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Sequencing Therapy for CRPC: 
A Practical Approach. 
Mohamed Abdulla M.D. 
Prof. of Clinical Oncology 
Kasr Al-Aini School of Medicine 
Cairo University 
SUN – Genitourinary Cancer Meeting 
Radisson Blue Hotel – Alexandria 
07/11/2014
Basic Facts & Figures: 
• Increasing Incidence: Aging and Screening 
Programs. 
• 2nd Most Common Cancer in Men. 
• 1/6 Men. 
• African Americans – Black Races, 
• Rare Before Age of 40 and then Readily Rises. 
• Prostate Cancer is an Androgenic Disease 
Circulating Androgens & Androgen Receptors. 
Uptodate.com 06/02/2014
Prostate Cancer is an Androgenic 
Disease: “Androgen Synthesis” 
Hypothalamus 
LHRH 
LH Pituitary 
ACTH 
Testes Supra-renal 
Testosterone
Prostate Cancer is an Androgenic 
Disease: “Androgen Receptor Structure” 
Mineralocorticoid 
Glucocorticoid 
HSP 
NTD DBD Hinge LBD 
Nuclear 
& Steroid 
Superfamily 
Androgen 
Estrogen 
Progesterone 
Constitutively Active DNA 
Promoter 
Gene 
N/C Androgens
Prostate Cancer is an Androgenic 
Disease: “Androgen Receptor Activity” 
5@ Reductase 
Genomic Activity 
PSA, IGF, …
Prostate Cancer is an Androgenic 
Disease: “Androgen Receptor Activity” 
Testosterone 5 α Reductase DHT + AR (LBD) 
AR Activation & 
Dimerization 
Non Genomic Activity 
PI3K 
Caveolae 
RTK 
GPCR 
HSP 
AKT 
Src 
MAPK 
ERK1/2 
Nuclear Transcription 
Factors 
• Proliferation, Angiogenesis, … 
• No AR Degradation.
Androgen 
Androgen 
Receptors 
Perfect Disease Control 
• Surgical Castration. 
• Medical Castration. 
• Blocking Receptors.
Sequencing therapy for crcp  a practical approach
Androgen Receptor in Prostate 
Cancer:
Steroidogenesis & Prostate Cancer : 
Cholesterol 
CYP 
11A1 
Pregnenolone 
CYP 
17A1 
Testosterone 
ASS
Castrate Resistant Prostate Cancer: 
Prognostic Factors: 
1. Site of Metastases: 5 RCTs: 
OAS 
0 5 10 15 20 25 30 
LNs 
Bone 
Lungs 
Liver 
Months 
Halabi et al. Journal of Clinical Oncology, 2014 ASCO Annual Meeting Abstracts. Vol 
32, No 15_suppl (May 20 Supplement), 2014: 5002
Castrate Resistant Prostate Cancer: 
Prognostic Factors: 
Halabi et al. J Clin Oncol 32:671-677. © 2014
Cabazitaxel7* 
Zoledronic Acid4 
Mitoxantrone3 Docetaxel5,6* 
1984-1989 
Sipuleucel-T8* 
1996 2002 2004 .... 2010 
Denosumab9 
Abiraterone10* 
Enzalutamide11* 
2011 
Radium 223? 
2012 
...but this rapid change has left many unanswered 
questions, including the optimal selection and 
sequence of therapy 
LHRH agonists1* 
Reversible AR 
blockers2 
1. The Leuprolide Study Group. N Engl J Med. 1984;311(20):1281-1286. 2. Crawford ED, et al. N Engl J Med. 1989;321(7):419-424. 3. Tannock I et 
al. J Clin Oncol. 1996;14(6):1756-1764. 4. Saad F, et al. J Natl Cancer Inst. 2002;94(19):1458-1468. 5. Petrylak DP, et al. N Engl J Med. 
2004;351(15):1513-1520. 6. Tannock I, et al. N Engl J Med. 2004;351(15):1502-1512. 7. de Bono JS, et al. Lancet. 2010;376(9747):1147-1154. 8. 
Kantoff P, et al. N Engl J Med. 2010;363(5):411-422. 9. Fizazi K, et al. J Clin Oncol. 2009;27(10)1564-1571. 10. de Bono JS, et al. N Engl J Med. 
2011;364(21):1995-2005. 11. Scher HI, et al. N Engl J Med. 2012;367(13):1187-1197.
• Pain 
• Bone vs visceral metastases 
• Performance status 
• Neuropathy 
• Comorbidity 
• “Early or late” CRPC 
• Prior therapy exposure and response 
• Response biomarkers 
• Tumor characteristics 
CRPC, castration-resistant prostate cancer
Management of CRPC: 
1. ADT should be continued. 
2. Choose between therapies associated with 
survival benefit.
COU-AA-301 Study Design 
Phase III Post-Docetaxel 
Phase 3, double-blind placebo-controlled trial of abiraterone + 
prednisone versus placebo + prednisone in mCRPC post-chemotherapy 
Abiraterone 1000 mg QD 
Prednisone 5 mg BID 
n = 797 
Primary endpoint: 
• OS 
Secondary endpoints: 
• PSA response 
• Time to PSA progression 
• rPFS 
Placebo QD 
Prednisone 5 mg BID 
n = 398 
R 
A 
N 
D 
O 
M 
I 
Z 
E 
D 
2:1 
• 1195 patients 
with progressive 
mCRPC 
• Failed 1 or 2 
chemotherapy 
regimens, 1 of 
which contained 
docetaxel 
de Bono JS, et al. N Engl J Med. 2011;346(21):1995-2005.
Overall Survival, % 
100 
80 
60 
40 
20 
0 
AA + P: 
Placebo + P: 
0 6 24 30 
12 18 
Time to Death, months 
AA + P 797 657 473 
Placebo + P 398 306 183 
273 15 0 
100 6 0 
AA, abiraterone acetate; CI, confidence interval; P, prednisone 
HR = 0.74 (95% CI,0.638-0.859) P<.0001 
26% reduction in risk of death 
Median follow-up: 20.2 months 
Fizazi K, et al. Lancet Oncol. 2012;13(10):983-992.
Variable Subgroup N HR 95% CI 
All subjects All 1195 0.66 0.56-0.79 
Baseline ECOG 0-1 1068 0.64 0.53-0.78 
2 127 0.81 0.53-1.24 
Baseline BPI < 4 659 0.64 0.50-0.82 
≥ 4 536 0.68 0.53-0.85 
1 833 0.63 0.51-0.78 
2 362 0.74 0.55-0.99 
Type of progression PSA only 363 0.59 0.42-0.82 
Radiographic 832 0.69 0.56-0.84 
Age, years < 65 0.66 0.48-0.91 
≥ 65 0.67 0.55-0.82 
Visceral disease at entry Yes 353 0.70 0.52-0.94 
Baseline PSA above 
Yes 591 0.65 0.52-0.81 
median 
Yes 581 0.71 0.58-0.88 
Yes 587 0.60 0.48-0.74 
Region N America 652 0.64 0.51-0.80 
Other 543 0.69 0.54-0.90 
0.5 0.75 1 1.5 
Favors abiraterone Favors placebo 
No of prior 
chemotherapy regimens 
Baseline LDH above 
median 
Baseline ALK-P above 
median 
de Bono JS, et al. N Engl J Med. 2011;364(21):1995-2005.
COU-AA-302 Study Design 
Phase III Pre-Docetaxel 
Phase 3, double-blind placebo-controlled trial of abiraterone + 
prednisone versus placebo + prednisone in mCRPC pre-chemotherapy 
Abiraterone 1000 mg QD 
+ Prednisone 5 mg BID 
n = 546 
Co-Primary endpoints: 
• OS 
• rPFS 
Placebo BID 
+ Prednisone 5 mg BID 
n = 542 
R 
A 
N 
D 
O 
M 
I 
Z 
E 
D 
1:1 
• 1088 progressive 
chemonaïve 
patients with 
mCRPC 
• Asymptomatic 
or mildly 
symptomatic 
Ryan CJ, et al. N Engl J Med. 2013;368(2):138-148.
COU-AA-302: rPFS 
HR = 0.53 (95% CI, 0.45-0.62) P<.001 
47% reduction in risk of progression 
Abiraterone + prednisone, 16.5 months 
Prednisone alone, 
8.3 months 
Progression-Free Survival, % 
110 – 
80 – 
60 – 
40 – 
20 – 
0 – 
0 3 6 9 12 15 18 21 24 27 30 
Ryan CJ, et al. N Engl J Med. 2013;368(2):138-148.
COU-AA-302: Updated OS 
Abiraterone + prednisone, 
Placebo + 
prednisone, 
30.1 months 
Months From Randomization 
35.3 months 
Second interim analysis: 43% death1 
Third interim analysis: 56% death2 
Subjects Without Death, % 
HR = 0.79 (95% CI, 0.66–0.95) P = .0151 
Prespecified P for significance: .0035 100 
80 
60 
40 
20 
0 
0 3 6 9 12 15 18 21 24 27 30 33 36 
1. Ryan CJ, et al. N Engl J Med. 2013;368(2):138-148. 2. Rathkopf DE, et al. J Clin Oncol. 2013;31(Suppl 6): Abstract 5.
Enzalutamide, an AR Signaling Inhibitor: 
Targets Multiple Steps in the (AR) Signaling 
Pathway 
A 
1. Competitively 
inhibits androgen 
binding to AR 
2. Impairs AR 
nuclear 
translocation 
3. Inhibits AR 
interaction with DNA 
A 
AR 
Cell cytoplasm 
Cell nucleus AR 
Tran C, et al. Science. 2009;324(5928):787-790.
AFFIRM Study Design: 
Phase III Post-Docetaxel 
Phase 3, double-blind placebo-controlled trial of enzalutamide 
versus placebo in mCRPC post-chemotherapy 
Enzalutamide 160 mg QD 
n = 800 
Efficacy end points (ITT) 
Primary endpoint: 
• OS 
Secondary endpoints: 
• PSA response 
• Time to PSA progression 
• rPFS 
• Time to first SRE 
Placebo QD 
n = 399 
R 
A 
N 
D 
O 
M 
I 
Z 
E 
D 
2:1 
No corticosteroids required 
• 1199 patients 
with progressive 
mCRPC 
• Failed 1 or 2 
chemotherapy 
regimens, 1 of 
which contained 
docetaxel 
Scher HI, et al. N Engl J Med. 2012;367(13):1187-1197
% OAS 
AFFIRM Overall Survival: 
Median of 4.8 Months 
HR = 0.631 (95% CI: 0.529, 0.752) P < .0001 
37% reduction in risk of death 
Enzalutamide: 18.4 months 
(95% CI: 17.3, NYR) 
Placebo: 13.6 months 
(95% CI: 11.3, 15.8) 
0 3 6 9 12 15 18 21 24 
100 
90 
80 
70 
60 
50 
40 
30 
20 
10 
0 
Duration of Overall Survival, months 
Enzalutamide 800 775 701 627 400 211 72 7 0 
Placebo 399 376 317 263 167 81 33 3 0 
Scher HI, et al. N Engl J Med. 2012;367(13):1187-1197.
PREVAIL Phase III Trial: Enzalutamide 
Pre-Docetaxel CRPC: 
1717 
Patients 
with CRPC 
Enzalutamide 
160 mg/d 
Placebo 
• Radiographic PFS 
• OAS 
NEJM, 01 JUNE 2014
PREVAIL Trial: 
Effect on Radiographic PFS: 
Rate PFS at 12 months 
65% vs 14% 
NEJM, 01 JUNE 2014
• Reduction of Risk of 
death by 29%. 
• mOAS: 32.4 vs 30.2 
months. 
• CTH Delay by 17 
months. 
PREVAIL Trial: 
Effect on OAS: 
NEJM, 01 JUNE 2014
ALLIANCE TRIAL: Co-Targeting 
Androgen Receptor & Biosynthesis: 
• 1224 pts. 
• Progressive 
Metastatic CRPC. 
• No Prior Taxanes 
Enzalutamide 160 mg 
QD 
Enzalutamide 160 mg 
QD 
Aberaterone 1000 mg 
QD 
Prednisone 5 mg bid 
2 
1 
OAS 
Clinicaltrials.gov:/01949337
Subsequent Hormonal Therapies 
Following ADT: Data From Last ASCO: 
• Gleason Score: No 
• Duration of Response to Previous ADT: 
Better Response to Subsequent Hormonal Therapy if: 
 PSA Control > 12 months. 
 Longer PFS. 
• Aberaterone or Enzalutamide First? 
Enz  Abt Abt  Enz 
PSA ↓ 50% 3% 29% 
PSA ↓30% 11% 37%
Metastatic 
Castration Resistant 
Symptomatic 
First Line 
Category 1 
• Docetaxel 
• Radium-223‡ 
Nonmetastatic 
Local 
Therapy 
Castration 
Hormone 
Therapy Asymptomatic or 
Minimally Symptomatic 
Category 1 
• Sipuleucel-T* 
• Abiraterone acetate 
Symptomatic 
Second Line 
Category 1: 
Post-Docetaxel 
• Abiraterone acetate 
• Enzalutamide 
• Cabazitaxel 
• Radium-223‡ 
Category 2A 
• Sipuleucel-T* 
• Salvage chemotherapy 
• Docetaxel rechallenge 
• Mitoxantrone 
• Secondary hormonal 
therapy 
• Clinical trial 
• Best supportive care 
Category 2A 
• Secondary 
hormonal therapy 
• Docetaxel† 
• Clinical trial 
Category 2A 
• Mitoxantrone§ 
• Abiraterone acetate§ 
• Enzalutamide§ 
• Palliative radiotherapy׀׀ 
• Clinical trial 
• Best supportive care 
Bone Health: Denosumab, ZoledronicAcid 
*For asymptomatic or minimally symptomatic mCRPC with ECOG PS 0/1, no hepatic metastases, and life expectancy 
≥6 months. †May be considered for rapid progression or hepatic metastases despite lack of symptoms. ‡For symptomatic 
mCRPC with bone metastases; not approved in combination with chemotherapy. §For patients who are not candidates for 
docetaxel-based regimens. ׀׀For symptomatic mCRPC with bone metastases. 
National Comprehensive Cancer Network Guidelines in Oncology (NCCN Guidelines®)—Prostate Cancer. V.2.2014. Available at: http://www.nccn.org. AccessedMay 15, 2014.
Take Home Message: 
• Unequivocal evidence of continued 
involvement of AR signaling axis. 
• We need to better understand prostate cancer 
heterogeneity. 
• Broad array of therapeutic options. 
• Non – Cytotoxic therapies are now of interest 
before chemotherapy administration. 
• Evaluate for the best sequence  Biomarker 
Studies.
Thank You

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Sequencing therapy for crcp a practical approach

  • 1. Sequencing Therapy for CRPC: A Practical Approach. Mohamed Abdulla M.D. Prof. of Clinical Oncology Kasr Al-Aini School of Medicine Cairo University SUN – Genitourinary Cancer Meeting Radisson Blue Hotel – Alexandria 07/11/2014
  • 2. Basic Facts & Figures: • Increasing Incidence: Aging and Screening Programs. • 2nd Most Common Cancer in Men. • 1/6 Men. • African Americans – Black Races, • Rare Before Age of 40 and then Readily Rises. • Prostate Cancer is an Androgenic Disease Circulating Androgens & Androgen Receptors. Uptodate.com 06/02/2014
  • 3. Prostate Cancer is an Androgenic Disease: “Androgen Synthesis” Hypothalamus LHRH LH Pituitary ACTH Testes Supra-renal Testosterone
  • 4. Prostate Cancer is an Androgenic Disease: “Androgen Receptor Structure” Mineralocorticoid Glucocorticoid HSP NTD DBD Hinge LBD Nuclear & Steroid Superfamily Androgen Estrogen Progesterone Constitutively Active DNA Promoter Gene N/C Androgens
  • 5. Prostate Cancer is an Androgenic Disease: “Androgen Receptor Activity” 5@ Reductase Genomic Activity PSA, IGF, …
  • 6. Prostate Cancer is an Androgenic Disease: “Androgen Receptor Activity” Testosterone 5 α Reductase DHT + AR (LBD) AR Activation & Dimerization Non Genomic Activity PI3K Caveolae RTK GPCR HSP AKT Src MAPK ERK1/2 Nuclear Transcription Factors • Proliferation, Angiogenesis, … • No AR Degradation.
  • 7. Androgen Androgen Receptors Perfect Disease Control • Surgical Castration. • Medical Castration. • Blocking Receptors.
  • 9. Androgen Receptor in Prostate Cancer:
  • 10. Steroidogenesis & Prostate Cancer : Cholesterol CYP 11A1 Pregnenolone CYP 17A1 Testosterone ASS
  • 11. Castrate Resistant Prostate Cancer: Prognostic Factors: 1. Site of Metastases: 5 RCTs: OAS 0 5 10 15 20 25 30 LNs Bone Lungs Liver Months Halabi et al. Journal of Clinical Oncology, 2014 ASCO Annual Meeting Abstracts. Vol 32, No 15_suppl (May 20 Supplement), 2014: 5002
  • 12. Castrate Resistant Prostate Cancer: Prognostic Factors: Halabi et al. J Clin Oncol 32:671-677. © 2014
  • 13. Cabazitaxel7* Zoledronic Acid4 Mitoxantrone3 Docetaxel5,6* 1984-1989 Sipuleucel-T8* 1996 2002 2004 .... 2010 Denosumab9 Abiraterone10* Enzalutamide11* 2011 Radium 223? 2012 ...but this rapid change has left many unanswered questions, including the optimal selection and sequence of therapy LHRH agonists1* Reversible AR blockers2 1. The Leuprolide Study Group. N Engl J Med. 1984;311(20):1281-1286. 2. Crawford ED, et al. N Engl J Med. 1989;321(7):419-424. 3. Tannock I et al. J Clin Oncol. 1996;14(6):1756-1764. 4. Saad F, et al. J Natl Cancer Inst. 2002;94(19):1458-1468. 5. Petrylak DP, et al. N Engl J Med. 2004;351(15):1513-1520. 6. Tannock I, et al. N Engl J Med. 2004;351(15):1502-1512. 7. de Bono JS, et al. Lancet. 2010;376(9747):1147-1154. 8. Kantoff P, et al. N Engl J Med. 2010;363(5):411-422. 9. Fizazi K, et al. J Clin Oncol. 2009;27(10)1564-1571. 10. de Bono JS, et al. N Engl J Med. 2011;364(21):1995-2005. 11. Scher HI, et al. N Engl J Med. 2012;367(13):1187-1197.
  • 14. • Pain • Bone vs visceral metastases • Performance status • Neuropathy • Comorbidity • “Early or late” CRPC • Prior therapy exposure and response • Response biomarkers • Tumor characteristics CRPC, castration-resistant prostate cancer
  • 15. Management of CRPC: 1. ADT should be continued. 2. Choose between therapies associated with survival benefit.
  • 16. COU-AA-301 Study Design Phase III Post-Docetaxel Phase 3, double-blind placebo-controlled trial of abiraterone + prednisone versus placebo + prednisone in mCRPC post-chemotherapy Abiraterone 1000 mg QD Prednisone 5 mg BID n = 797 Primary endpoint: • OS Secondary endpoints: • PSA response • Time to PSA progression • rPFS Placebo QD Prednisone 5 mg BID n = 398 R A N D O M I Z E D 2:1 • 1195 patients with progressive mCRPC • Failed 1 or 2 chemotherapy regimens, 1 of which contained docetaxel de Bono JS, et al. N Engl J Med. 2011;346(21):1995-2005.
  • 17. Overall Survival, % 100 80 60 40 20 0 AA + P: Placebo + P: 0 6 24 30 12 18 Time to Death, months AA + P 797 657 473 Placebo + P 398 306 183 273 15 0 100 6 0 AA, abiraterone acetate; CI, confidence interval; P, prednisone HR = 0.74 (95% CI,0.638-0.859) P<.0001 26% reduction in risk of death Median follow-up: 20.2 months Fizazi K, et al. Lancet Oncol. 2012;13(10):983-992.
  • 18. Variable Subgroup N HR 95% CI All subjects All 1195 0.66 0.56-0.79 Baseline ECOG 0-1 1068 0.64 0.53-0.78 2 127 0.81 0.53-1.24 Baseline BPI < 4 659 0.64 0.50-0.82 ≥ 4 536 0.68 0.53-0.85 1 833 0.63 0.51-0.78 2 362 0.74 0.55-0.99 Type of progression PSA only 363 0.59 0.42-0.82 Radiographic 832 0.69 0.56-0.84 Age, years < 65 0.66 0.48-0.91 ≥ 65 0.67 0.55-0.82 Visceral disease at entry Yes 353 0.70 0.52-0.94 Baseline PSA above Yes 591 0.65 0.52-0.81 median Yes 581 0.71 0.58-0.88 Yes 587 0.60 0.48-0.74 Region N America 652 0.64 0.51-0.80 Other 543 0.69 0.54-0.90 0.5 0.75 1 1.5 Favors abiraterone Favors placebo No of prior chemotherapy regimens Baseline LDH above median Baseline ALK-P above median de Bono JS, et al. N Engl J Med. 2011;364(21):1995-2005.
  • 19. COU-AA-302 Study Design Phase III Pre-Docetaxel Phase 3, double-blind placebo-controlled trial of abiraterone + prednisone versus placebo + prednisone in mCRPC pre-chemotherapy Abiraterone 1000 mg QD + Prednisone 5 mg BID n = 546 Co-Primary endpoints: • OS • rPFS Placebo BID + Prednisone 5 mg BID n = 542 R A N D O M I Z E D 1:1 • 1088 progressive chemonaïve patients with mCRPC • Asymptomatic or mildly symptomatic Ryan CJ, et al. N Engl J Med. 2013;368(2):138-148.
  • 20. COU-AA-302: rPFS HR = 0.53 (95% CI, 0.45-0.62) P<.001 47% reduction in risk of progression Abiraterone + prednisone, 16.5 months Prednisone alone, 8.3 months Progression-Free Survival, % 110 – 80 – 60 – 40 – 20 – 0 – 0 3 6 9 12 15 18 21 24 27 30 Ryan CJ, et al. N Engl J Med. 2013;368(2):138-148.
  • 21. COU-AA-302: Updated OS Abiraterone + prednisone, Placebo + prednisone, 30.1 months Months From Randomization 35.3 months Second interim analysis: 43% death1 Third interim analysis: 56% death2 Subjects Without Death, % HR = 0.79 (95% CI, 0.66–0.95) P = .0151 Prespecified P for significance: .0035 100 80 60 40 20 0 0 3 6 9 12 15 18 21 24 27 30 33 36 1. Ryan CJ, et al. N Engl J Med. 2013;368(2):138-148. 2. Rathkopf DE, et al. J Clin Oncol. 2013;31(Suppl 6): Abstract 5.
  • 22. Enzalutamide, an AR Signaling Inhibitor: Targets Multiple Steps in the (AR) Signaling Pathway A 1. Competitively inhibits androgen binding to AR 2. Impairs AR nuclear translocation 3. Inhibits AR interaction with DNA A AR Cell cytoplasm Cell nucleus AR Tran C, et al. Science. 2009;324(5928):787-790.
  • 23. AFFIRM Study Design: Phase III Post-Docetaxel Phase 3, double-blind placebo-controlled trial of enzalutamide versus placebo in mCRPC post-chemotherapy Enzalutamide 160 mg QD n = 800 Efficacy end points (ITT) Primary endpoint: • OS Secondary endpoints: • PSA response • Time to PSA progression • rPFS • Time to first SRE Placebo QD n = 399 R A N D O M I Z E D 2:1 No corticosteroids required • 1199 patients with progressive mCRPC • Failed 1 or 2 chemotherapy regimens, 1 of which contained docetaxel Scher HI, et al. N Engl J Med. 2012;367(13):1187-1197
  • 24. % OAS AFFIRM Overall Survival: Median of 4.8 Months HR = 0.631 (95% CI: 0.529, 0.752) P < .0001 37% reduction in risk of death Enzalutamide: 18.4 months (95% CI: 17.3, NYR) Placebo: 13.6 months (95% CI: 11.3, 15.8) 0 3 6 9 12 15 18 21 24 100 90 80 70 60 50 40 30 20 10 0 Duration of Overall Survival, months Enzalutamide 800 775 701 627 400 211 72 7 0 Placebo 399 376 317 263 167 81 33 3 0 Scher HI, et al. N Engl J Med. 2012;367(13):1187-1197.
  • 25. PREVAIL Phase III Trial: Enzalutamide Pre-Docetaxel CRPC: 1717 Patients with CRPC Enzalutamide 160 mg/d Placebo • Radiographic PFS • OAS NEJM, 01 JUNE 2014
  • 26. PREVAIL Trial: Effect on Radiographic PFS: Rate PFS at 12 months 65% vs 14% NEJM, 01 JUNE 2014
  • 27. • Reduction of Risk of death by 29%. • mOAS: 32.4 vs 30.2 months. • CTH Delay by 17 months. PREVAIL Trial: Effect on OAS: NEJM, 01 JUNE 2014
  • 28. ALLIANCE TRIAL: Co-Targeting Androgen Receptor & Biosynthesis: • 1224 pts. • Progressive Metastatic CRPC. • No Prior Taxanes Enzalutamide 160 mg QD Enzalutamide 160 mg QD Aberaterone 1000 mg QD Prednisone 5 mg bid 2 1 OAS Clinicaltrials.gov:/01949337
  • 29. Subsequent Hormonal Therapies Following ADT: Data From Last ASCO: • Gleason Score: No • Duration of Response to Previous ADT: Better Response to Subsequent Hormonal Therapy if:  PSA Control > 12 months.  Longer PFS. • Aberaterone or Enzalutamide First? Enz  Abt Abt  Enz PSA ↓ 50% 3% 29% PSA ↓30% 11% 37%
  • 30. Metastatic Castration Resistant Symptomatic First Line Category 1 • Docetaxel • Radium-223‡ Nonmetastatic Local Therapy Castration Hormone Therapy Asymptomatic or Minimally Symptomatic Category 1 • Sipuleucel-T* • Abiraterone acetate Symptomatic Second Line Category 1: Post-Docetaxel • Abiraterone acetate • Enzalutamide • Cabazitaxel • Radium-223‡ Category 2A • Sipuleucel-T* • Salvage chemotherapy • Docetaxel rechallenge • Mitoxantrone • Secondary hormonal therapy • Clinical trial • Best supportive care Category 2A • Secondary hormonal therapy • Docetaxel† • Clinical trial Category 2A • Mitoxantrone§ • Abiraterone acetate§ • Enzalutamide§ • Palliative radiotherapy׀׀ • Clinical trial • Best supportive care Bone Health: Denosumab, ZoledronicAcid *For asymptomatic or minimally symptomatic mCRPC with ECOG PS 0/1, no hepatic metastases, and life expectancy ≥6 months. †May be considered for rapid progression or hepatic metastases despite lack of symptoms. ‡For symptomatic mCRPC with bone metastases; not approved in combination with chemotherapy. §For patients who are not candidates for docetaxel-based regimens. ׀׀For symptomatic mCRPC with bone metastases. National Comprehensive Cancer Network Guidelines in Oncology (NCCN Guidelines®)—Prostate Cancer. V.2.2014. Available at: http://www.nccn.org. AccessedMay 15, 2014.
  • 31. Take Home Message: • Unequivocal evidence of continued involvement of AR signaling axis. • We need to better understand prostate cancer heterogeneity. • Broad array of therapeutic options. • Non – Cytotoxic therapies are now of interest before chemotherapy administration. • Evaluate for the best sequence  Biomarker Studies.