New Concept of Anti-androgen Treatment for Castration- Resistant Prostate Cancer … · 2016. 12....
Transcript of New Concept of Anti-androgen Treatment for Castration- Resistant Prostate Cancer … · 2016. 12....
![Page 1: New Concept of Anti-androgen Treatment for Castration- Resistant Prostate Cancer … · 2016. 12. 27. · Current Landscape for Systemic Therapy in Castration-Resistant Prostate Cancer](https://reader036.fdocuments.us/reader036/viewer/2022081620/6106544d7426b355431cd753/html5/thumbnails/1.jpg)
New Concept of Anti-androgen Treatment for Castration-Resistant
Prostate Cancer (CRPC)
Hyo Jin Lee, MD, PhD
Division of Hematology/Oncology, Department of Internal Medicine, Chungnam National University Hospital
![Page 2: New Concept of Anti-androgen Treatment for Castration- Resistant Prostate Cancer … · 2016. 12. 27. · Current Landscape for Systemic Therapy in Castration-Resistant Prostate Cancer](https://reader036.fdocuments.us/reader036/viewer/2022081620/6106544d7426b355431cd753/html5/thumbnails/2.jpg)
Prostate Cancer Most common amongst men in the USA 2nd most common malignant cause of
male death worldwide The life time risk of having microscopic
evidence of prostate cancer for a 50 year old man is 42%
Global Health Problem
![Page 3: New Concept of Anti-androgen Treatment for Castration- Resistant Prostate Cancer … · 2016. 12. 27. · Current Landscape for Systemic Therapy in Castration-Resistant Prostate Cancer](https://reader036.fdocuments.us/reader036/viewer/2022081620/6106544d7426b355431cd753/html5/thumbnails/3.jpg)
Stage Distribution & 5YSR, US, 2001-2007
Siegel R, et al. CA Cancer J Clin 2012
Stage distribution (%) at diagnosis Survival (%)
All Races White African American
![Page 4: New Concept of Anti-androgen Treatment for Castration- Resistant Prostate Cancer … · 2016. 12. 27. · Current Landscape for Systemic Therapy in Castration-Resistant Prostate Cancer](https://reader036.fdocuments.us/reader036/viewer/2022081620/6106544d7426b355431cd753/html5/thumbnails/4.jpg)
Current Landscape for Systemic Therapy in Castration-Resistant Prostate Cancer
Modified from Attard G, et al. Clin Cancer Res 2011; Massard C, et al. Clin Cancer Res 2011
Disease Phenotype
Surgical or medical castration
Asymptomatic or minimally
symptomatic
Symptomatic
Pre-Doc With Doc Post-Doc
2nd hormonal therapy
Sipuleucel-T (2010)
Docetaxel (2004)
Mitoxantrone (1996)
Cabazitaxel (2010)
Abiraterone (2011)
MDV3100 (2012 ?)
![Page 5: New Concept of Anti-androgen Treatment for Castration- Resistant Prostate Cancer … · 2016. 12. 27. · Current Landscape for Systemic Therapy in Castration-Resistant Prostate Cancer](https://reader036.fdocuments.us/reader036/viewer/2022081620/6106544d7426b355431cd753/html5/thumbnails/5.jpg)
Hypothalamus
Ant. Pituitary
Adrenal Gland Testis
Prostate
Androgen Action in Prostate Cells
Androgen
LHRH
ACTH LH
Stewart AB, et al. Curr Med Chem Anticancer Agents 2005; Attard G, et al. Clin Cancer Res 2011
T, testosterone, SHBG, sex hormone- binging globulin, 5αR, 5α- reductase, DHT, dehydrotesterone, AR, androgen receptor, HRE hormone-responsive element
Androgen & AR signaling ▪ Main Oncogenic Driver ▪ Therapeutic Target
![Page 6: New Concept of Anti-androgen Treatment for Castration- Resistant Prostate Cancer … · 2016. 12. 27. · Current Landscape for Systemic Therapy in Castration-Resistant Prostate Cancer](https://reader036.fdocuments.us/reader036/viewer/2022081620/6106544d7426b355431cd753/html5/thumbnails/6.jpg)
Hypothalamus
Ant. Pituitary
Adrenal Gland Testis
Prostate
Androgen Deprivation Therapy (ADT)
Androgen
LHRH
ACTH LH
Stewart AB, et al. Curr Med Chem Anticancer Agents 2005; Attard G, et al. Clin Cancer Res 2011
▪ LHRH analogue ▪ LHRH antagonist
Orchiectomy
Anti-androgen AR
![Page 7: New Concept of Anti-androgen Treatment for Castration- Resistant Prostate Cancer … · 2016. 12. 27. · Current Landscape for Systemic Therapy in Castration-Resistant Prostate Cancer](https://reader036.fdocuments.us/reader036/viewer/2022081620/6106544d7426b355431cd753/html5/thumbnails/7.jpg)
Surgical Castration as an ADT
Cancer Res 1941
![Page 8: New Concept of Anti-androgen Treatment for Castration- Resistant Prostate Cancer … · 2016. 12. 27. · Current Landscape for Systemic Therapy in Castration-Resistant Prostate Cancer](https://reader036.fdocuments.us/reader036/viewer/2022081620/6106544d7426b355431cd753/html5/thumbnails/8.jpg)
Structure of LHRH
LHRH analogue
Increased life span Increased affinity for receptor 100 times more potent A flare period at initial administration need co-administration of anti-androgen
Lutenising Hormone-Releasing Hormone Analogues (LHRHa)
Stewart AB, et al. Curr Med Chem Anticancer Agents 2005
![Page 9: New Concept of Anti-androgen Treatment for Castration- Resistant Prostate Cancer … · 2016. 12. 27. · Current Landscape for Systemic Therapy in Castration-Resistant Prostate Cancer](https://reader036.fdocuments.us/reader036/viewer/2022081620/6106544d7426b355431cd753/html5/thumbnails/9.jpg)
Anti-Androgens (AAs)
Cyproterone Acetate
Bicalutamide Flutamide Nilutamide
▪ Bind to the androgen receptor in a competitive fashion
▪ Steroidal anti-androgen ▪ Non-steroidal anti-androgen
![Page 10: New Concept of Anti-androgen Treatment for Castration- Resistant Prostate Cancer … · 2016. 12. 27. · Current Landscape for Systemic Therapy in Castration-Resistant Prostate Cancer](https://reader036.fdocuments.us/reader036/viewer/2022081620/6106544d7426b355431cd753/html5/thumbnails/10.jpg)
Androgen Deprivation Therapy (ADT)
Surgical castration - Bilateral orchiectomy
Chemical castration - LHRH agonist - LHRH antagonist
Anti-androgen monotherapy
Combined androgen blockade (CAB) - Castration plus anti-androgen
Triple androgen blockade - Castration + anti-androgen + 5α reductase inhibitor
![Page 11: New Concept of Anti-androgen Treatment for Castration- Resistant Prostate Cancer … · 2016. 12. 27. · Current Landscape for Systemic Therapy in Castration-Resistant Prostate Cancer](https://reader036.fdocuments.us/reader036/viewer/2022081620/6106544d7426b355431cd753/html5/thumbnails/11.jpg)
Androgen-Independent Prostate Cancer (?)
Androgen deprivation therapy
Androgen-dependent PCa
18-24 Mos
Debes JD, et al. N Engl J Med 2004
2nd line hormonal therapy, chemotherapy
Androgen-independent PCa
![Page 12: New Concept of Anti-androgen Treatment for Castration- Resistant Prostate Cancer … · 2016. 12. 27. · Current Landscape for Systemic Therapy in Castration-Resistant Prostate Cancer](https://reader036.fdocuments.us/reader036/viewer/2022081620/6106544d7426b355431cd753/html5/thumbnails/12.jpg)
New Mechanism of Castration Resistance
Primary PCa AIPC BM
AIPC Prostate AIPC soft tissue
Stanbrough M, et al. Cancer Res 2006
AKR1C3
![Page 13: New Concept of Anti-androgen Treatment for Castration- Resistant Prostate Cancer … · 2016. 12. 27. · Current Landscape for Systemic Therapy in Castration-Resistant Prostate Cancer](https://reader036.fdocuments.us/reader036/viewer/2022081620/6106544d7426b355431cd753/html5/thumbnails/13.jpg)
New Mechanism of Castration Resistance
Montgomery RB, et al. Cancer Res 2008
![Page 14: New Concept of Anti-androgen Treatment for Castration- Resistant Prostate Cancer … · 2016. 12. 27. · Current Landscape for Systemic Therapy in Castration-Resistant Prostate Cancer](https://reader036.fdocuments.us/reader036/viewer/2022081620/6106544d7426b355431cd753/html5/thumbnails/14.jpg)
New Strategies in CRPC-Targeting Persistent Dependency on Androgen and AR Signaling
Yamaoka M, et al. Clin Cancer Res 2010
![Page 15: New Concept of Anti-androgen Treatment for Castration- Resistant Prostate Cancer … · 2016. 12. 27. · Current Landscape for Systemic Therapy in Castration-Resistant Prostate Cancer](https://reader036.fdocuments.us/reader036/viewer/2022081620/6106544d7426b355431cd753/html5/thumbnails/15.jpg)
Abiraterone Acetate (AA) in CRPC
Barrie SE, et al. J Steroid Biochem Mol Biol 1994 Potter GA, et al. J Med Chem 1995
![Page 16: New Concept of Anti-androgen Treatment for Castration- Resistant Prostate Cancer … · 2016. 12. 27. · Current Landscape for Systemic Therapy in Castration-Resistant Prostate Cancer](https://reader036.fdocuments.us/reader036/viewer/2022081620/6106544d7426b355431cd753/html5/thumbnails/16.jpg)
Abiraterone Acetate (AA) in CRPC
Attard G, et al. J Clin Oncol 2008 Before and after AA treatment (6 months)
Phase I trial (n=21) • CRPC resistant to multiple hormonal therapies
• AA, 250 to 2,000 mg (1,000 mg selected because of a plateau in PD) •
• PSA deliine [≥ 30% (66%), ≥ 50% (57%), ≥ 90% (29%)] •
![Page 17: New Concept of Anti-androgen Treatment for Castration- Resistant Prostate Cancer … · 2016. 12. 27. · Current Landscape for Systemic Therapy in Castration-Resistant Prostate Cancer](https://reader036.fdocuments.us/reader036/viewer/2022081620/6106544d7426b355431cd753/html5/thumbnails/17.jpg)
Phase III study of Abiraterone Acetate in CRPC (COU-AA-301)
R A N D O M I Z A T I O N
Abiraterone 1,000 mg daily + Prednisone 5 mg x 2, daily N= 797
Placebo + Prednisone N= 398
N=1,195
Eligibility Criteria
▪ mCRPC ▪ Progression during or after docetaxel-based Tx
Stratification factor ▪ ECOG 0,1 vs. 2 ▪ Prior CTX 1 vs. 2
April 2008 -
Primary Outcome
OS
TTPP PSA RR
rPFS
Median F/U (12.8 mos)
35th ESMO Congress 2010; de Bono JS, et al. N Engl J Med 2011
2
1
TTPP, time to PSA progression; rPFS, radiographic PFS Unblinded following the 1st interim analysis on Aug 20, 2010
![Page 18: New Concept of Anti-androgen Treatment for Castration- Resistant Prostate Cancer … · 2016. 12. 27. · Current Landscape for Systemic Therapy in Castration-Resistant Prostate Cancer](https://reader036.fdocuments.us/reader036/viewer/2022081620/6106544d7426b355431cd753/html5/thumbnails/18.jpg)
Overall survival
![Page 19: New Concept of Anti-androgen Treatment for Castration- Resistant Prostate Cancer … · 2016. 12. 27. · Current Landscape for Systemic Therapy in Castration-Resistant Prostate Cancer](https://reader036.fdocuments.us/reader036/viewer/2022081620/6106544d7426b355431cd753/html5/thumbnails/19.jpg)
Overall survival
![Page 20: New Concept of Anti-androgen Treatment for Castration- Resistant Prostate Cancer … · 2016. 12. 27. · Current Landscape for Systemic Therapy in Castration-Resistant Prostate Cancer](https://reader036.fdocuments.us/reader036/viewer/2022081620/6106544d7426b355431cd753/html5/thumbnails/20.jpg)
Efficacy
TTPP, time to PSA progression; rPFS, radiographic PFS
![Page 21: New Concept of Anti-androgen Treatment for Castration- Resistant Prostate Cancer … · 2016. 12. 27. · Current Landscape for Systemic Therapy in Castration-Resistant Prostate Cancer](https://reader036.fdocuments.us/reader036/viewer/2022081620/6106544d7426b355431cd753/html5/thumbnails/21.jpg)
Second-generation Antiandrogen in CRPC
Chen CD, et al. Nat Med 2004
![Page 22: New Concept of Anti-androgen Treatment for Castration- Resistant Prostate Cancer … · 2016. 12. 27. · Current Landscape for Systemic Therapy in Castration-Resistant Prostate Cancer](https://reader036.fdocuments.us/reader036/viewer/2022081620/6106544d7426b355431cd753/html5/thumbnails/22.jpg)
Second-generation Antiandrogen in CRPC
Science 2009
![Page 23: New Concept of Anti-androgen Treatment for Castration- Resistant Prostate Cancer … · 2016. 12. 27. · Current Landscape for Systemic Therapy in Castration-Resistant Prostate Cancer](https://reader036.fdocuments.us/reader036/viewer/2022081620/6106544d7426b355431cd753/html5/thumbnails/23.jpg)
MDV3100 in CRPC
Scher HI, et al. Lancet 2010
Phase I-II trial (n=140) • Patients with progressive CRPC
• MDV3100, 30 to 600 mg •
• PSA response (≥ 50%) - 56% • Soft tissue response - 22% • Time to radiologic progression - 47 weeks
No previous chemotherapy (n=65) Previous chemotherapy (n=75)
PSA
chan
ge fr
om b
asel
ine
(%)
Patient number
![Page 24: New Concept of Anti-androgen Treatment for Castration- Resistant Prostate Cancer … · 2016. 12. 27. · Current Landscape for Systemic Therapy in Castration-Resistant Prostate Cancer](https://reader036.fdocuments.us/reader036/viewer/2022081620/6106544d7426b355431cd753/html5/thumbnails/24.jpg)
Phase III study of MDV3100 in CRPC (AFFIRM trial)
R A N D O M I Z A T I O N
MDV3100 160 mg daily
N= 797
Placebo
N= 399
N=1,199
Eligibility Criteria
▪ mCRPC ▪ Progression after docetaxel-based Tx
Stratification factor ▪ ECOG 0,1 vs. 2 ▪ Mean BPI score
Sept 2009 ~ Nov 2010
Primary Outcome
OS
PSA-R Soft tissue-R
QoL-R rPFS TTPP CTC
Median F/U (14.4 mos)
2012 Genitourinary Cancers Symposium
2
1
R, response; QoL, quality of life; rPFS, radiographic PFS; TTPP, time to PSA progression; CTC, circulating tumor cells Unblinded following the planned interim analysis (Sept 25, 2011)
![Page 25: New Concept of Anti-androgen Treatment for Castration- Resistant Prostate Cancer … · 2016. 12. 27. · Current Landscape for Systemic Therapy in Castration-Resistant Prostate Cancer](https://reader036.fdocuments.us/reader036/viewer/2022081620/6106544d7426b355431cd753/html5/thumbnails/25.jpg)
Overall survival
![Page 26: New Concept of Anti-androgen Treatment for Castration- Resistant Prostate Cancer … · 2016. 12. 27. · Current Landscape for Systemic Therapy in Castration-Resistant Prostate Cancer](https://reader036.fdocuments.us/reader036/viewer/2022081620/6106544d7426b355431cd753/html5/thumbnails/26.jpg)
Overall survival
![Page 27: New Concept of Anti-androgen Treatment for Castration- Resistant Prostate Cancer … · 2016. 12. 27. · Current Landscape for Systemic Therapy in Castration-Resistant Prostate Cancer](https://reader036.fdocuments.us/reader036/viewer/2022081620/6106544d7426b355431cd753/html5/thumbnails/27.jpg)
Efficacy
![Page 28: New Concept of Anti-androgen Treatment for Castration- Resistant Prostate Cancer … · 2016. 12. 27. · Current Landscape for Systemic Therapy in Castration-Resistant Prostate Cancer](https://reader036.fdocuments.us/reader036/viewer/2022081620/6106544d7426b355431cd753/html5/thumbnails/28.jpg)
Current Landscape for Systemic Therapy in Castration-Resistant Prostate Cancer
Modified from Attard G, et al. Clin Cancer Res 2011; Massard C, et al. Clin Cancer Res 2011
Disease Phenotype
Surgical or medical castration
Asymptomatic or minimally
symptomatic
Symptomatic
Pre-Doc With Doc Post-Doc
2nd hormonal therapy
Sipuleucel-T (2010)
Docetaxel (2004)
Mitoxantrone (1996)
Cabazitaxel (2010)
Abiraterone (2011)
MDV3100 (2012 ?)
TAK-700
ARN-509
![Page 29: New Concept of Anti-androgen Treatment for Castration- Resistant Prostate Cancer … · 2016. 12. 27. · Current Landscape for Systemic Therapy in Castration-Resistant Prostate Cancer](https://reader036.fdocuments.us/reader036/viewer/2022081620/6106544d7426b355431cd753/html5/thumbnails/29.jpg)
Phase III study of Abiraterone Acetate in CRPC (COU-AA-302)
R A N D O M I Z A T I O N
Abiraterone 1,000 mg daily + Prednisone 5 mg x 2, daily N= 546
Placebo + Prednisone
N= 542
N=1,088
Eligibility Criteria
▪ mCRPC ▪ chemo-naïve ▪ asymtomatic or mildly symptomatic
Stratification factor ▪ ECOG 0,1 vs. 2
1Q2010 -
Primary Outcome
rPFS/OS
Time to opiate use
Time to chemotherapy Time to PS deterioration
TTPP
Median F/U (22.3 mos)
Ryan et al. ASCO 2012
1
1
rPFS, radiographic PFS; TTPP, time to PSA progression
(55% OS events) 425 Events
(~15% OS Events) 116 Events
(40% OS Events) 311 Events
![Page 30: New Concept of Anti-androgen Treatment for Castration- Resistant Prostate Cancer … · 2016. 12. 27. · Current Landscape for Systemic Therapy in Castration-Resistant Prostate Cancer](https://reader036.fdocuments.us/reader036/viewer/2022081620/6106544d7426b355431cd753/html5/thumbnails/30.jpg)
Progression-Free Survival
Ryan et al. ASCO 2012
![Page 31: New Concept of Anti-androgen Treatment for Castration- Resistant Prostate Cancer … · 2016. 12. 27. · Current Landscape for Systemic Therapy in Castration-Resistant Prostate Cancer](https://reader036.fdocuments.us/reader036/viewer/2022081620/6106544d7426b355431cd753/html5/thumbnails/31.jpg)
Progression-Free Survival
Ryan et al. ASCO 2012
![Page 32: New Concept of Anti-androgen Treatment for Castration- Resistant Prostate Cancer … · 2016. 12. 27. · Current Landscape for Systemic Therapy in Castration-Resistant Prostate Cancer](https://reader036.fdocuments.us/reader036/viewer/2022081620/6106544d7426b355431cd753/html5/thumbnails/32.jpg)
Overall Survival
Ryan et al. ASCO 2012
![Page 33: New Concept of Anti-androgen Treatment for Castration- Resistant Prostate Cancer … · 2016. 12. 27. · Current Landscape for Systemic Therapy in Castration-Resistant Prostate Cancer](https://reader036.fdocuments.us/reader036/viewer/2022081620/6106544d7426b355431cd753/html5/thumbnails/33.jpg)
Secondary End Points
Ryan et al. ASCO 2012
![Page 34: New Concept of Anti-androgen Treatment for Castration- Resistant Prostate Cancer … · 2016. 12. 27. · Current Landscape for Systemic Therapy in Castration-Resistant Prostate Cancer](https://reader036.fdocuments.us/reader036/viewer/2022081620/6106544d7426b355431cd753/html5/thumbnails/34.jpg)
Conclusions
Abiraterone acetate and MDV3100 developed on the basis of this science show big advances
A better understanding of tumor biology implicated in CRPC provides new room to further
suppress androgenic stimulation of prostate cancer
Large gaps in our knowledge and understanding of CRPC persist, and a major effort is needed to
exploit the full potential of these agents.
![Page 35: New Concept of Anti-androgen Treatment for Castration- Resistant Prostate Cancer … · 2016. 12. 27. · Current Landscape for Systemic Therapy in Castration-Resistant Prostate Cancer](https://reader036.fdocuments.us/reader036/viewer/2022081620/6106544d7426b355431cd753/html5/thumbnails/35.jpg)
In your opinion, which of the following is the best treatment option in patients with metastatic
prostate cancer ?
1. Bilateral orchiectomy
2. LHRH agonist ± anti-androgen of at least 7 days
3. LHRH agonist + anti-androgen
4. LHRH antagonist
![Page 36: New Concept of Anti-androgen Treatment for Castration- Resistant Prostate Cancer … · 2016. 12. 27. · Current Landscape for Systemic Therapy in Castration-Resistant Prostate Cancer](https://reader036.fdocuments.us/reader036/viewer/2022081620/6106544d7426b355431cd753/html5/thumbnails/36.jpg)
Which of the following is the standard treatment of symptomatic patients with castration-resistant
prostate cancer ?
1. Ketoconazole
2. Anti-androgen withdrawal
3. Mitoxantrone-based chemotherapy
4. Docetaxel-based chemotherapy
5. Abiraterone acetate
![Page 37: New Concept of Anti-androgen Treatment for Castration- Resistant Prostate Cancer … · 2016. 12. 27. · Current Landscape for Systemic Therapy in Castration-Resistant Prostate Cancer](https://reader036.fdocuments.us/reader036/viewer/2022081620/6106544d7426b355431cd753/html5/thumbnails/37.jpg)
In your opinion, which of the following is the best treatment option in CRPC patients who have
failed docetaxel-based chemotherapy ?
1. Mitoxantrone-based chemotherapy
2. Docetaxel rechallenge
3. Cabazitaxel-based chemotherapy
4. Abiraterone acetate
5. MDV3100
![Page 38: New Concept of Anti-androgen Treatment for Castration- Resistant Prostate Cancer … · 2016. 12. 27. · Current Landscape for Systemic Therapy in Castration-Resistant Prostate Cancer](https://reader036.fdocuments.us/reader036/viewer/2022081620/6106544d7426b355431cd753/html5/thumbnails/38.jpg)
Thanks for your attention !!!