Update on the Treatment of Prostate Cancer

David M. Nanus, MD

Chief, Division of Hematology and Medical Oncology

Weill Medical College of Cornell University

New York Presbyterian Hospital

Demographics

238,590 estimated new cases in 2013- 27.9% of all cancers in males- most common cancer in men- Lifetime risk: 16% (1 in 6)

29,720 estimated deaths- 9.7% of cancer deaths in males- second to lung cancer in men

ClinicallyLocalizedDisease

RisingPSA

ClinicalMetastases

Non-Castrate

CastrateRisingPSA

CastrateMetastaticDisease

Death from other causes Death fromProstate cancer

Adapted from Scher et al.

PSA – Like a Clint Eastwood Movie

The Good

PSA-based early detection decreases mortality

The Bad

Not perfectly sensitive or specific

Over-detection compounded by Over-treatment

The Ugly

Treatment arbitrary, variable, often unnecessary and increasingly costly

Screening Recommendations

Shared decision making Annual PSA and DRE

- from age of 40 (AUA); age 50 (ACS)- High risk: 40-45 (African American; 1rst degree relative)

Frequency- AUA: annually (based on initial PSA)- ACS: annually (every 2 year if PSA < 2.5 ng/ml)

Discontinue: life expectancy <10 years

The Changing Face of Prostate Cancer in the United States

Cooperberg et al. J Urol 2007; 178:S14

Significance of cancer:Determining need for treatment

Patient (age, comorbidities) Gleason score

- sum of two predominant areas

Tumor characteristics- Number of positive cores

- Percent positive within each core

Molecular profile

Active Surveillance

Surveillance in low risk patients is feasible and associated with a limited risk of progression

Progression can be quantitated

Predictors of progression and treatment can be identified

Screening results in the detection of very early stage/grade lesions - many indolent

Current staging/grading techniques accurate

Natural history prolonged and can be measured

Rationale Hypotheses

Intervention

62% free of intervention at 10 y

Surveillance Survival (years)

Su

rviv

al d

istr

ibu

tion

fu

nct

ion

0 2 4 6 8 10 12 14

0.0

0.2

0.4

0.6

0.8

1.0

Klotz L, et al. J Clin Oncol 2010;26:126–31

Overall Survival (years)

Su

rviv

al d

istr

ibu

tion

fu

nct

ion

0 2 4 6 8 10 12 14

0.0

0.2

0.4

0.6

0.8

1.0

Overall Survival

N=452

Ca-Specific Survival

5/452 patients

All PSADT ≤ 1.6 years

97% at 10 years

Defining the Triggers for Intervention

• Change in PSA kinetics: PSADT <3 y

• Progression on follow-up biopsy• Increase in Gleason grade

• Increase in tumor volume– Increase in absolute cores involved with cancer– Increase in percent of positive cores >33%– Increase in absolute tumor length (mm)– Increase in percent of tumor tissue >50% within single core

• Patient preference

• Clinical/radiographic evidence of local/distant progression

What’s new in prostate cancer therapy?

Targeting the androgen axis Immunotherapy Chemotherapy Bone targeted therapies

Molecular genetics Circulating prostate cancer tumor cells

Intermittent versus continuous androgen deprivation in hormone sensitive metastatic prostate cancer patients:

Results of S9346 (INT-0162), An international phase III trial

3040 hormone naïve metastatic patients- PS 0-2- PSA ≥ 5 ng/ml- treated with 7 months of goserelin + bicalutamide

1535 pts PSA ≤4 ng/ml- randomized to CAD or IAD

Primary objective: non-inferior Median Follow up: 10 years

Management of Castrate Resistant Metastatic Prostate Cancer

Androgen Signaling Axis Therapy- Abiraterone- Enzalutamide (MDV3100)

Chemotherapy- Docetaxel- Cabazitaxel- Mitoxantrone

Bone Targeted- Radium-223

Adapted from Harris et al. Nature Reviews Clin Onc 2009

Intra-cellular androgenAlternatively-spliced AR

cholesterol

pregnenolone

17α-hydroxy-pregnenolone

DHEAandrostenedione

TestosteroneDHT

CYP17

CYP17

Mineralocorticoids

Cortisol

Simplified view of cholesterol testosterone synthesis

Occurs in: Testes, Adrenal Gland, Prostate cancer cells

Montgomery et al. Cancer Res 2008Locke et al. Cancer Res

cholesterol

pregnenolone

17α-hydroxy-pregnenolone

DHEAandrostenedione

TestosteroneDHT

CYP17

CYP17

Mineralocorticoids

Cortisol

Montgomery et al. Cancer Res 2008Locke et al. Cancer Res

AbirateroneAcetate

Oral irreversible inhibitor of CYP17

- 17α –hydroxylase

- C17,20-lyase Inhibits testosterone

production in testis, adrenal, and prostate

Overall survival HR=hazard ratio. AA=abiraterone acetate. P=prednisone.

COU-AA-301Abiraterone Acetate + prednisone vs Placebo + prednisonein men with progressive metastatic CPRC after docetaxel

Fizazi et al. Lancet Oncol 2013;13:983.de Bono JS et al. N Engl J Med 2011;364:1995-2005.

Secondary End Points

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

Hazard Ratios for the Risk of Death, According to Subgroup

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

Chemo-naïve CRPC (n=1088)

Asymptomatic or mildly symptomatic

Abiraterone 1000 mg/dPrednisone mg bid

Placebo dailyPrednisone mg bid

Primary endpoint: Radiographic PFS, OSSecondary endpoints: Time to – opiate use; chemotherapy; EOCS-PS deterioration; progression

COU-AA-302

Prednisone Abiraterone + Prednisone

Radiographic PFS

8.3 mos 16.5 mos HR 0.53; p < 0.0001

Overall Survival 30.1 mos 35.3 mos HR 0.79;p = 0.0151*

> 50% PSA decline

69% 29%

Median Time to Chemotherapy

16.8 mos 26.5 mos HR: 0.61p < 0.0001

Median Time to Opiate Use

23.7 mos NR HR 0.71p = 0.0002

COU-AA-302: Updated interim results

* did not cross the prespecified boundary for significance (p = 0.0035)

Ryan CJ et al. N M2013;368:138-148 + GU ASCO 2013

Adverse Events of Special Interest.

Ryan CJ et al. N Engl J Med 2013;368:138-148.

AFFIRM: Enzalutamide (MDV3100)

Scher HI et al. N Engl J Med 2012;367:1187-1197.

Subgroup Analyses of Hazard Ratios for Death in the Two Study Groups

Scher HI et al. N Engl J Med 2012;367:1187-1197.

Enzalutamide

• PREVAIL trial: Phase 3 CRPC before chemotherapy

• TERRAIN trial: Phase 2 comparing Enzalutamide with bicalutamide in men who have progressed on LHRH analogue therapy or following surgical castration

Other studies:Enzalutamide + docetaxel

Enzalutamide + abiraterone

Cabazitaxel/Prednisone vs Mitoxantrone/Prednisone

de Bono et al, Lancet 2010: 1147-54

Immunotherapy

Cancer vaccines Modulation of immune regulatory mechanisms

- Blocking CTLA-4- Blocking PD-1 or PDL-1

Monoclonal antibody targeting of tumour growth

IMPACT Trial

HR=0.759 (95% CI: 0.606, 0.951)P=.017 (Cox model)

Median Survival Benefit: 4.1 months

Sipuleucel-T (n=341)Median Survival: 25.8 months

36-months survival: 32.1%

Control (n=171)Median Survival: 21.7 months

36-months survival: 23.0%

Kantoff et al, ASCO GU 2010

Radium-223 Targets Bone Metastases

Radium-223 acts as a calcium mimic

Naturally targets new bone growth in and around bone metastases

Radium-223 is excreted by the small intestine

Ra

Ca

Parker et al; ECCO-ESMO 2011

TREATMENT

6 injections at 4-week intervals

Radium-223 (50 kBq/kg) + Best standard of care

Radium-223 (50 kBq/kg) + Best standard of care

Placebo (saline) + Best standard of care

Placebo (saline) + Best standard of care

N = 922

PATIENTS

• Confirmed symptomatic

CRPC

• ≥ 2 bone metastases

• No known visceral

metastases

• Post-docetaxel or unfit for docetaxel

• Confirmed symptomatic

CRPC

• ≥ 2 bone metastases

• No known visceral

metastases

• Post-docetaxel or unfit for docetaxel

ALSYMPCA (ALpharadin in SYMptomatic Prostate CAncer) Phase III Study Design

Clinicaltrials.gov identifier: NCT00699751.

• Total ALP: < 220 U/L vs ≥ 220 U/L• Bisphosphonate use:

Yes vs No• Prior docetaxel:

Yes vs No

• Total ALP: < 220 U/L vs ≥ 220 U/L• Bisphosphonate use:

Yes vs No• Prior docetaxel:

Yes vs No

STRATIFICATION

Parker et al; ECCO-ESMO 2011

RANDOMISED

2:1

Month 0 3 6 9 12 15 18 21 24 27

Radium- 223 541 450 330 213 120 72 30 15 3 0

Placebo 268 218 147 89 49 28 15 7 3 0

ALSYMPCA Overall Survival

00

1010

2020

3030

4040

5050

6060

7070

8080

9090

100100

% %Radium-223, n = 541

Median OS: 14.0 monthsRadium-223, n = 541

Median OS: 14.0 months

Placebo, n = 268Median OS: 11.2 months

Placebo, n = 268Median OS: 11.2 months

HR 0.695; 95% CI, 0.552-0.875

P = 0.00185HR 0.695; 95% CI, 0.552-0.875

P = 0.00185

Parker et al; ECCO-ESMO 2011

Increase in median survival

Relative reduction in risk of death

Hazard ratio (95% CI; P-value)

Abiraterone/P vs. placebo/P

3. 9 mos 35% 0.65 (0.54-0.77; P<0.001)

Enzalutamide vs. placebo

4.8 mos 37% 0.63(P<0.0001)

Docetaxel(q3w)/P vs. Mitoxantrone/P

2.4 mos 24% 0.76 (0.62-0.94; P=0.009)

Cabazitaxel/P vs. mitoxantrone/P

2.8 mos 30% 0.70 (0.59-0.83; P<0.0001)

Sipuleucel T vs. placebo

4.1 mos 22% 0.78 (0.61- 0.98;P:0.03)

Alpharadin vs. placebo

2.8 mos 31% 0.70 (0.55-0.88; P:0.00185)

CRPC Therapeutic Options

Trial Name Arm B: DocPred plus Mechanism

ASCENT-2 DN101 Calcitriol

CALGB 90401 Bevacizumab VEGF

SWOG 0421 Atrasentan Endothelin receptor antagonist

MAINSAIL Lenalinomide Anti-angiogenic; immune

VENICE Aflibercept Soluble VEGF fusion protein

ENTHUSE 33 Zibotentan Endothelin receptor antagonist

READY Dasatinib SRC kinase inhibitor

SYNERGY OGX-11 Antisense to clusterin (cell survival protein)

FIRSTANA vs. Cabazitaxel (unTxed)

Taxane Chemotherapy

Phase III Randomized Trials vs. Docetaxel + PrednisonePrimary Endpoint: Overall Survival

Molecular Markers

Beyond the microscope May be diagnostic, prognostic, and/or predictive Gene fusions

TMRPSS2-ERG

Expression of abnormal proteinsMany may be targetable

Circulating Tumor Cells (CTCs)

Molecular Classification of Prostate Cancer

* Discoveries led by NYP-Weill Cornell Medical College

Frequency Therapy

Ets gene fusion 50-60% PARP inhibitor

PTEN/MAGI2 25-40% PI3K inhibitor

BRAC2/ATM 20% PARP inhibitor

Spink1 10-15% EGFr inhibitor

Aurora kinase A 5-40% AURK inhibitor

SPOP 10% ?

BRaf fusion 1% Raf inhibitor

Frequency Therapy

Ets gene fusion 50-60% PARP inhibitor

PTEN/MAGI2 25-40% PI3K inhibitor

BRAC2/ATM 20% PARP inhibitor

Spink1 10-15% EGFr inhibitor

Aurora kinase A 5-40% AURK inhibitor

SPOP 10% ?

BRaf fusion 1% Raf inhibitor

Neuroendocrine or anaplastic prostate cancer

Multi-institutional Phase II Trial of The Aurora kinase A inhibitor MLN8237 for Patients with Neuroendocrine Prostate Cancer

Inclusion Criteria: - Pathologic diagnosis

- Clinical diagnosis: visceral metastases in absence of PSA progression, elevated serum neuroendocrine marker

MLN8237 50 mg bid orally x 7 d on 21 day cycle Molecular biomarkers

- Tumor biopsies

- CTC analyses

- Exome/transcriptome sequencing

RANDOMIZE

2:1

100 men with Chemotherapy naïve metastaticCRPC

TAXSYNERGY: Phase II Trial to Evaluate Benefit of Early Switch from first-Line Docetaxel/Prednisone to Cabazitaxel/Prednisone and the opposite sequence,

exploring molecular markers and mechanisms of taxane resistance in men with Metastatic mCRPC who have not received prior chemotherapy

Docetaxel 75 mg/m2

Cabazitaxel 25 mg/m2

4 cycles

>30% PSA reduction

<30% PSA reduction

>30% PSA reduction

<30% PSA reduction

Docetaxel Continued

CabazitaxelContinued

Switch to Cabazitaxel

Switch to Docetaxel

Primary Objective: Explore benefit of an early switch from DOC to CBZEvaluate the association of biomarkers with clinical response/resistance to Rx

- Molecular Drug Target Engagement (DTE) in CTCs - RNA sequencing on CTCs to assess for tubulin mutations and AR isoforms

RANDOMIZE

2:1

100 men with Chemotherapy naïve metastaticCRPC

Docetaxel 75 mg/m2

Cabazitaxel 25 mg/m2

4 cycles

>30% PSA reduction

<30% PSA reduction

>30% PSA reduction

<30% PSA reduction

Docetaxel Continued

CabazitaxelContinued

Switch to Cabazitaxel

Switch to Docetaxel

GEDI CTCs

Baseline: Multiplex confocal, AR Taqman variant, RNA-Seq, ex-vivo predictive assaysCycle 1/Day 8 : Multiplex confocal (enumeration; AR subcellular localization; endogenous DTE)C4 Crossover :Mutliplex confocal, AR Taqman variant, ex-vivo predictive assaysC5/Day 8: Multiplex confocal Relapse: Mutliplex confocal, AR Taqman variant, RNA-Seq

Bone Targeted Therapy

Eligibility:> 1 bone metastasis, ADT therapy within 6 mos of enrollment

Therapy:Zoledronic acid or placebo q 4 weeks

Median time to first SRE (skeletal-related event)32.5 vs 29.8 mos (HR = 0.96 [0.76-1.22]; P=0.74)

> Grade 3 toxicity same (15% vs. 12% in ZA and P)

Overall survival (HR= 0.89 [0.70-1.14]; P=0.34)

CALGB 90202: A Randomized, Double-Blind, Placebo-Controlled Phase III Study of Early versus Standard Zoledronic Acid (ZA) to Prevent Skeletal

Related Events in Men with Prostate Cancer Metastatic to Bone

Smith MR et al. 2013 GU Cancers Symposium

Targeted Therapy: Denosumab vs zoledronic acid for Skeletal Related Events risk-reduction in CRPC

Fizazi et al, Lancet 2011; 377: 813

Denosumab vs placebo to improve bone-metastases free survival

Smith et al, Lancet 2011

Management of Metastatic CRPCSequencing???

Chemotherapy- Docetaxel, Cabazitaxel, Mitoxantrone

Androgen Signaling Axis Therapy- Abiraterone- Enzalutamide

Bone Targeted- Denosumab- Alpharadin

Prostate cancer clinical states model

Scher H I et al. JCO 2011;29:3695-3704

enzalutamide

Prostate cancer clinical states model

Scher H I et al. JCO 2011;29:3695-3704

enzalutamide

Smith D C et al. JCO 2013;31:412-419

Cabozantinib (XL184): orally bioavailable tyrosine kinase inhibitoragainst MET and VEGFr2 in men with CRPC

PFS in (A) randomly assigned patients with CRPC; and (B) patients with CRPC by docetaxel pretreatment status

Smith D C et al. JCO 2013;31:412-419

Bone scan effects of cabozantinib treatment on study patients

Smith D C et al. JCO 2013;31:412-419

Where We Are Now: Positive Phase 3 Trials in Met CRPCTrial Design HR Endpoint Comment

CanadianN = 161

Mitoxantrone/prednisone vsprednisone

NR Palliation in 29% vs 12% (duration 42 vs

18 wks)

Approval of mitoxantrone (also CALGB 9182)

TAX 327N = 1006

Docetaxel/prednisone vs mitoxantrone/prednisone

0.76 OS 18.9 vs 16.5 mo

Docetacel/pred approved as new standard

SWOG 9916N = 770

Docetaxel/estramustine vs mitoxantrone/prednisone

0.80 OS 17.5 vs 15.6 mo

Support docetaxel as new standard

ZAPCSGN = 643

Zoledronic acid vs placebo NR SRE 33.2% vs 44.2%

Zoledronic acid reduces SRE’s

IMPACT N = 512

Sipuleucel-T vs Control 0.78 OS 25.8 vs 21.7 mo

Sip-T approved min symptomatic metCRPC

Dmab 103N = 1904

Denosumab vs zoledronic acid 0.82 SRE-free 20.7 vs 17.1 mo

Denosumab approved

TROPICN = 755

Cabazitaxel/prednisone vs mitoxantrone/prednisone

0.70 OS 15.1 vs 12.7 mo

Cabazitaxel approved post-docetaxel

COU-AA-301N = 1195

Abiraterone/prednisone vsPlacebo/prednisone

0.65 OS 14.8 vs 10.9 mo

Abi/pred approved post-docetaxel

ALSYMPCAN = 922

Radium-223/BSC vs placebo/BSC 0.70 OS 14.0 vs 11.2 mo

Pending approval

AFFIRMN=1199

Enzalutamide vs Placebo 0.63 OS 18.4 vs 13.6 mo

Enzalutamide approved post-docetaxel

COU-AA-302N = 1088

Abiraterone/prednisone vsPlacebo/prednisone

0.43 16.5 mos vs 8.3 mo

Strong trend for OS