Trends, Issues & Treatment in Late-Stage Prostate Cancer

Trends, Issues & Treatment in Late-Stage Prostate Cancer

Oliver Sartor, M.D.

LaBorde Professor for Cancer Research

Medical Director, Tulane Cancer Center

Tulane Medical School

New Orleans, LA

Charles B. Huggins

“Despite regressions of great magnitude, it is obvious that there are many failures of endocrine therapy to control the disease.”

Nobel Lecture

December 13, 1966

“Castrate-Refractory” Prostate Cancer

• Progressive prostate cancer despite surgical or medical castration

• Serum Testosterone (<50 ng/dL)

“Castrate-Refractory” Prostate Cancer: The Face of Change

• Many changes have occurred in our understanding of this disease– Pathophysiology

• The evolution from “hormone-refractory” and “androgen-independent”, to “castrate-refractory”

– Therapeutic options• Current Standards

• Multiple new paradigms on the rise

Pathophysiology: The Continued Importance of the Androgen Receptor

Androgen Receptor Gene Over-Expression in “Castrate-Refractory”

Prostate Cancer

Linja et al., Can Res 61:3550 2001

Tissue Androgen Levels in Benign Prostate vs. Castrated Cancer Tissue

Mohler et al., Clin Cancer Res 10:440, 2004

Shaded=Benign Clear=Castrate

Over-Expression of Enzymes in the Androgen Synthesis Pathway in Metastatic Castrate-

Refractory Prostate Cancer Cells Stanbrough et al. Cancer Res. 66:2815, 2006

Ligand-Independent Androgen Receptor Variants Derived from Splicing of Cryptic

Exons Signify CRPCHu et al. Cancer Research 69:16-22, 2009

Conclusions

• Androgen receptor signaling remains a key factor in prostate cancer growth despite castrate serum levels of testosterone

• The prostate cancer switches from a traditional endocrine paradigm to an autocrine/paracrine paradigm BUT some of the apparent mechanisms of AR activation are ligand-independent

Therapeutic Options for CRPC Today• Secondary Hormonal Manipulations

– Antiandrogen Withdrawal, Antiandrogen Administration, Adrenal Suppressives (ketoconazole), Corticosteroids (prednisone, dexamethasone, etc.), Estrogens (DES, etc.)

• External Beam Radiation Therapy• Intravenous Bone-seeking Radioisotopes

– Samarium-153 EDTMP, Strontium-89 (FDA approvals)• Bisphosphonates

– Zoledronate (FDA approval)• Chemotherapy

– Mitoxantrone, docetaxel, estramustine, cabazitaxel (FDA approvals)

• Immune Therapies– Sipuleucel T (FDA approved)

• Experimental Therapies (Clinical Trials)

Despite Many New Promising Agents, Docetaxel was, For Many Years, the only FDA Approved Chemotherapy shown to have a Survival Benefit in

CRPC

Ra

nd

om

ize

Mitoxantrone 12 mg/m2

Prednisone 10 mg q dayQ 21 days up to 10 cycles

Docetaxel 75 mg/m2

Prednisone 10 mg q dayQ 21 days up to 10 cycles

Docetaxel 30 mg/m2/wkPrednisone 10 mg q day5 on; 1 off x 6 cycles

N=1006

TAX 327

SWOG 9916

Ra

nd

om

ize

Mitoxantrone 12 mg/m2

Prednisone 5 mg bidQ 21 days

Docetaxel 60 mg/m2 d 2Estramustine 280 mg d1-5*Dexamethasone 20 mg, tid d 1 & 2

N=770

*Warfarin and aspirin

Phase III Docetaxel Studies in HRPC Demonstrating Survival Benefit

Tannock et al. N Engl J Med 2004:351;1502-1512; Petrylak et al. N Engl J Med 2004;351:1513-1520.

0%

20%

40%

60%

80%

100%

0 12 24 36 48Months

D+EM+P

# at Risk

338 336

# of Deaths

217235

Medianin Months

17.515.6

HR: 0.80 (95% CI 0.67, 0.97), p = 0.01

Overall SurvivalPetrylak et al. N Engl J Med 2004;351:1513-1520

Overall Survival: Tax 327 Tannock et al. N Engl J Med 2004:351;1502-1512

Mediansurvival Hazard

(mos) ratio P-value

Combined: 18.2 0.83 0.03D 3 wkly: 18.9 0.76 0.009D wkly: 17.3 0.91 0.3Mitoxantrone 16.4 – –

Months

Pro

bab

ilit

y o

f S

urv

ivin

g

0 6 12 18 24 36

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0. 9

1.0

Docetaxel 3 wkly

Docetaxel wkly

Mitoxantrone

New Agents in CRPC Clinical Trials (#1)

• Vaccines and immune stimulants

– PROSTVAC-VF-Tricom Vaccine (phase III in planning)

– Anti-CTLA4 (Ipilimumab phase III underway post-docetaxel)

– GMCSF• Angiogenesis inhibitors

– Lenalinomide (Revlimid phase III well underway)

– Bevacizumab (Avastin phase III negative 3/12/10)

– VEGF TRAP (Aflibercept phase III accrual completed)

• Novel Anti-Tubular Agents

– Cabazitaxel (phase III announced positive 12/09 and FDA approved June 17, 2010!)

– Ixabepalone (phase III in combination with mitoxantrone in planning post-docetaxel)

New Agents in CRPC Clinical Trials (#2)

• Newer Androgen-Signaling Targeted Therapies

– Abiraterone , Cougar phase III post-docetaxel accrual complete in 4/09 and pre-docetaxel accrual completed 5/10)

– Takeda and Tokai androgen synthesis now in trials

– AR blockade (MDV3100, Sawyers new compound)

• MDV3100 phase III underway

• Newer Signal Transduction Inhibitors

– PI3 Kinase (Exelexis XL147, Novartis BEZ235, Genentech GDC-0941, Semafore SF 1126)

– p60src and other kinases (dasatinib phase III well underway)

– Multi-kinase inhibitor (sunitinib phase III well underway)

New Agents in CRPC Clinical Trials (#3)

• Bone targeted agents

– Isotopes: radium-223 (alpharadin phase III well underway)

– Isotopes: strontium-89 (phase III underway with taxotere)

– RANK ligand: denusomab phase III accrual complete for metastases prevention vs placebo and also vs zoledronic acid for SREs (announced as positive 2/10)

• Endothelin antagonists

- Atrasentan (failed monotherapy phase III but in docetaxel combination phase III completed accrual 5/10)

- ZD4054 (Three phase III trials, one with docetaxel and 2 without (M0 and M+): All but M0 completed accrual

New Agents in CRPC Clinical Trials (#4)

• Stem cell targeted agents– Anti-Prostate stem cell antigen (PSCA), – Sonic hedgehog (IPI-926, others)

• Prostate specific surface targets– Anti-PSMA (J591, 7E11, MLN2704, others)– New generation of various aptamers and targeted

nanoparticles

• Chemotherapeutic resistance and apoptotic regulators– Anti-Clusterin (OGX-011 or custirsen) phase IIIs in

planning for both chemo-naïve and post-docetaxel– AT-101 (gossypol) phase III in planning

Selected Phase III Trials That Have Completed Accrual in Prostate Cancer

• Docetaxel/bevacizumab vs docetaxel in chemo-naïve mCRPC (CALGB)– Announced negative March 12, 2009

• XRP6258 (cabazitaxel) vs mitoxatrone post-docetaxel in mCRPC (Sanofi-Aventis)– Announced positive 12/09, presented 3/10 at ASCO GU, FDA 6/10

• Abiraterone vs prednisone post-docetaxel in mCRPC (Cougar)– Anticipated late 2010

• Denusomab vs placebo in metastases prevention in non-metastatic CRPC – Fall/Winter 2010 anticipated

• Denosumab vs zoledronate for SRE prevention in mCRPC– Announced positive 2/9/10 for SRE, presented ASCO 6/10

Selected Novel Therapeutics and Concepts in for CRPC

• New hormonal therapies– Abiraterone and MDV3100

• A new chemotherapy

– Cabazitaxel

• A new immunotherapy

– Sipuleucel-T

• A brief mention, “Stromal Targeted” therapies

Abiraterone: Potent Inhibitor of CYP17: (17-20 Lyase and 17-Alpha Hydroxylase)

Maximal PSA Declines in Abiraterone Post-Docetaxel

Reid et al. JCO 28:1489, 2010

MDV3100: A New Anti-AndrogenTran et al: Science 324:787-790, 2009

MDV3100 PSA Changes in Phase I TrialScher et al. ASCO GU, 2009, #151

PSA Declines with MDV3100 Pre- and Post-Docetaxel

Scher et al. Lancet 375:1437, 2010

Reminder

• AR targeted therapy effects PSA disproportionately to tumor volume– PSA gene has an androgen response element in

the promoter

• Effects on survival with the new AR targeted therapies are yet to be reported

Cabazitaxel:A New Tubulin-Targeting Agent

• New semi-synthetic taxane

– Selected to overcome the emergence of taxane resistance¹,²

• Preclinical data¹,²

– As potent as docetaxel against sensitive cell lines and tumor models

– Active against tumor cells/models resistant to currently available taxanes

• Clinical data

– Antitumor activity in mCRPC including docetaxel-resistant disease³

1. Attard G, Greystoke A, Kaye S, De Bono J. Pathol Biol (Paris). 2006;54(2):72-84. 2. Pivot X, Koralewski P, Hidalgo JL, et al. Ann Oncol. 2008;19(9):1547-1552. 3. Mita AC, Denis LJ, Rowinsky EK, de bono JS et al. Clin Can Res. 2009; Jan

15;15(2):723-30.

Primary endpoint = Overall Survival, Secondary endpoint = PFS, response rate and safety, interim (futility) PFS based analysis after 225 events

TROPIC: Phase 3 Study: 146 Sites, 26 Countries

Sartor et a. GU ASCO 2010

Randomization (1:1)Stratified for Measurability of Disease and ECOG PS

Randomization (1:1)Stratified for Measurability of Disease and ECOG PS

cabazitaxel 25 mg/m² q3w + Prednisone*

cabazitaxel 25 mg/m² q3w + Prednisone*

mitoxantrone 12 mg/m² q3w + Prednisone*

mitoxantrone 12 mg/m² q3w + Prednisone*

755 patients, Maximum treatment duration 10 cycles, planned 511 events to detect 25% reduction in hazard ratio, 90% power, 2 sided 5% alpha level

* Or prednisolone – 10 mg given orally daily

Hormone Resistant Metastatic Prostate Cancer Patients Previously Treated With A Taxotere Containing Regimen

Hormone Resistant Metastatic Prostate Cancer Patients Previously Treated With A Taxotere Containing Regimen

Eligibility Criteria

• mCRPC patients with documented disease progression

– If measureable: RECIST progression

– If non-measurable : Documented rising PSA levels (at least2 consecutive rises in PSA over a reference value taken at least 1 week apart ) or appearance of new lesion

• Previous treatment with at least 225 mg/m2 docetaxel-containing regimen (protocol amended)

• No previous treatment with mitoxantrone

• ECOG-PS: 0–2

• Normal organ function (CBC and serum chemistries)

• No grade 2 or worse neuropathies

MP (n=377) CBZP (n=378)

Age (years)

Median [range] 67 [47–89] 68 [46–92]≥65 (%) 57.0 64.9

ECOG PS (%)

0, 1 91.2 92.62 8.8 7.4

PSA* (ng/mL)

Median [range] 127.5 [2–11220] 143.9 [2–7842]Measurability of disease (%)

Measurable 54.1 53.2Non-measurable 45.9 46.8

Disease site (%)

Bone 87.0 80.2Lymph node 44.8 45.0Visceral 24.9 24.9

Summary of Patient Characteristics

Pre-Protocol Treatments MP (n=377) CBZP (n=378)

Chemotherapy (%)

1 regimen 71.1 68.82 regimens 21.0 24.9≥3 regimens 8.0 6.3

Docetaxel-containing regimens administered (% patients)

1 regimen 86.7 83.62 regimens 11.4 14.0≥3 regimens 1.9 2.4

Total prior docetaxel dose (mg/m²)

Median 529.2 576.6Months from last docetaxel dose to progression

Median 0.70 0.80

Pre-Protocol Treatments

MP (n=377) CBZP (n=378)

Total prior docetaxel dose

Median (mg/m²) 529.2 576.6

Median cycles 7 7

% of patients per docetaxel dose

<225 mg/m² 8.0 7.7

≥225 to 450 mg/m² 29.7 24.9

≥450 to 675 mg/m² 27.9 29.6

≥675 to 900 mg/m² 15.1 19.6

≥900 mg/m² 18.0 17.5

Unknown 1.3 0.8

Primary Endpoint: Overall Survival (ITT Analysis)

MP 377 300 188 67 11 1

CBZP 378 321 231 90 28 4Number

at risk

Proportionof OS (%)

80

60

40

20

0

100

0 months 6 months 12 months 18 months 24 months 30 months

Median OS

0.59–0.8395% CI

<.0001P-value

0.70Hazard Ratio

CBZPMP

12 .7 15.1

Sartor et al. GU ASCO, 2010

35

Subgroup Overall Survival Analysis

Factor Hazard Ratio (95% CI)

All patients 0.69 (0.57 – 0.84)

ECOG status: 0,1 0.68 (0.57 – 0.82)

ECOG status: 2 0.81 (0.48 – 1.38)

Measurable disease: No 0.72 (0.55 – 0.93)

Measurable disease: Yes 0.68 (0.54 – 0.85)

No of prior chemo: 1 0.71 (0.54 – 0.93)

No of prior chemo: >=2 0.68 (0.54 – 0.86)

Age: < 65 0.81 (0.61 – 1.08)

Age: >=65 0.62 (0.50 – 0.78)

Country: Europe 0.68 (0.53 – 0.86)

Country: North America 0.59 (0.43 – 0.82)

Country: Other country 1.00 (0.65 – 1.54)

Pain: no 0.57 (0.43 – 0.77)

Pain: Yes 0.76 (0.59 – 0.98)

Rising PSA: No 0.87 (0.59 – 1.29)

Rising PSA: Yes 0.65 (0.53 – 0.82)

Hazard Ratio0 1 2

Favors CBZ

Subgroup Overall Survival AnalysisCategory Factor Hazard Ratio (95% CI)

ITT population All Patients 0.69 (0.57 – 0.84)

Last taxotere to random < 6 months 0.78 (0.62 – 0.97)

Last taxotere to random >=6 months 0.66 (0.46 – 0.96)

Total taxotere dose < 225 mg/m2 0.96 (0.46 – 2.03)

Total taxotere dose >= 225 to 450 mg/m2 0.61 (0.43 - 0.88)

Total taxotere dose >= 450 to 675 mg/m2 0.80 (0.56 – 1.16)

Total taxotere dose >= 675 to 900 mg/m2 0.73 – (0.46 – 1.13)

Total taxotere dose >= 900 mg/m2 0.49 (0.31 – 0.79)

Progression During last taxotere treatment

0.67 (0.47 – 0.96)

Progression Within first 3 monthssince last taxotere dose

0.69 (0.52 – 0.91)

Progression Between 4th & 6th month since last taxotere dose

0.82 (0.48 – 1.40)

Progression More than 6 months since 0.73 (0.35 – 1.53)

Hazard Ratio0 1 2 3

Favors CBZ

Progression-Free Survival

Pro

por

tion

of

PF

S (

%)

377378

5592

1218

61

41

100

80

60

40

20

0Time (months)0 6 12 18 213 9 15

117168

3055

96

25% reduction in risk of progression

MP CBZP

Median PFS (months) 1.4 2.8

Hazard ratio 0.75

95% CI 0.65–0.87

P-value 0.0002

Numberat Risk

MP CBZP

CensoredMPCBZP

Combined medianfollow-up: 13.7 months

Secondary Endpoints:Response Rate and Time to Progression

MP (n=377) CBZP (n=378) Hazard ratio (95% CI) P-value

Tumor assessment

Response rate* (%) 4.4 14.4 – .0005

Median TTP (months) 5.4 8.8 0.61 (0.49–0.76) <.0001

PSA assessment

Response rate* (%) 17.8 39.2 – .0002

Median TTP (months) 3.1 6.4 0.75 (0.63–0.90) .001

Pain assessment

Response rate* (%) 7.8 9.2 – .6286

Median TTP (months) NR 11.1 0.91 (0.69–1.19) .5192

*Determined only for subjects with at baseline measurable disease, PSA ≥20 ng/ml, or pain, respectively. NR=Not reached.

Exposure: Median 6 cycles CBZ vs 4 cycles MTZ

Mitozantrone + P(N=1736)

Cabazitaxel + P(N=2251)

Actual dose level (mg/m2) Full dose level (%) Reduced by 20% More than 20% reduction Unknown actual dose

MTX1648 (94.9) 77 (4.4) 9 (0.5) 2 (0.1)

CBZ2030 (90.2)

193 (8.6) 27 (1.2)

1 (<0.1)

Number of cycles delayed Delay 4 to 6 days Delay 7 to 9 days Delay > 9 days

28 (1.6)82 (4.7)28 (1.6)

42 (1.9)115 (5.1) 51 (2.3)

40

MP (n=371) CBZP (n=371)

All grades (%)

Grade ≥3 (%)

All grades (%)

Grade ≥3 (%)

Any adverse event 88.4 39.4 95.7 57.4

Febrile neutropenia 1.3 1.3 7.5 7.5

Diarrhea 10.5 0.3 46.6 6.2

Fatigue 27.5 3 36.7 4.9

Back pain 12.1 3 16.2 3.8

Nausea 22.9 0.3 34.2 1.9

Vomiting 10.2 0 22.6 1.9

Hematuria 3.8 0.5 16.7 1.9

Abdominal pain 3.5 0 11.6 1.9

Most Frequent Treatment-EmergentAdverse Events*

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

Hematological Results

MP (n=371) CBZP (n=371)All grades

(%)Grade ≥3

(%)All grades

(%)Grade ≥3

(%)

Hematology

Anemia 81.4 4.9 97.3 10.5

Leukopenia 92.5 42.3 95.7 68.2

Neutropenia* 87.6 58.0 93.5 81.7

Thrombocytopenia 43.1 1.6 47.4 4.0

*Prophylactic use of G-CSF was permitted except for cycle 1 of treatment at the discretion of the investigator.

58% grade ≥3 neutropenia in MP arm of the TROPIC study compares to 22% reported for the TAX 327 (first-line) study

Fatal Events—Update (cut-off date 3/10/10)

MP (n=371) CBZP (n=371)

Total deaths during study 304 (81.9%) 270 (72.8%)

Due to progression 264 (71.2%) 218 (58.8%)

Due to AE 7 (1.9%) 18 (4.9%)

Due to AE (N America, n=235) 1 (0.8%) 1 (0.9%)

Due to AE (Europe, n=402) 6 (3.0%) 10 (4.9%)

Due to other reasons 15 (4.0%) 12 (3.2%)

Cause unknown (> 3 mo following last dose)

11 (3.0%) 20 (5.4%)

FDA Package Insert on Growth Factors

• Primary prophylaxis with G-CSF should be considered for pts >65 years, poor performance status, prior febrile neutropenia, poor nutritional status, or other serious co-morbidities

Cabazitaxel Conclusion

• An effective drug fulfilling an unmet need with a safety profile that demands meticulous attention to detail in particular with careful management of neutropenia and diarrhea

• It should be reserved for patients with metastatic CRPC with progressive disease post-docetaxel and a good performance status and organ function

Immune Based Therapies

GM-CSF Induces the Greatest Anti-Tumor Immunity in Cytokine Transduced Tumor Cells

Dranoff et al, PNAS 90:3539, 1993

100

0

20

40

60

80

% T

um

or

Fre

e A

nim

als

IL- 7

GM

-CS

FIL

-3

IL-6

IL-4

SC

FG

-CS

FIL

-2 +

IL-

1

IL-2

TN

F-

IFN

-

MIF

B7-

1

M-C

SF

CD

2

IL-1

0

ICA

M-1

IL-5

MIP

-1

MIP

-1

IL-1

RA

Antigen Delivery Fusion Protein Used to Stimulate Antigen Presenting Cells

(APCs) in Preparation of Sipuleucel-T

Prostatic Acid Phosphatase (PAP)

Granulocyte MacrophaseColony Stimulating Factor

(GM-CSF)

Vaccination with Antigen (GM-CSF/PAP) Loaded Antigen Presenting Cells (APCs)

Leukapheresis

Isolation of APC

Antigen-loadedAPCs

PAP-GM-CSF“Antigen”

Patient

Randomized Phase III Trial with Sipuleucel-T (IMPACT or D9902B)

Primary endpoint: Overall SurvivalSecondary endpoint: Time to Objective Disease Progression

Asymptomatic or Minimally Symptomatic Metastatic Castrate Resistant Prostate Cancer (N=512)

Asymptomatic or Minimally Symptomatic Metastatic Castrate Resistant Prostate Cancer (N=512)

Placebo Q 2 weeks x 3

Placebo Q 2 weeks x 3

Sipuleucel-T Q 2 weeks x 3

Sipuleucel-T Q 2 weeks x 3

P R O G R E S S I O N

P R O G R E S S I O N

2:1

SURVIVAL

SURVIVAL

Treated at Physician discretion and/or Salvage Protocol

Treated at Physician discretion and/or Salvage Protocol

Treated at Physician discretion

Treated at Physician discretion

Sipuleucel T: IMPACT Phase III Trial Overall Survival

0 6 12 18 24 30 36 42 48 54 60 660

25

50

75

100

Perc

ent

Surv

ival

Survival (Months)

P = 0.032 (Cox model)HR = 0.775 [95% CI: 0.614, 0.979]Median Survival Benefit = 4.1 Mos.

Provenge (n = 341) Median Survival: 25.8 Mos.

Placebo (n = 171)Median Survival: 21.7 Mos.

Stromal Targeted Therapy

Castrate-Refractory Prostate Cancer Is a Heterogeneous Group of Diseases: Lessons

from a Rapid Autopsy Program

Shah RB, et al. Cancer Res. 2004;64:9209-9216.

Cancer Stem Cell Model

Heterogeneity and Stem Cells:The Dual Challenge of Advanced

Prostate Cancer

• How do we target cancers that are heterogeneous in both genotype and phenotype in the same patient?– Targeting a stable stroma?

• How do we kill a stem cell in patients with widespread cancer?– The critical question in oncology today!

• Destruction of “ecologic” niches that support cancer growth?????

Lessons from the Ivory Bill Woodpecker: Habitat Destruction is the Key to Extinction

Stromal Targeted Therapy: New Concept in Cancer Therapeutics

• Anti-angiogenesis inhibitors– Bevacizumab, sunitinib, thalidomide, lenalidomide

• Bone + tumor targeting with endothelin antagonism– Atrasentan and ZD4054

• Bone + tumor targeting with anti-p60src– Dasatinib

• Bone stromal targeted radiopharmaceuticals– Strontium-89, Samarium-153 EDTMP, Radium-223

• Osteoclast inhibition– Zolendronic acid and denosumab– No effects seen in CRPC to date

Where do we go from here?

• It takes 4 drugs to cure Hodgkin’s disease, one of our most curable malignancies– Clearly multiple drugs will be necessary to cure

mCRPC and that is our greatest challenge today

• Multi-targeted therapy to multiple micro-environmental sites and the tumor too?

• If we ever figure out how to kill metastatic stem cells, then the game changes

Trends, Issues & Treatment in Late-Stage Prostate Cancer

Oliver Sartor, M.D.

LaBorde Professor for Cancer Research

Medical Director, Tulane Cancer Center

Tulane Medical School

New Orleans, LA