non-metastatic crpc and asymptomatic metastatic crpc...

May 4, 2012 1

Non-metastatic CRPC and Asymptomatic Metastatic CRPC- Which treatment for which patient

Michael A. Carducci, M.D., FASCO AEGON Professor in Prostate Cancer Research Johns Hopkins Kimmel Cancer Center Baltimore, MD

Disclosures

• Consultant Amgen Bayer Sanofi Data Safety Monitoring Medivation/Astellas

Educational Objectives

• Discuss the clinical state “non-metastatic castration -resistant prostate cancer”

• Review treatment options and controversies for this patient population

• Examine differences between “non-metastatic” to “asymptomatic” CRPC and the treatment landscape

July 11, 2013 3

Definition of Castration-resistant Prostate Cancer (CRPC) • CRPC defined as disease progression on androgen

deprivation therapy • Criteria defining CRPC vary

– Presence of progressive metastatic measurable disease (by RECIST)

– Progression of bone metastases (by bone scan) – Biochemical progression: 2 consecutive increases in PSA – Castrate testosterone levels (<50 ng/mL or <20ng/mL) – Progression despite anti-androgen withdrawal

(up to 4-6 weeks earlier)

Sternberg C, et al. BJU Intl. 2006;99:22-27. Bubley G, et al. J Clin Oncol. 1999;17:3461-3467. Winquist E, et al. BMC Cancer. 2006;6:112.

Scher HI. Et al. J Clin Oncol 2008; Mar 01.

What is meant by “Non-metastatic Castration-Resistant Prostate Cancer

• A state where the patient appears “radiographically-free” of metastatic disease

• Artificially created by early use of androgen deprivation therapy for rising PSA patients/ high risk patients after local therapy

• In general, it is assumed that these men have micro-metastatic disease

July 11, 2013 5

Clinical States of Prostate Cancer

Clinically localized

Biochemically Relapsed-

Rising PSA

Non-metastatic, hormone-

responsive

Metastatic, Hormone-responsive

Non-metastatic

CRPC

Metastatic

CRPC

10-15 years +

Death from co-morbidities

Death from disease

PSA=prostate-specific antigen; CRPC= castrate resistant prostate cancer Modified from: Scher HI, et al. Urology. 2000;55:323-327. Adapted from George D. ASCO Prostate 2007.

Issues with the Management of Men with “Non-metastatic” CRPC • Duration of ADT prior to CRPC and long term

effects of ADT – Estimates of time to metastatic disease vary – Bone health- osteopenia / fracture risk – Metabolic issues- ongoing cardiovascular risks

• Asymptomatic - so “concern” about side-effects of additional therapies – Again, estimates of time to metastatic disease

would help determine “aggressiveness” of treatment

July 11, 2013 7

Issues with the Management of Men with “Non-metastatic” CRPC • No standard approach to treatment but

“concern” is present for progression risk – What if we improve imaging to detect micro-mets? – Androgen pathway still active and inhibitors should

provide benefit – Immunotherapy may be more effective if provided

early • Clinical trials difficult to design and identify

clinically meaningful endpoint – Delay in time to metastasis- what is signficant?

July 11, 2013 8

Bone Health and Metabolic Issues

July 11, 2013 9

Negative Aspects of Androgen Deprivation • Hot flashes • Loss libido / erectile dysfunction • Bone mineral loss/ accelerated osteopenia • Weight gain • Changes in lipid/ glycemic metabolic profiles • Anemia • Neuro-cognitive changes

July 11, 2013 10

Osteoporosis From Hormonal Deprivation

• Normally seen in aging men • Fractures in spine most prevalent • Trabecular bone at highest risk • Deprivation accelerated by systemic

cancer therapy, especially problematic with use of antihormonal cancer agents

July 11, 2013 11

Fractures Affect Mortality and Life Expectancy • Hip fracture

– Affects life expectancy dramatically

• Aged 60-69 yrs: 11.5 yrs of decreased life expectancy • Aged 0-79 yrs: 5.0 yrs of decreased life expectancy

• Vertebral facture – Prevalence in men is high (20%)

– Clinical consequences: pain, kyphosis, loss of height, respiratory problems

• 4 x increased risk of subsequent fracture – Predict increased mortality in men with a 10-yr HR of 2.4

(95% CI: 1.6-3.9)

July 11, 2013 12

Quarterly Zoledronic Acid Increases BMD During GnRH Agonist Therapy

Lumbar Spine

Total Hip

Smith MR, et al. J Urol. 2003;169:2008-2012.

-4

-2

0

2

4

6

8 P < .001 for each comparison

Final 12-Mo Data

BM

D P

erce

nt C

hang

e

Zoledronic acid Placebo

Annual Zoledronic Acid Increases BMD During GnRH Agonist Therapy

Michaelson MD, et al. J Clin Oncol. 2007;25:1038-1042.

-6

-4

-2

0

2

4

6 P < .005 for each comparison

Final 12-Mo Data

BM

D P

erce

nt C

hang

e

Zoledronic acid 4 mg/yr IV Placebo

Lumbar Spine

Total Hip

Denosumab Increased BMD at All Skeletal Sites

10 8 6 4 2 0

-2 -4 -6

0 1 3 6 12 24 36 Mos

Cha

nge

in B

MD

Fr

om B

asel

ine

(%)

Femoral Neck

Denosumab

Placebo

Difference at 24 mos, 3.9 percentage points

10 8 6 4 2 0

-2 -4 -6

0 1 3 6 12 24 36 Mos

Cha

nge

in B

MD

Fr

om B

asel

ine

(%) 8

6 4 2 0

-2 -4 -6

0 1 3 6 12 24 36 Mos

Cha

nge

in B

MD

Fr

om B

asel

ine

(%)

Lumbar Spine

Denosumab

Placebo

Difference at 24 mos, 6.7 percentage points

Denosumab

Placebo

Difference at 24 mos, 4.8 percentage points

Total Hip

8 6 4 2 0

-2 -4 -6

0 1 3 6 12 24 36 Mos

Cha

nge

in B

MD

Fr

om B

asel

ine

(%)

Placebo

Difference at 24 mos, 5.5 percentage points

Distal Third of Radius

Smith MR, et al. N Engl J Med. 2009;361:745-755.

Denosumab

10

10

Denosumab for Fracture Prevention

12 Mos

24 36

P = .004 P = .004 P = .006

1.9

0.3

3.3

1.0

3.9

1.5

0

2

4

6

8

10

New

Ver

tebr

al F

ract

ure

(%) Placebo

Denosumab

13 2 22 7 26 10 Pts at Risk, n

Smith MR, et al. N Engl J Med. 2009;361:745-755.

Metabolic Complications of ADT

Metabolic Syndrome

Insulin Resistance Hyperglycemia

Dyslipidemia

Long Term Effect of ADT

Met

abol

ic S

yndr

ome

in M

en o

n L

ong-

term

AD

T Br

aga-

Bas

aria

M e

t al J

CO

200

6

Metabolic Syndrome

• Metabolic syndrome present in more than 50% of men undergoing long-term ADT – Abdominal obesity, hyperglycemia,

hypertriglyceridemia, hypertension, and low HDL • Abdominal obesity and hyperglycemia were

responsible for this higher prevalence • Maybe one factor for accelerated

cardiovascular mortality in men with PCA

• Patients and physicians require education about increased incidence of metabolic issue in men on long term ADT July 11, 2013 19

Predicting Progression

July 11, 2013 20

Smith MR, et al. J Clin Oncol. 2005;23:2918-2925. Reprinted with permission. © 2005 American Society of Clinical Oncology. All rights reserved.

PSA > 24.0 ng/mL PSA 7.7-24.0 ng/mL PSA < 7.7 ng/mL

Prop

ortio

n of

Pat

ient

s W

ith B

one

Met

asta

ses

or D

eath

Yrs Since Random Assignment

0.8

0.6

0.4

0.2

0

1.0

Rising PSA in Nonmetastatic CRPC: PSA Levels

0 0.5 1.0 1.5 2.0 2.5 3.0

Smith MR, et al. J Clin Oncol. 2005;23:2918-2925. Reprinted with permission. © 2005 American Society of Clinical Oncology. All rights reserved.

Rising PSA in Nonmetastatic CRPC: PSA Doubling Time

PSADT < 6.3 mos PSADT 6.3-18.8 mos PSADT > 18.8 mos

Prop

ortio

n of

Pat

ient

s W

ith B

one

Met

asta

ses

or D

eath

Yrs Since Random Assignment

0.8

0.6

0.4

0.2

0

1.0

0 0.5 1.0 1.5 2.0 2.5 3.0

Denosumab to Prevent Metastases

Primary endpoint: bone metastasis–free survival

Denosumab 120 mg monthly Patients with CRPC and no bone metastases;

PSA > 8 or PSADT < 10 mos

(N = 1435)

Placebo monthly

Smith MR, et al. Lancet. 2012.

Primary Endpoint: Bone Metastasis-Free Survival

716 716

691 695

569 605

500 521

421 456

375 400

345 368

300 324

259 279

215 228

0 3 6 9 12 15 18 21 24 27 Study Mo

Pro

porti

on o

f Pat

ient

s W

ith

Bon

e M

etas

tasi

s–Fr

ee S

urvi

val

Placebo Denosumab

30 33 36 39 42

Median Mos 25.2 29.5

HR: 0.85 (95% CI: 0.73-0.98; P = .028)

Placebo Denosumab

168 185

137 153

99 111

60 59

36 35

Patients at Risk, n

Smith MR, et al. Lancet. 2012.

1.0

0.8

0.6

0.4

0

0.2

Metastasis-Free Survival What is meaningful? • ODAC meeting to discuss 11/2011

– Meaningful > 1 year, and based on toxicity profile

• ARN-509 / Enzalutamide / Orteronel- each will launch Phase III studies to delay metastasis

• Can immunotherapy be moved to this setting, when no improved PFS noted in more advanced disease

July 11, 2013 25

Androgen Pathways Still Active

• Maintenance of castrate level of testosterone life long

• Second line hormonal therapy most commonly used – Anti-androgens- bicalutamide, nilutamide,

flutamide – Androgen synthesis inhibitors- ketoconazole – Estrogens – Newer agents (not yet approved but available)

July 11, 2013 26

M0 M1 Death

Low-volume metastases, no/minimal symptoms

Progressive metastases,

symptomatic

High-volume or symptomatic

metastases

1st line

Docetaxel Curtisen

Cabazitaxel Mitoxantrone

1st line Cytotoxic

Sipuleucel-T Ketoconazole

Estrogens Abiraterone

Orteronel Enzalutamide Tasquinimod Ipilumimab Radium-223

1st line

Mitoxantrone Abiraterone Cabazitaxel

Enzaluatmide Radium 223

Cabozantinib

2nd line

M0 M1 Death

Low-volume metastases, no/minimal symptoms

Progressive metastases,

symptomatic

High-volume or symptomatic

metastases

1st line

Docetaxel Curtisen

Cabazitaxel Mitoxantrone

1st line Chemotherapy

Based

Sipuleucel-T Ketoconazole

Estrogens Abiraterone

Orteronel Enzalutamide Tasquinimod Ipilumimab

1st line

Extend time Delay symptoms

Defer chemotherapy

Improve survival QoL

FDA-Approved Agents for Prevention of SREs in Metastatic Prostate Cancer

NCCN recommends either zoledronic acid or denosumab for prevention/delay of SREs in men with metastatic CRPC[1]

Choice between agents may be guided by

– Underlying comorbidities

– Adverse events: renal insufficiency, ONJ, hypocalcemia

– Logistics - Differences in administration (SQ vs IV)

– Cost considerations

Agent Drug Class Recommended Dose and Schedule Zoledronic acid Bisphosphonate 4 mg IV q3-4w Denosumab RANKL-targeted MAb 120 mg SQ q4w

1. NCCN. Clinical practice guidelines in oncology: prostate cancer. v.4.2011.

Summary

• In 2013, “Non-metastatic” CRPC remains a clinical state

• Management remains conservative – Reliance on traditional agents – Bone health – Attention to metabolic issues

• Asymptomatic metastatic CRPC in the midst of changing treatment landscape, with limited data on sequence /timing

July 11, 2013 30