Transcript No Slide Title
Castration Resistant Prostate Cancer in 2011: What are the Treatment Options?
Lori Wood, MD, MSc, FRCP(C) Associate Professor of Medicine, Dalhousie University Medical Oncologist, Capital Health Cancer Care Program Halifax, Nova Scotia 15 th Annual Atlantic Canada Oncology Group Symposium June 23-25, 2011
Objectives
Understand the term “Castrate Resistant Prostate Cancer” (vs. HRPCa) Review systemic treatment options pre-2010
Prednisone Mitoxantrone Docetaxel Bone targeted therapy – Zoledronic Acid* Discuss systemic treatment options post-2010
Abiraterone
MDV3100 Cabazitaxel Sipuleucel-T (Provenge) Bone targeted therapy – Denosumab* Learn about other new agents/trials
Disclosure
I have participated in advisory boards/ consultant meetings with
Pfizer, Novartis, Janssen, Amgen, AstraZeneca
No personal financial compensation
I have clinical trials with
Pfizer, Novartis, Janssen, Medivation, AstraZeneca
No personal financial compensation
Progression of Advanced Prostate Cancer
PSA rises CRPC Failed localized therapy Hormonal therapy Clinical Metastases Biochemical Asymptomatic Symptomatic Mo 24+ months M+ 12-36 months M+ 6-24 months Death
Prostate Cancer
PCa is an androgen receptor (AR) dependent disease
Blocking AR signalling = hallmark of treatment
Majority of men initially respond to androgen dependent therapy (ADT) when initiated
Progress after 12-48 months
Over time, the cancers “castrate resistant”
Castrate Resistant Prostate Cancer
In the past, we used terms like
Hormone Refractory
Androgen Independent
Androgen Resistant
Now … Castrate Resistant Prostate Cancer (CRPCa)
Why?
CRPCa
Even though patients have castrate levels of serum testosterone (
1.75 mmol/L), AR signalling is still happening
By our current methods of “castration”, they are resistant but these tumors are still responding to AR signalling
Current methods of castration (or ADT)
LHRH agonists
LHRH antagonists Orchiectomy
Nonsteroidal antiandrogens
How Do Cancers Maintain AR Signalling
Androgen receptor
Upregulation by gene amplification Mutations
Intratumoral synthesis of testosterone
Overexpression of key enzymes
P-450c17 (CYP17) involved in extragonadal androgen biosynthesis
Others
Systemic Therapy for CRPCa Pre-2004
Prednisone for palliation
n = 38; 38% improvement in pain
Antiandrogen withdrawal response
n = 9; 29% had a
50%
in PSA
Mitoxantrone and Prednisone for palliative
Phase III RCT, not blinded, n = 161
Primary endpoint = palliative response Tannock et al. J Clin Oncol 1989;7:590-597. H.I. Scher and W.K. Kelly. J Clin Oncol 1993;11:1566-1572. Tannock et al. J Clin Oncol 1996;14:1756-1764.
Mitoxantrone and Prednisone: Results
Palliative Response Duration of Response 1 ° and 2° Palliative Response PSA (
50% Decrease) Overall Survival Prednisone (n=81) 12% 18 wks Mitoxantrone & Prednisone (n=80) 29% 43 wks 21% 22%
10.3m
38% 33% 10.3m
p Value 0.01
0.0001
0.025
0.11
0.27
Mitoxantrone and Prednisone became the new standard of care
Systemic Therapy for CRPCa 2004-2010
Docetaxel
Bisphosphonates
Zoledronic Acid
Docetaxel
TAX 327 study Tannock et al. N Eng J Med 2004;351:1502-1512
SWOG study Petrylak et al. N Eng J Med 2004;351:1513-1520
TAX-327 Study: Design
Stratification: Pain level PPI ≥2 or AS ≥10 vs.
PPI <2 or AS <10 KPS ≤70 vs. ≥80 A T I O N R A N D O M I Z Docetaxel 75 mg/m 2 q3 wkly + Prednisone 5 mg bid Docetaxel 30 mg/m 5 of 6 wks 2 wkly + Prednisone 5 mg bid Mitoxantrone 12 mg/m 2 q3 wkly + Prednisone 5 mg bid Treatment duration in all 3 arms = 30 wks n=1,006 patients Tannock IF. N Engl J Med 2004;351:1502-1512.
TAX-327 Study: Results
PSA Decreased Pain MITOX (n=337) TAX qw (n=334) TAX q3w (n=335) p Value 32% 48% 45%
0.001
22% 31% 35% 0.01
QOL 13% 23% 22% 0.009
TAX-327 Study: Overall Survival
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
Combined: D 3 wkly: Mitoxantrone Median survival (mos) 18.2
18.9
16.4 Hazard ratio 0.83
0.76
– p-value 0.03
0.009
– 0.0
0 6 12 Months 18 Eisenberger MA. Proc Am Soc Clin Oncol 2004;23:2, Abstract 4.
24 Docetaxel 3 wkly Mitoxantrone 30
SWOG 9916: Phase III Trial
Hormone-Refractory Advanced Prostate Cancer R A N D O M I Z A T I O N Docetaxel 60 mg/m 2 d2 + Estramustine 280 mg tid d1-5 q3 weekly Mitoxantrone 12 mg/m 2 d1 + Prednisone 5 mg bid d1-21 q3 weekly
• • •
Survival Quality of life:
–
pain questionnaire and log of analgesic requirements Improved performance status n=770 patients Petrylak DP. N Engl J Med 2004;351:1513-1520.
Conclusions Regarding TAX-327 and SWOG 9916
For the first time, a survival benefit was clearly demonstrated in this patient population
Docetaxel chemotherapy given every three weeks increased overall survival
decreased risk of death by 24%
absolute increase in median survival of 2.5 months
Docetaxel chemotherapy demonstrated a higher rate of pain response, quality of life improvement and PSA Tannock IF. N Engl J Med 2004;351:1502-1512. Petrylak DP. N Engl J Med 2004;351:1513-1520.
Docetaxel “Plus” Phase III Trials
DN101 (high dose Vitamin D) Scher et al. J Clin Oncol 2011 June;29:2191-2198.
Bevacizumab Kelley et al. ASCO 2010 (Abstract 4511).
Sunitinib ASCO 2011 (Abstract 4515).
Risedronate ASCO 2011 (Abstract 4518).
Bisphosphonates
Option in the management of bone metastasis
Powerful inhibitor of osteoclast mediated bone resorption
Zoledronic acid – first bisphosphonate to show efficacy in prostate cancer
Zoledronic Acid in PCa: Trial Design
0 n=214 R A N D O M I Z E D n=221 zoledronic acid zoledronic acid 4 mg 8 mg q 3 wk q 3 wk n= 208 placebo q 3 wk + daily oral vitamin D 400 IU and calcium 500 mg 15 months Core analysis 24 months Final analysis
Proportion (%) of Patients With a Skeletal Related Event
60 50 40 30 20 10 0 33 p=0.021
44 Zoledronic acid 4 mg (n=214) Placebo (n=208) Saad F. J Natl Cancer Inst 2004;96(11):879-882.
Time to First Skeletal Related Event
100 80 60 40 20 0 0 Zol 4 mg Placebo Median, days p value ZOMETA ® Placebo 4 mg 488 321 .009
n
214 298 120
n
149 128 240
n
97 78 360 Days
n
70 44 480
n
47 32 600
n
35 20 Saad F. J Natl Cancer Inst 2004 96(11):879-882.
720
n
3 3
Systemic Therapy For CRPCa Since 2010
Post-Docetaxel
Pre-Docetaxel
Abiraterone
Small molecule inhibitor of CYP17
Therefore blocks testosterone and estradiol synthesis
Steroid Synthesis
Cholesterol Desmolase Pregnenolone Progesterone CYP17 17 X 17 α-OH pregnenolone 17 α –OH progesterone DHEA C17,20-lyase Androstenedione Deoxy corticosterone Corticosterone 11-Deoxy cortisol Cortisol 5 α -reductase Testosterone DHT CYP19: aromatase Estradiol Attard et al. J Clin Oncol 2008.
Aldosterone ACTH
Steroid Synthesis
Cholesterol Low-dose steroid replacement minimizes mineralocorticoid-related toxicity Desmolase Pregnenolone Progesterone CYP17 17 X 17 α-OH pregnenolone 17 α –OH progesterone DHEA C17,20-lyase Androstenedione Deoxy corticosterone Corticosterone 11β-Hydroxylase 11-Deoxy cortisol Cortisol 5 α-reductase Testosterone DHT CYP19: aromatase Estradiol Attard et al. J Clin Oncol 2008.
Aldosterone ACTH
Phase III COU-AA-301 Study Design
Patients
• 1195 patients with progressive, mCRPC • Failed 1 or 2 chemotherapies, one of which contained docetaxel
R A N D O M I Z E D 2:1
Abiraterone 1000 mg daily Prednisone 5 mg BID N=797 Placebo daily Prednisone 5 mg BID n=398
Efficacy endpoints (ITT) Primary end point:
• OS (25% improvement; HR 0.8; 12 mo vs 15 mo)
Secondary end points (ITT):
• TTPP • rPFS • PSA response • QoL ( FACT-P, EORTC-QLQ-C30 )
Stratification according to
ECOG performance status (0-1 vs. 2)
Worst pain over previous 24 hours (BPI short form; 0-3 [absent] vs. 4-10 [present]) Prior chemotherapy (1 vs. 2) Type of progression (PSA only vs. radiographic progression with/without PSA progression) de Bono et al. NEJM 2011 May;364:1995-2005.
Baseline Demographics
Median age, years (range) ECOG-PS 2 Significant pain present 2 Prior chemotherapies Radiographic Progression AA (n = 797) 69.0 (42-95) 10.7% 44.3% 28.2% 70.1% Placebo (n = 398) 69.0 (39-90) 11.1% Total (n = 1195) 69.0
(39-95) 10.8% 44.0% 44.2% 28.4% 68.6% 28.3% 69.6%
Baseline Disease Characteristics
Extent of disease Bone Node Visceral Metastases Liver Lung Other Visceral PSA (median, ng/mL) AA (n = 797) 89.2% 45.4% 29.0% 11.3% 13.0% 5.8% 128.8
Placebo (n = 398) 90.4% 41.5% 24.1% 7.6% 11.4% 5.3% 137.7
Reasons to Stop Treatment
All three criteria had to be met
PSA progression
Radiographic progression
Progression on bone scans
Soft tissue disease progression by modified RECIST criteria
Symptomatic or clinical progression
Pain progression
Development of a SRE
Increase/change in steroid use
Initiation of new systemic anti-cancer therapy
COU-AA-301 Results: ESMO October 2010
The Independent Data Monitoring Committee’s (IDMC) recommendation to un-blind the study
Based on a pre-specified interim analysis
Demonstrated statistically significant improvement in OS (p< 0.0001)
HR for OS exceeded the trial HR (0.789)
Secondary endpoints also met
Acceptable expected safety profile, easily managed
Based on these results, IDMC also recommended that patients in the placebo arm be offered treatment with Abiraterone acetate
Overall Survival Results (ESMO 2010)
100 80 HR = 0.646 (0.54-0.77) P < 0.0001
Abiraterone acetate: 14.8 months (95%CI: 14.1, 15.4) 60 40 Placebo: 10.9 months (95%CI: 10.2, 12.0) 20 0 0 2 Prior Chemo OS: 14.0 mos AA vs 10.3 mos placebo 100 200 300 400 1 Prior Chemo OS 15.4 mos AA vs 11.5 mos placebo 500 Days from Randomization 600 700
Overall Survival (NEJM 2011)
ASCO 2011 Update
Median follow-up = 20.2m
Median overall survival (Abstract 4517)
15.8m vs. 11.2m (4.6m difference)
HR = 0.74, p
0.0001
Palliation (Abstract 4520)
44.4% vs. 27%, p=0.0002
Survival Benefit Observed Across Patient Subgroups
Variable
All subjects Baseline ECOG Baseline BPI No. of prior chemo regimens Type of progression Baseline PSA above median Visceral disease at entry Baseline LDH above median
Subgroup
All 0-1 2 < 4 4 1 2 PSA only Radiographic YES YES YES
N
1195 1068 127 659 536 833 362 363 832 591 709 581 Baseline ALK-P above median Region YES North America Other 587 652 543
Favors AA BPI; Brief Pain Inventory, ALK-P, alkaline phosphatase 0.5 0.75
1 HR
0.66
0.64
0.81
0.64
0.68
0.63
0.74
0.59
0.69
0.65
0.60
0.71
95% CI
0.56-0.79
0.53-0.78
0.53-1.24
0.50-0.82
0.53-0.85
0.51-0.78
0.55-0.99
0.42-0.82
0.56-0.84
0.52-0.81
0.48-0.74
0.58-0.88
1.5
0.60
0.64
0.69
Favors placebo
0.48-0.74
0.51-0.80
0.54-0.90
Secondary Endpoints
TTPP (months) rPFS (months) PSA response rate Total Confirmed AA (n = 797) 10.2 5.6
38.0% 29.1% Placebo (n = 398) 6.6 3.6
HR 95% CI 0.58
(0.46, 0.73) 0.67
(0.59, 0.78) p Value < 0.0001
< 0.0001
10.1% 5.5% < 0.0001
< 0.0001
Tertiary Endpoints
Time to SRE (days) Pain Palliation Time to Pain Progression (days) AA 301 44.4% 225 Placebo 150 27.0% 142 HR 0.64
0.69
p Value 0.0006
0.0002
0.0051
Toxicity
Fluid retention Hypokalemia LFT abnormalities AA (n = 791) All Grades Grades 3/4 30.5% 2.3% 17.1% 10.4% 3.8% 3.5% Hypertension Cardiac disorders 9.7% 13.3% 1.3% 4.1% Placebo (n = 394) All Grades Grades 3/4 22.3% 1.0% 8.4% 8.1% 7.9% 10.4% 0.8% 3.0% 0.3% 2.3% LFT, liver function test
Pearls of Wisdom
Available through Health Canada SAP
Blood work q4 weeks
LFT’s and lytes q2 weeks x first and third cycles
Need Prednisone 5 mg b.i.d. with it
MDV3100
MDV3100 is a potent androgen receptor antagonist
Blocks DHT from binding to AR
Impairs nuclear translocation
Inhibits binding to DNA
Well-tolerated
Phase II Results
Scher et al. Lancet, 2010 April;375:1437-1446.
Phase III AFFIRM Study Design
Patients
mCRPCa Failed 1 or 2 prior chemo therapies, one of which was docetaxel n=1680
R A N D O M I Z E D 2:1 MDV3100 160 mg p.o. qd + Prednisone Placebo + Prednisone Efficacy Endpoints
Overall survival
Results
Study closed to accrual
Results pending
Toxicity – very well-tolerated
Cabazitaxel
Tubulin binding taxane
Activity against Docetaxel resistant tumors
Phase III TROPIC Study Design mCRPC patients who progressed during and after treatment with a docetaxel-based regimen (N=755) Stratification factors
ECOG PS (0, 1 vs. 2) • Measurable vs. non-measurable disease cabazitaxel 25 mg/m² q 3 wk + prednisone * for 10 cycles (n=378) mitoxantrone 12 mg/m² q 3 wk + prednisone * for 10 cycles (n=377)
Primary endpoint:
OS
Secondary endpoints:
Progression-free survival (PFS), response rate, and safety
de Bono et al. Lancet 2010 October;376:1147-1154.
TROPIC Baseline Demographics
n Median age (years) ECOG PS 0-1 Bone Metastases Visceral Metastases Pain at Baseline Mitoxantrone 377 67 91% 87% 25% 45% Cabazitaxel 378 68 93% 80% 25% 46%
TROPIC Results
OS RECIST RR PSA RR Pain Response Mitoxantrone Cabazitaxel 12.7m
15.1m
HR 0.70
p Value
0.0001
4.4% 14.4% 0.0005
17.8% 7.7% 39.2% 9.2% 0.0002
0.63
Overall Survival Results
Proportion of OS (%)
100 80 60 Median OS (months) Hazard Ratio 95% CI P-value MP CBZP 12.7
15.1
0.70
0.59
– 0.83
<.0001
40 20 0 0 months Number at risk MP CBZP 377 378 6 months 300 321 12 months 188 231 18 months 67 90 24 months 11 28 30 months 1 4
TROPIC Toxicity (Grade
3)
Mitoxantrone Cabazitaxel Neutropenia Febrile Neutropenia 58% 1.1% 82% 8% Anemia Diarrhea Neuropathy Deaths Due to AE Within 30 Days of Last Dose 5%
1% (11% all grades) 1% 1% (3 patients) 11% 6% (47% all grades) 1% 7.9% (18 patients)
Pearls of Wisdom
Really have to watch for neutropenia and diarrhea
Watch prior doses of chemotherapy and RT
Sipuleucel-T (Provenge)
Active cellular immunotherapy “Cancer vaccine”
Autologous PBMC (including APC’s)
The APC have been activated with a fusion protein (PA2024) PA2024 is a combination of
Prostate antigen
Prostatic acid phosphatase
GMCSF (an immune cell activator)
Leukopharesis weeks 0, 2, 4 and infusion 3 days later
Manufactured centrally
Sipuleucel-T Background
RCT, placebo-controlled, double-blind, n = 127 metastatic CRPCa patients; 2:1 randomization
Overall survival HR = 0.59 (95% CI: 0.39-0.88); p = 0.01
RCT, placebo-controlled, n = 98
Trend towards
survival
No effect on time to progression which was the primary endpoint in both studies Small et al. JCO 2006;24:3089-94. Higano et al. Cancer 2009;115:3670-9.
Phase III IMPACT Study Design
RCT, double-blind, placebo-controlled n = 512 metastatic CRPCa; 2:1 randomization Primary Endpoint = overall survival (not initially) Patients
Gleason score
7 (initially) Asymptomatic (initially)
ECOG 0, 1 No visceral metastases; SCC Could have had chemotherapy There was crossover Statistics
Power = 88%; 2-sided
= 0.05; HR = 0.69
IMPACT Trial Baseline Demographics
August 2003 – November 2007
75 centres
Median follow-up = 34.1m
n ECOG PS = 0 Gleason
7 Chemotherapy Pain = 0 Sipuleucel-T 341 82.1% 75.4% 19.6% 51.5% Kantoff et al. NEJM 2010;363:411-22.
Placebo 171 81.3% 75.4% 15.2% 48.5%
IMPACT Trial Results
Overall Survival Median Time to Objective Response Time to Clinical Progression PSA Response Sipuleucel-T 25.8m
3.7m
2.6% Placebo 21.7m
3.6m
p Value 0.03
0.63
HR 0.78
(0.61-0.98) 0.95
1.3% 0.40
NS 0.92
Overall Survival (NEJM 2010)
Pearl of Wisdom
Ever a reality in Canada?
Denosumab
Human monoclonal antibody to RANK ligand
RANK ligand is an essential mediator of osteoclast formation, function and survival
q4 weeks s.c.
Study Design
Phase III RCT, placebo-controlled, double blind
Primary endpoint = time to first SRE
n = 1901 Fizazi et al. Lancet 2011 March;377:813-822.
Study Results
n Median Time on Study Median Time to First SRE # of SRE’s Radiation Therapy Pathological Fracture Spinal Cord Compression Surgery to Bone Denosumab 950 12.2m
20.7m
(18.8-24.9) 341 (36%) 177 (19%) 137 (14%) Zoledronic Acid 951 11.2m
17.1m
(15.0-19.4) 386 (41%) 203 (21%) 143 (15%) HR 0.82
26 (3%) 1 (
1%) 36 (4%) 4 (
1%) p Value 0.0002 Inferiority 0.0008 Superiority
Summary
Pre-2004:
Prednisone, antiandrogen withdrawal
Mitoxantrone
2004-2010:
Docetaxel; Zoledronic Acid
2010:
Abiraterone Acetate, MDV3100, Cabazitaxel, Provenge, Denosumab
Beyond:
New drugs New indications
New Drugs: Phase III Trials in CRPCa
Pre-chemotherapy
Ipilimumab (CTLA4) Orteronel (TAK-700), (AR) Tasquinimod (angiogenesis) PROSTVAC (poxiviral vaccine) EMD525797 (integrin inhibitor) With chemotherapy
Docetaxel
Docetaxel
Docetaxel
Lenalidomide (immunovaccine) OGX-011 (apoptosis) Zibotentan (Endothelin-A Receptor Antagonist) Post-Chemotherapy
Orteronel
Ipilimumab
New Drugs: ASCO 2011
Cabozantinib (Abstract 4516)
TKI of MET and VEGFR
Phase II randomized discontinuation trial
122/171 had clinical benefit and accrual discontinuation
75% bone scan improvements (19% CR, 56% PR)
67% pain improvement
74% RECIST RR to soft tissue
New Indications: Phase III Trials in CRPCa
Pre-Docetaxel
Abiraterone
MDV3100
Instead of Docetaxel
Docetaxel vs. Cabazitaxel
Summary
Exciting times on the horizon for prostate cancer
Pre-clinically
Clinically
Objectives
Understand the term “Castrate Resistant Prostate Cancer” (vs. HRPCa) Review systemic treatment options pre-2010
Prednisone Mitoxantrone Docetaxel Bone targeted therapy – Zoledronic Acid* Discuss systemic treatment options post-2010
Abiraterone
MDV3100 Cabazitaxel Sipuleucel-T (Provenge) Bone targeted therapy – Denosumab* Learn about other new agents/trials