Optimal Integration of New Treatments for Castration-Resistant Prostate Cancer

Dr. Sankar Srinivasan, AB, FACPConsultant Oncologist, Apollo HospitalsVisiting 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 androgens

– COU-AA-301 phase III study: abiraterone

– Other androgen-targeted agents: MDV3100

The evolving role of chemotherapy

– TAX 327 study: weekly vs 3-weekly docetaxel vs mitoxantrone

– TROPIC phase III study: second-line cabazitaxel

Autologous cellular immunotherapy: understanding a new paradigm

– IMPACT phase III study: sipuleucel-T

– TBC-PRO-002 phase II study: ProstVac-VF

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

Patients with mCRPC progressing after 1-2

chemotherapy regimens,

1 of which contained docetaxel

(N = 1195)

Abiraterone acetate 1000 mg/day +Prednisone 5 mg BID

(n = 797)

Placebo +Prednisone 5 mg BID

(n = 398)

Stratified by ECOG PS, worst pain over previous 24 hrs, previous

chemotherapy, type of progression

de Bono J, et al. N Engl J Med. 2011;364:1995-2005.

Randomized 2:1

AA 797 736 657 520 282 68 2 0

Placebo 398 355 306 210 105 30 3 0

HR: 0.646 (95% CI: 0.54-0.77; P < .0001)

Placebo Median OS: 10.9 mos (95% CI: 10.2-12.0)

0 3 6 9 12 15 18 210

20

40

60

80

100

Survival (%

)

Months

Abiraterone acetate Median OS: 14.8 mos (95% CI: 14.1-15.4)

Median OS with 2 prior chemo:14.0 mos AA vs 10.3 mos placebo

de Bono J, et al. N Engl J Med. 2011;364:1995-2005.Copyright © 2011 Massachusetts Medical Society. All rights reserved.

Median OS with 1 prior chemo 15.4 mos AA vs 11.5 mos placebo

COU-AA-301: Abiraterone Acetate Improves OS in mCRPC

COU-AA-301: All Secondary Endpoints Achieved Statistical SignificanceEndpoint Characteristic Abiraterone

(n = 797)Placebo (n = 398)

HR(95% CI)

P Value

Time to PSA progression, mos

10.2 6.6 0.58(0.46-0.73)

< .0001

rPFS, mos 5.6 3.6 0.67(0.59-0.78)

< .0001

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.

COU-AA-301: Adverse Events of Special Interest

Adverse Event, %Abiraterone

(n = 791)Placebo (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.

AR

T

MDV3100: Phase I/II Study in Advanced Prostate Cancer[1]

MDV3100: novel, oral AR antagonist

– Blocks testosterone binding to AR, impedes movement of AR to nucleus, inhibits DNA binding

– Slows tumor growth and causes cell death in cancers resistant to bicalutamide

Phase I/II trial conducted to determine safety, PK, and antitumor activity of MDV3100[2]

– N = 140 patients with progressive CRPC, pre- or postchemotherapy

1. Higano CS, et al. ASCO GU 2011. Abstract 134. 2. Scher HI, et al. Lancet. 2010;375:1437-1446.

Testosterone synthesis

Tumor deathTestosterone

MDV3100

No prednisone required

AR binding blocked

Nuclear translocation impaired

Cell nucleus

DNA binding and activation blocked

T

X X

X3

2

1

– Cohorts treated with sequentially escalating doses of MDV3100 (30-600 mg/day)

Long-term Follow-up of MDV3100: Antitumor Activity MDV3100 antitumor activity durable both before and

after chemotherapy

Higano CS, et al. ASCO GU 2011. Abstract 134.

Outcome ChemotherapyNaïve

(n = 65)

PostChemotherapy

(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 392 175*≥ 25% increase in PSA from baseline with increase ≥ 5 ng/mL

†≥ 25% increase in PSA from nadir with increase ≥ 2 ng/mL

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

Berthold DR, et al. J Clin Oncol. 2008;26:242-245.Reprinted with permission. © 2008 American Society of Clinical Oncology. All rights reserved.

Proportion A

live

1.0

0.8

0.6

0.4

0.2

00 1 2 3 4 5 6 7

Time (years)

Docetaxel 3-weeklyDocetaxel weeklyMitoxantrone

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 Docetaxel/Prednisone(n = 335)

Weekly Docetaxel/Prednisone(n = 334)

Mitoxantrone/Prednisone(n = 337)

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

Cabazitaxel 25 mg/m2 IV q3w + Prednisone 10 mg/day PO for 10 courses

(n = 378)

Mitoxantrone 12 mg/m2 IV q3w + Prednisone 10 mg/day PO for 10 courses

(n = 377)Patients with metastatic

CRPC progressingon docetaxel

(N = 755)

Stratified by ECOG PS(0,1 vs 2) and measurable vs

nonmeasurable disease

TROPIC: Phase III Registration Trial of Second-line Cabazitaxel in CRPC

Primary endpoint: OS

Secondary endpoints: PFS, response rate, safety

de Bono JS, et al. Lancet. 2010;376:1147-1154de 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)de Bono JS, et al. Lancet. 2010;376:1147-1154de Bono JS, et al. Lancet. 2010;376:1147-1154..

TROPIC: Preprotocol Treatment

Previous Treatment Mitoxantrone/Prednisone(n = 377)

Cabazitaxel/Prednisone(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 docetaxel dose, mg/m2 (range)

529.2 (380.9-787.2)

576.6 (408.4-761.2)

Median time from last docetaxel dose to progression, mos (range)

0.70 (0-2.9) 0.80

(0-3.1)

de Bono JS, et al. Lancet. 2010;376:1147-1154de Bono JS, et al. Lancet. 2010;376:1147-1154..

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

Treatment-Emergent Grade 3/4 Adverse Events,* %

Mitoxantrone/Prednisone(n = 371)

Cabazitaxel/Prednisone(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

TROPIC: Treatment-EmergentGrade 3/4 Adverse Events

*Sorted by ≥ 2% incidence rate for grade ≥ 3 events in the cabazitaxel arm.

de Bono JS, et al. ASCO 2010. Abstract 4508de 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

ClinicalTrials.gov. NCT01308567.

Autologous Cellular Immunotherapy: Understanding

a New Paradigm

•

Patient’s white blood cells harvested

Short-term culture with protein “cassette”

Shipping

Cells infused back into patient (IV)

GM-CSF

Prostatic acid phosphatase (PAP)

Active Cellular Immunotherapy(Sipuleucel-T)

Immunotherapy for Prostate Cancer:Mechanism(s) of Action

CD4+ T cell

TCR

CD8 T cell

TCR

Cytokines

Activated CD8+ T cells: traffic to tumor, lyse tumor cells

Class II MHC

Class I MHC

Activated dendriticcell

Tumor antigen Antibodies: circulate in serabind to tumor cells

IMPACT: Phase III Study

Primary endpoint: OS

Secondary endpoint: TTP

Placebo q2w x 3

Sipuleucel-T q2w x 3

PROGRESSION

Physician’s discretion

Physician’s discretion, including phase II

open-label sipuleucel-T*

study

Kantoff PW, et al. N Engl J Med. 2010;363:411-422.

2:1

Patients with metastatic,

asymptomatic or minimally

symptomatic CRPC, no visceral metastases

(N = 512)

*Prepared using cryopreserved peripheral blood lymphocytes

•

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)HR: 0.775 (95% CI: 0.614-0.979)

Median survival benefit: 4.1 mos

Sipuleucel-T (n = 341)Median survival: 25.8 mos

Placebo (n = 171)Median survival: 21.7 mos

Kantoff PW, et al. N Engl J Med. 2010;363:411-422.Copyright © 2010. Massachusetts Medical Society. All rights reserved.

Patients R

emaining

Alive (%

)

100

75

50

25

0

Survival (Mos)0 6 12 18 24 30 36 42 48 54 60 66

IMPACT: Results

Clinical Outcomes

– TTP not significantly different between arms

– 1 objective response (in active treatment group)

– Extensive subgroup analyses were inconclusive

Kantoff PW, et al. N Engl J Med. 2010;363:411-422.

Adverse Event, % Sipuleucel-T Placebo

Chills 54 13

Pyrexia 29 14

Headache 16 5

Another Cancer Vaccine Approach:ProstVac-VF

PSA

LFA-3

ICAM-1

B7-1

Costimulatory Molecules

Target antigen

Plasmid DNA

Vaccinia virusFowlpox virus

rV-PSA-TRICOMrF-PSA-TRICOM

Packaging cell line

Vaccine

Kantoff PW, et al. J Clin Oncol. 2010;28:1099-1105.Reprinted with permission. © 2008 American Society of Clinical Oncology. All rights reserved.

rV-PSA ->rF-PSA

100

80

60

40

20

00 12 24 36 48 60

Mos

OS

(%

)

HR: 0.56 (95% CI: 0.37-0.85)

ControlProstVac-VF

n4082

Deaths3765

Median OS, mo16.625.1

TBC-PRO-002: Phase II ProstVac-VF Study—OS

Prospect Phase III Trial: ProstVac ± GM-CSF in Metastatic CRPC

Patients with asymptomatic or minimally symptomatic

metastatic CRPC

(Planned N = 1200)

ProstVac-VF + TRICOM + low-dose adjuvant GM-CSF

Vector placebo +adjuvant placebo

SURVIVAL

No cross-over

ProstVac-VF + TRICOM +

adjuvant placebo

Standard of Care

Primary endpoint: OS

ClinicalTrials.gov. NCT01322490.

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]

(Sipuleucel-T vaccine)

Chemo-naiveCRPC

Placebo 0.775 .032

TAX327[2]

(Docetaxel)Chemo-naive

CRPC MitoxantronePrednisone

0.76 .009

TROPIC[3]

(Cabazitaxel)Post-

docetaxel CRPC

MitoxantronePrednisone

0.70 < .0001

COU-AA-301[4]

(Abiraterone acetate)Post-

docetaxelCRPC

PlaceboPrednisone

0.646 < .0001

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.

Thanks for the attention

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

Case Study: Part 2Discussion 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 3Discussion Question How would you manage this patient now?

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 4Discussion Question How would you manage this patient now?

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.

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.