Optimal Integration of New Treatments for Castration-Resistant Prostate Cancer Dr. Sankar Srinivasan, AB, FACP Consultant Oncologist, Apollo Hospitals

1. Optimal Integration of New Treatments for
Castration-Resistant Prostate Cancer
Dr. Sankar Srinivasan, AB, FACP
Consultant Oncologist, Apollo Hospitals
Visiting Consultant, Ironwood Cancer and Research
Center, Phoenix, AZ, USA

2. Std Hormonal treatments
 Orchiectomy or Zoladex or Lupron
 Bicalutamide added for combined hormonal blockade

3. Case-1
 57-yr-old man – T3a PCa, Gleason 4+4 = 8,
PSA = 8.2 ng/mL
 Undergoes radical prostatectomy
 Develops PSA recurrence none in prostatic bed
 Started on leuprolide + bicalutamide, and responds for 18 months
 Then develops rising PSA, despite bicalutamide withdrawal
 PSAs: 4.2 → 5.6 → 7.2 ng/mL
 Testosterone: 28 ng/dL
 Bone scan and CT scan: Negative for metastatic disease
•PSADT = prostate-specific antigen doubling time; CT = computed tomography.
•NCCN, 2011.

4.  Does this patient meet criteria for CRPC?
 How would you manage this patient?

5. •HRPC Definition
Practical definition: a consecutive series of increasing
PSA levels after a nadir is reached with HT. Must
have had a trial of anti-androgen withdrawal and
must have castrate levels of testosterone
• Men with HRPC are not treated to cure their
disease but simply to improve their quality of life.
• The lack of effective treatments for HRPC leads
patients to turn to unproven therapies.

6. Overview
 Modern approaches to targeting  Autologous cellular
androgens immunotherapy: understanding
a new paradigm
– COU-AA-301 phase III study:
abiraterone – IMPACT phase III study:
sipuleucel-T
– Other androgen-targeted agents:
MDV3100 – TBC-PRO-002 phase II study:
ProstVac-VF
 The evolving role of
chemotherapy
– TAX 327 study: weekly vs 3-
weekly docetaxel vs
mitoxantrone
– TROPIC phase III study: second-
line cabazitaxel

7. Modern Approaches to
Targeting Androgens

8. Androgen Receptor Addiction Is a Hard Habit to
Break
 Hormonal treatments continue to have antitumor activity
 High levels of intratumoral androgens despite castration
– Preclinical and clinical evidence of intracrine synthesis
 Castration resistance associated with
– AR amplification (increased gene dose)
– AR mutations that increase AR (transcriptional) activity
– ↑ AR (< 2x) expression (ligand driven) in isogenic resistant lines
 Identification of oncogenic translocations/fusions driven by
androgens + estrogen-response elements (ETS genes;
TMPRSS2/ERG in 50% to 70% of prostate cancer)
Attard G, et al. Cancer Cell. 2009;16:458-462.

9. Abiraterone Acetate: Androgen Biosynthesis
Inhibitor
 Androgens produced at 3 critical sites lead to tumor
proliferation
– Testes
– Adrenal gland
– Prostate tumor cells
 Abiraterone inhibits biosynthesis of androgens that
stimulate tumor cell growth
 PSA and radiographic responses in phase I/II studies
– Chemotherapy-naive and postchemotherapy patients[1-5]
1. Attard G, et al. J Clin Oncol. 2008;26:4563-4571. 2. Attard G, et al. J Clin Oncol. 2009;27:3742-3748.
3. Reid AH, et al. J Clin Oncol. 2010;28:1489-1495. 4. Ryan C, et al. J Clin Oncol. 2010;28:1481-1488.
5. Danila D, et al. J Clin Oncol. 2010;28:1496-1501.

10. COU-AA-301: Phase III Study of Abiraterone
Acetate in mCRPC
Randomized 2:1
Abiraterone acetate 1000 mg/day +
Patients with mCRPC Prednisone 5 mg BID
progressing after 1-2 (n = 797)
chemotherapy
Stratified by ECOG PS, worst pain
regimens,
over previous 24 hrs, previous
1 of which contained
chemotherapy, type of progression
docetaxel
Placebo +
(N = 1195)
Prednisone 5 mg BID
(n = 398)
de Bono J, et al. N Engl J Med. 2011;364:1995-2005.

11. COU-AA-301: Abiraterone Acetate Improves
OS in mCRPC
100
HR: 0.646 (95% CI: 0.54-0.77;
P < .0001)
80
Abiraterone acetate
Median OS: 14.8 mos
Survival (%)
60 (95% CI: 14.1-15.4)
40
Placebo
Median OS: 10.9 mos
20 (95% CI: 10.2-12.0)
Median OS with 2 prior chemo: Median OS with 1 prior chemo
14.0 mos AA vs 10.3 mos placebo 15.4 mos AA vs 11.5 mos placebo
0
0 3 6 9 12 15 18 21
Months
AA 797 736 657 520 282 68 2 0
de Bono J, et al. N Engl J Med. 355
Placebo 398 2011;364:1995-2005.
306 210 105 30 3 0
Copyright © 2011 Massachusetts Medical Society. All rights reserved.

12. COU-AA-301: All Secondary Endpoints
Achieved Statistical Significance
Endpoint Characteristic Abiraterone Placebo HR P Value
(n = 797) (n = 398) (95% CI)
Time to PSA 10.2 6.6 0.58 < .0001
progression, mos (0.46-0.73)
rPFS, mos 5.6 3.6 0.67 < .0001
(0.59-0.78)
PSA response rate, %
 Total 38.0 10.1 < .0001
 Confirmed 29.1 5.5 < .0001
de Bono J, et al. N Engl J Med. 2011;364:1995-2005.
Copyright © 2011 Massachusetts Medical Society. All rights reserved.

13. COU-AA-301: Adverse Events of Special
Interest
Abiraterone Placebo
Adverse Event, % (n = 791) (n = 394)
All Grades Grades 3/4 All Grades Grades 3/4
Fluid retention 30.5 2.3 22.3 1.0
Hypokalemia 17.1 3.8 8.4 0.8
LFT abnormalities 10.4 3.5 8.1 3.0
Hypertension 9.7 1.3 7.9 0.3
Cardiac disorders 13.3 4.1 10.4 2.3
de Bono J, et al. N Engl J Med. 2011;364:1995-2005.

14. MDV3100: Phase I/II Study in Advanced
Prostate Cancer[1]
 MDV3100: novel, oral AR
antagonist
– Blocks testosterone binding to AR, Testosterone synthesis
impedes movement of AR to Tumor death
nucleus, inhibits DNA binding Testosterone
T T
– Slows tumor growth and X MDV3100
causes cell death in cancers DNA binding and AR 1 AR binding
resistant to bicalutamide 3 activation blocked
blocked
X X 2 Nuclear
 Phase I/II trial conducted to Cell nucleus translocation
determine safety, PK, and No prednisone impaired
antitumor activity of MDV3100[2] required
– Cohorts treated with
– N = 140 patients with progressive sequentially escalating doses
CRPC, pre- or postchemotherapy of MDV3100 (30-600 mg/day)
1. Higano CS, et al. ASCO GU 2011. Abstract 134. 2. Scher HI, et al. Lancet. 2010;375:1437-1446.

15. Long-term Follow-up of MDV3100: Antitumor
Activity
 MDV3100 antitumor activity durable both before and
after chemotherapy
Outcome Chemotherapy Post
Naïve Chemotherapy
(n = 65) (n = 75)
≥ 50% PSA decline from baseline, % 62 51
Median time to PSA progression, days
Per protocol* NYR 316
PCCTWG 2 criteria† 281 148
Median time to radiographic progression,
days increase in PSA from baseline with increase ≥ 5 ng/mL 392 175
*≥ 25%
†
≥ 25% increase in PSA from nadir with increase ≥ 2 ng/mL
Higano CS, et al. ASCO GU 2011. Abstract 134.

16. Conclusion: Targeting Androgens
 Advanced prostate cancer is neither hormone
refractory nor androgen independent and remains
nuclear steroid receptor driven
– Hormone therapy works after chemotherapy
 CYP17 blockade does not cause adrenal insufficiency
 Multiple lines of treatment available for advanced
prostate cancer
– Sipuleucel-T, docetaxel, abiraterone, cabazitaxel
– The optimal sequence of administration now needs to
be defined

17. Evolving Role of Chemotherapy in the
Management of Castration-Resistant
Metastatic Prostate Cancer

18. TAX 327: Weekly vs 3-Weekly Docetaxel vs
Mitoxantrone in CRPC—OS
1.0 Docetaxel 3-weekly
Docetaxel weekly
Mitoxantrone
0.8
Proportion Alive
0.6
0.4
0.2
0
Berthold DR, et al.0 Clin Oncol. 2008;26:242-245.
J 1 2 3 4 5 6 7
Reprinted with permission. © 2008 American Society of Clinical Oncology. All
rights reserved.
Time (years)

19. Docetaxel-Based Therapy in CRPC:
Observations From Long-term Follow-up
 After 5 yrs of follow-up, 867 deaths (86% of 1006 patients) have
occurred
 Median OS difference between every-3-wk docetaxel and
mitoxantrone groups remains highly significant (P = .004)
Outcome Every-3-Wk Weekly Mitoxantrone/
Docetaxel/ Docetaxel/ Prednisone
Prednisone Prednisone (n = 337)
(n = 335) (n = 334)
Median OS, mos 18.9 17.4 16.5
3-yr OS, % 18.6 16.8 13.5
Berthold DR, et al. J Clin Oncol. 2008;26:242-245.

20. Cabazitaxel: A Novel Tubulin-Targeting Agent
 Selected to overcome the emergence of taxane resistance
 Preclinical data
– Potency equivalent to docetaxel against sensitive cell lines and tumor models
– Evidence of activity against tumor cells/models resistant to currently available
taxanes
 Early clinical data from phase I studies demonstrated:
– Dose-limiting toxicity: neutropenia
– Activity in patients with metastatic CRPC
– Moved from phase I to phase III development in a series of trials in a variety of
epithelial neoplasms
Pivot X, et al. Ann Oncol. 2008;19:1547-1552.
Mita AC, et al. Clin Can Res. 2009;15:723

21. TROPIC: Phase III Registration Trial of
Second-line Cabazitaxel in CRPC
Stratified by ECOG PS
(0,1 vs 2) and measurable vs
nonmeasurable disease
Mitoxantrone 12 mg/m2 IV q3w +
Prednisone 10 mg/day PO for 10 courses
Patients with (n = 377)
metastatic
CRPC progressing
on docetaxel Cabazitaxel 25 mg/m2 IV q3w +
Prednisone 10 mg/day PO for 10 courses
(N = 755) (n = 378)
 Primary endpoint: OS
 Secondary endpoints: PFS, response rate, safety
de Bono JS, et al. Lancet. 2010;376:1147-1154 .

22. TROPIC: Main Eligibility Criteria
 mCRPC patients with documented disease
progression
– Measurable by RECIST or
– Nonmeasurable: documented rising PSA levels (≥ 2
consecutive rises in PSA over a reference value taken at
least 1 week apart) or appearance of new lesion
 Previous treatment with a docetaxel-containing
regimen
 No previous treatment with mitoxantrone
 ECOG PS: 0-2
 Normal organ function (CBC and serum chemistries)
de Bono JS, et al. Lancet. 2010;376:1147-1154 .

23. TROPIC: Preprotocol Treatment
Previous Treatment Mitoxantrone/Prednisone Cabazitaxel/Prednisone
(n = 377) (n = 378)
Chemotherapy, n (%)
 1 regimen 268 (71) 260 (69)
 2 regimens 79 (21) 94 (25)
 ≥ 3 regimens 30 (8) 24 (6)
Docetaxel, n (%)
 1 regimen 327 (87) 316 (84)
 2 regimens 43 (11) 53 (14)
 ≥ 3 regimens 7 (2) 9 (2)
Median total previous 529.2 576.6
docetaxel dose, mg/m2 (range) (380.9-787.2) (408.4-761.2)
Median time from last 0.70
docetaxel dose to progression, (0-2.9) 0.80
mos (range) (0-3.1)
de Bono JS, et al. Lancet. 2010;376:1147-1154 .

24. TROPIC: OS (Updated ITT Analysis)
Survival MP CBZP
Median OS, mos 12.7 15.1
HR 0.72
95% CI 0.61-0.84
P value < .0001
Combined median follow-up: 13.7 mos
de Bono JS, et al. ASCO 2010. Abstract 4508. de Bono JS, et al. Lancet. 2010;376:1147-1154.

25. TROPIC: Treatment-Emergent
Grade 3/4 Adverse Events
Treatment-Emergent Grade 3/4 Mitoxantrone/ Cabazitaxel/
Adverse Events,* % Prednisone Prednisone
(n = 371) (n = 371)
Any adverse event 39.4 57.4
 Febrile neutropenia 1.3 7.5
 Diarrhea 0.3 6.2
 Fatigue 3.0 4.9
 Back pain 3.0 3.8
*Sorted by ≥ 2% incidence rate for grade ≥ 3 events in the cabazitaxel arm.
de Bono JS, et al. ASCO 2010. Abstract 4508 .

26. Cabazitaxel: Evolving Clinical Issues
 Following FDA approval, the first wave of patients
treated were more heavily pretreated than would be
expected over time
– Effect of dose/toxicity
 Many important questions remain undefined
– Optimal dose
– Growth factors?
– Cabazitaxel vs docetaxel retreatment
– Upcoming clinical trials

27. Ongoing Cabazitaxel Clinical Trials:
Phase III PROSELICA Study
 Cabazitaxel 20 mg/m² vs 25 mg/m² for the treatment of
patients with metastatic castration-resistant prostate
cancer and prior treatment with docetaxel
– Both doses administered with prednisone
 Primary objective: overall survival
ClinicalTrials.gov. NCT01308580.

28. Ongoing Cabazitaxel Clinical Trials:
Phase III FIRSTANA Study
 Cabazitaxel vs docetaxel for the treatment of patients
with metastatic castration-resistant prostate cancer
and no prior chemotherapy
– Cabazitaxel 25 mg/m2 and 20 mg/m2 evaluated
– Cabazitaxel and docetaxel both given with prednisone
 Primary objective: overall survival
ClinicalTrials.gov. NCT01308567.

29. Autologous Cellular Immunotherapy:
Understanding
a New Paradigm
•

30. Active Cellular Immunotherapy
(Sipuleucel-T)
Patient’s white blood
cells harvested
Short-term culture with protein
“cassette”
GM-CSF
Prostatic acid
phosphatase
(PAP)
Shipping
Cells infused back into
patient (IV)

31. Immunotherapy for Prostate Cancer:
Mechanism(s) of Action
CD4+ T cell
Activated
TCR
dendritic
cell
Class II MHC Cytokine
s
TCR
Tumor antigen Antibodies: circulate in sera
Class I MHC bind to tumor cells
CD8 T cell
Activated CD8+ T cells: traffic
to tumor, lyse tumor cells

32. IMPACT: Phase III Study
Physician’s
P discretion,
Patients with R
Placebo including
metastatic,
asymptomatic or q2w x 3 O phase II
G open-label
minimally
R sipuleucel-T*
symptomatic CRPC,
2:1 study
no visceral E
metastases S
Sipuleucel-T S Physician’s
(N = 512)
q2w x 3 I discretion
O
N
 Primary endpoint: OS
 Secondary endpoint: TTP
*Prepared using cryopreserved
peripheral blood lymphocytes
Kantoff PW, et al. N Engl J Med. 2010;363:411-422.

33. IMPACT: Baseline Characteristics
 Key Inclusion Criteria
– Metastatic and castrate resistant
– Asymptomatic or minimally symptomatic
– Prior chemotherapy permitted
 Selected Patient Characteristics
– Median age: 71
– Median PSA: 50 ng/mL
– Hemoglobin: 12.8 g/dL
– Bone-only disease: 50%
– Bone and soft-tissue disease: 44%
Kantoff PW, et al. N Engl J Med. 2010;363:411-422. •

34. IMPACT Study: OS (ITT Population)
P = .032 (Cox model)
100 HR: 0.775 (95% CI: 0.614-0.979)
Median survival benefit: 4.1 mos
Patients Remaining
75
Alive (%)
50 Sipuleucel-T (n = 341)
Median survival: 25.8 mos
25 Placebo (n = 171)
Median survival: 21.7 mos
0
0 6 12 18 24
30 36 42 48 54 60 66
Survival (Mos)
Kantoff PW, et al. N Engl J Med. 2010;363:411-422.
Copyright © 2010. Massachusetts Medical Society. All rights reserved.

35. IMPACT: Results
 Clinical Outcomes
– TTP not significantly different between arms
– 1 objective response (in active treatment group)
– Extensive subgroup analyses were inconclusive
Adverse Event, % Sipuleucel-T Placebo
Chills 54 13
Pyrexia 29 14
Headache 16 5
Kantoff PW, et al. N Engl J Med. 2010;363:411-422.

36. Another Cancer Vaccine Approach:
ProstVac-VF Costimulatory
Molecules
PSA
LFA ICAM- B7-1
Target -3 1
antigen Vaccinia virus
Fowlpox virus
Plasmid
DNA
Packaging
cell line
rV-PSA-TRICOM
rF-PSA-TRICOM
Vaccine

37. TBC-PRO-002: Phase II ProstVac-VF Study
—OS
HR: 0.56 (95% CI: 0.37-0.85)
100
n Deaths Median OS, mo
Control 40 37 16.6
80
ProstVac-VF 82 65 25.1
rV-PSA ->
60 rF-PSA
OS (%)
40
20
0
0 12 24 36 48 60
Mos
Kantoff PW, et al. J Clin Oncol. 2010;28:1099-1105.
Reprinted with permission. © 2008 American Society of Clinical Oncology. All rights
reserved.

38. Prospect Phase III Trial: ProstVac ± GM-CSF
in Metastatic CRPC
ProstVac-VF +
Patients with TRICOM + low-dose
asymptomatic adjuvant GM-CSF S
or minimally U
symptomatic R
ProstVac-VF + V
metastatic TRICOM + Standard of
Care I
CRPC adjuvant placebo V
A
(Planned No cross-over
L
N = 1200) Vector placebo +
adjuvant placebo
 Primary endpoint: OS
ClinicalTrials.gov. NCT01322490.

39. Conclusions
 Sipuleucel-T: a current treatment option
– Asymptomatic or minimally symptomatic patients
 ProstVac-VF: entering phase III prechemotherapy
 Challenges
– Sipuleucel-T: timing with regard to abiraterone
– Integration of immunotherapy with chemotherapy and
multiple other agents
– An embarrassment of riches?

40. Hormone Refractory Prostate Cancer
Multiple treatment options
– Stop oral anti-androgens
– Switch to another anti-androgen
– Steroids
– Ketoconazole
– Megestrol acetate
– Chemotherapy
– ?immunotherapy
– ?Target therapy

41. OS Benefit in Recent CRPC Trials
Trial/Agent Approved Disease State Comparator HR P Value
IMPACT[1] Chemo-naive Placebo 0.775 .032
(Sipuleucel-T CRPC
vaccine)
TAX327[2] Chemo-naive Mitoxantrone 0.76 .009
(Docetaxel) CRPC Prednisone
TROPIC[3] Post- Mitoxantrone 0.70 < .0001
(Cabazitaxel) docetaxel Prednisone
CRPC
COU-AA-301[4] Post- Placebo 0.646 < .0001
(Abiraterone acetate) docetaxel Prednisone
CRPC
1. Kantoff PW, et al. N Engl J Med. 2010;363:411-422.
2. Tannock IF, et al. N Engl J Med. 2004;351:1502-1512.
3. de Bono JS, et al. Lancet. 2010;376:1147-1154.
4. de Bono J, et al. N Engl J Med. 2011;364:1995-2005.

42.  Thanks for the attention

43. Case Study: Part 2
 Same patient – non-mCRPC
 Enrolls in phase II study or oral TAK-700 (orteronel)
 Has a PSA response lasting 6 months
 Then PSA begins to rise: 4.6 → 7.5 → 11.2 ng/mL
 Testosterone: 2 ng/dL
 CT scan repeated: Remains normal
 Bone scan: New lesions left 5th rib and L1 vertebral
body
 He remains asymptomatic – no bone pain – ECOG 0

44. Case Study: Part 2
Discussion Question
 How would you manage this patient now?

45. Case Study: Part 3
 Same patient – asymptomatic mCRPC
 Patient receives 3 infusions of sipuleucel-T
 PSA rises after 3 months, and again after 6 months
 CT scan: Para aortic lymphadenopathy (up to 3.8 cm)
 Bone scan: 2 rib, 2 vertebral, and 1 pelvic bone lesion
 Patient reports new rib and back pain (intensity 3/10)
 ECOG PS 0

46. Case Study: Part 3
Discussion Question
 How would you manage this patient now?

47. Case Study: Part 4
 Same patient – symptomatic mCRPC
 He receives docetaxel q3wks and denosumab q4wks
 Obtains PSA response and objective radiologic response
 After 8 cycles, stops docetaxel due to grade 3 neuropathy
 4 months later, he has further PSA progression
 CT: New liver lesions (up to 4 cm) and lung lesions (8 mm)
 Bone lesions: Stable
 Has persistent grade 2 peripheral neuropathy
 ECOG PS 1

48. Case Study: Part 4
Discussion Question
 How would you manage this patient now?

49. Case Study: Part 1
 57-yr-old man – T3a PCa, Gleason 4+4 = 8,
PSA = 8.2 ng/mL
 Undergoes radical prostatectomy
 Develops PSA recurrence with PSADT = 6 months
 Started on leuprolide + bicalutamide, and responds for 18
months
 Then develops rising PSA, despite bicalutamide withdrawal
 PSAs: 4.2 → 5.6 → 7.2 ng/mL
 Testosterone: 28 ng/dL
 Bone scan and CT scan: Negative for metastatic disease
•PSADT = prostate-specific antigen doubling time; CT = computed tomography.
•NCCN, 2011.

50. Case Study: Part 1
 57-yr-old man – T3a PCa, Gleason 4+4 = 8,
PSA = 8.2 ng/mL
 Undergoes radical prostatectomy
 Develops PSA recurrence with PSADT = 6 months
 Started on leuprolide + bicalutamide, and responds for 18
months
 Then develops rising PSA, despite bicalutamide withdrawal
 PSAs: 4.2 → 5.6 → 7.2 ng/mL
 Testosterone: 28 ng/dL
 Bone scan and CT scan: Negative for metastatic disease
•PSADT = prostate-specific antigen doubling time; CT = computed tomography.
•NCCN, 2011.