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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
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
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
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
Natural History of CRPC
CRPC Mets
asymptomatic symptomatic
Death
3-5 years
Natural History of CRPC
CRPC Mets
asymptomatic symptomatic
Death
3-5 years
D
O
C
E
T
A
X
E
L
Natural History of CRPC
CRPC Mets
asymptomatic symptomatic
Death
3-5 years
D
O
C
E
T
A
X
E
L
Natural History of CRPC
CRPC Mets
asymptomatic symptomatic
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
Natural History of CRPC
CRPC Mets
asymptomatic symptomatic
Death
3-5 years
D
O
C
E
T
A
X
E
L
Cabazitaxel
Abiraterone
Enzalutamide
Orchiectomy orLHRH therapy -Leuprolide-Goserelin-Buserelin-Degarelix
Anti-AndrogensBicalutamideNilutamideFlutamide
Hoimes CJ, et al. Ther Adv Med Oncol. 2010;2:107-123.
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
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
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
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
Natural History of CRPC
CRPC Mets
asymptomatic symptomatic
Death
3-5 years
D
O
C
E
T
A
X
E
L
Cabazitaxel
Abiraterone
Enzalutamide
Natural History of CRPC
CRPC Mets
asymptomatic symptomatic
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
Presented By Andrew Armstrong at 2014 ASCO Annual Meeting
Enzalutamide Reduced Risk of Death by 29%
Presented By Andrew Armstrong at 2014 ASCO Annual Meeting
<br />Review of Specific Adverse Events<br />
Presented By Andrew Armstrong at 2014 ASCO Annual Meeting
Conclusions
Presented By Andrew Armstrong at 2014 ASCO Annual Meeting
Natural History of CRPC
CRPC Mets
asymptomatic symptomatic
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
Natural History of CRPC
CRPC Mets
asymptomatic symptomatic
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
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