I

Z

E

D

2:1

N = 921

PATIENTS

• Confirmed

symptomatic

CRPC

• ≥ 2 bone

metastases

• No known

visceral

metastases

• Post-

docetaxel or

unfit for

docetaxel

ALSYMPCA (ALpharadin in SYMptomaticProstate CAncer) Phase III Study Design

Clinicaltrials.gov identifier: NCT00699751.

• Total ALP:

< 220 U/L vs ≥ 220 U/L

• Bisphosphonate use:

Yes vs No

• Prior docetaxel:

Yes vs No

STRATIFICATION

Planned follow-up is 3 years

ALSYMPCA Updated AnalysisOverall Survival

Radium-223, n = 614

Median OS: 14.9 months

Placebo, n = 307

Median OS: 11.3 months

HR = 0.69595% CI, 0.581, 0.832

P = 0.00007

Month 0 3 6 9 12 15 18 21 24 27 30 33 36 39

Radium-223 614 578 504 369 274 178 105 60 41 18 7 1 0 0

Placebo 307 288 228 157 103 67 39 24 14 7 4 2 1 0

0

10

20

30

40

50

60

70

80

90

100

%

Prior docetaxel use NO prior docetaxel use

ALSYMPCA Updated Analysis OS by Stratification Variables:

Prior Docetaxel Use

Radium-223 352 327 238 155 88 45 27 5 1 0 0

Placebo 174 152 104 61 35 15 5 4 1 1 0

Radium-223, n = 352

Median: 14.4 months

Placebo, n = 174

Median: 11.3 months

HR = 0.710

95% CI, 0.565, 0.891

P = 0.00307

Radium-223, n = 262

Median: 16.1 months

Placebo, n = 133

Median: 11.5 months

HR = 0.745

95% CI, 0.562, 0.987

P = 0.03932

100

90

80

70

60

50

40

30

20

10

0

0 4 8 12 16 20 24 28 32 36 40Month

%

Radium-223 262 236 168 119 70 31 14 7 1 0

Placebo 133 113 74 42 24 14 9 3 1 0

100

90

80

70

60

50

40

30

20

10

0

0 4 8 12 16 20 24 28 32 36

%

Month

Toxicity

• Mild bone marrow suppression

• Diarrhea

• Fatigue

May 2010 Jan 2011

*Croke J, Leung E, Segal R, Malone S. Clinical benefits of alpharadin in castrate-chemotherapy-resistant prostate cancer: case report and literature review, BMJ Case Reports 2012.

Bone Scan Response to Ra 223*

RAD223

In CRPC patients with bone metastases:

• Prolonged OS

• Significantly prolonged time to first SRE

• Radium-223 improved QOL and was well tolerated

Lessons Learned

• Patients must have good marrow reserve prior to starting

• Check CBC before each injection

• Wait at least 4-6 weeks if considering chemotherapy post-RAD223

• To be used in pts with bone only mets


CRPC Mets


Death

3-5 years

D

O

C

E

T

A

X

E

L

Cabazitaxel

Abiraterone

Enzalutamide

Abiraterone

Enzalutamide

RAD - 223

Bone Targeted Agent

In Summary…

• Castrate Resistant Prostate Cancer (CRPC) is defined as progressive disease despite castrate levels of testosterone

• Docetaxel and prednisone is first line chemotherapy for mCRPC

In Summary…• Pre-docetaxel

– Abiraterone and Enzalutamide are oral, second generation hormonal therapies that show improved survival with minimal toxicity

• Post-docetaxel

– Cabazitaxel is a 2nd line chemotherapy

– Cabazitaxel, Abiraterone, and Enzalutamide have shown survival benefit

– Abiraterone and Enzalutamide improve quality of life with less toxicity compared to Cabazitaxel

• RAD-223 – novel radio-pharmaceutical agent with survival benefit

In Summary…

• Don’t forget about the bones

• Calcium, Vit D

• Consider zolendronic acid or denosumab

In Summary…• Still learning how to use these drugs optimally

• Challenges:

– Selection

– When to stop and start new systemic therapy

– Sequencing

• Slowly moving these drugs into earlier stages of disease

• Consider clinical trials

Documents

Castrate Resistant Prostate Cancer: Optimizing Outcomes Canil... · Learning Objectives • Discuss the evolving treatment in metastatic Castrate Resistant Prostate Cancer (CRPC)