Optimal integration of new treatments for castration resistant prostate cancer

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

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

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.

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

•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.

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

Modern Approaches to
Targeting Androgens

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.

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.

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.

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.

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

Copyright © 2011 Massachusetts Medical Society. All rights reserved.

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


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.

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.

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

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

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)

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.

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

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 .

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)

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)


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.

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 .

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

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.

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


Autologous Cellular Immunotherapy:
Understanding
a New Paradigm

•

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)

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

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

 Secondary endpoint: TTP
*Prepared using cryopreserved
peripheral blood lymphocytes
Kantoff PW, et al. N Engl J Med. 2010;363:411-422.

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. •

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)
Copyright © 2010. Massachusetts Medical Society. All rights reserved.

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


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

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.

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



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?

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

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.

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
 CT scan repeated: Remains normal
 Bone scan: New lesions left 5th rib and L1 vertebral
body
 He remains asymptomatic – no bone pain – ECOG 0

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

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

Case Study: Part 3
Discussion Question

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

Case Study: Part 4
Discussion Question

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
 Bone scan and CT scan: Negative for metastatic disease
•PSADT = prostate-specific antigen doubling time; CT = computed tomography.
•NCCN, 2011.

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