Castrate-resistant prostate cancer: Bone-targeted agents

Karim Fizazi, MD, PhDInstitut Gustave Roussy

Villejuif, France

Disclosure

Participation in advisory boards or as a speaker for: Amgen, Astellas, Astrazeneca, Bayer, Curevac, Janssen, Orion, Roche, Sanofi-Aventis

1. Roodman GD. N Engl J Med 2004;350:1655–16642. Amgen, data on file

Osteoblastosis

Osteolysis

PC

Osteolytic and osteoblastic bone metastases: presence of osteoclasts irrespective of radiology

Osteolysis1 Osteoblastosis2

Black arrows = osteoclasts

The prognostic importance of bone-related factors in mCRPC

Alkaline Phosphatase Urinary N-telopeptide

Bone pain Previous SRE

Fizazi K, Eur Urol 2015; 68: 42-50

Skeletal-Related Events (SRE) in men with bone metastases from prostate cancer

Pathologic Fracture

25%

Pain requiring Radiation to

Bone

33%

Surgery to Bone

4%

Spinal Cord Compression

8%

Saad, et al. J Urol 2003;169(Suppl).

Median, days P valueZOMETA® 4 mg 488 .009Placebo 321

0

20

40

60

80

100

0 120 240 360 480 600 720Days§

Perc

ent w

ithou

t eve

nt

Zoledronate: Time to Skeletal-Related Event in mCRPC

Zol 4 mg 214 149 97 70 47 35 3Placebo 298 128 78 44 32 20 3

Interval over 5 Months

Saad et al. JNCI 2004; 96:879

488321

ZoledronatePlacebo

0.009

Proportion (%) of Patients With Each SRE

26

17

46

20

33

25

8 74

10

5

10

15

20

25

30

35

Radiation tobone

Fractures Spinal cordcompression

Antineoplastictherapy

Surgery tobone

Hypercalcemia

Perc

ent o

f pat

ient

s

Zoled acid 4 mg (N = 214) Placebo (N = 208)

Saad et al. JNCI 2004; 96:879

Trapeze Phase III trial in mCRPC: Symptomatic Skeletal Events (SSE)

James N, JAMA Oncol 2016; 2: 493-99

Zoledronic Acid for CRPC: Overall survival

• Median OS: 18.2 vs 15.6 months• 1-year survival 85.2% vs. 78.3% (P = 0.21)2

1Saad F: Cancer Treatment Reviews (2008) 34, 183– 1922Weinfurt KP, et al. Annals of Oncology. 2006;17: 986-989.

Clodronate in Hormone-Sensitive Prostate Cancer

Metastatic disease (PR05 trial, n = 278)HR: 0.77 (0.60-0.98), P = .032

Nonmetastatic disease (PR04 trial, n = 471)HR: 1.12 (0.89-1.42), P = .94

Dearnaley DP, et al. Lancet Oncol 2009;10: 872-876.

Overall survival

The “vicious cycle” of bone metastases

BoneRANK

RANKL

Bone Resorption

Osteoclast

Prostate cancer cells

Ca2+

Growth Factors (TGF-β, IGFs, FGFs, PDGFs,

BMPs)

Cytokines and Growth Factors (ET-1, IL-6, IL-8, TNF-α, PTHrP, etc)

Adapted from Roodman GD. N Engl J Med. 2004;350:1655-64.

RAN

KL

Direct effectson tumor?

Targeting RANK-L: Proof of concept

OPG

RANKL

CTR CTROSB+ 2b

OSB+ 2a

OSB + LNCaP

OSB+ PC3

Fizazi et al., Clin Cancer Res 2003;9:2587–2597Fizazi et al., J Clin Oncol 2009; 27: 1564-71

RANK-L overexpressed by osteoblasts

in bone metastases

Positive randomized Phase II: Denosumab decreases uNTx (biomarker for osteolysis)

Denosumab: Time to First SRE in patients with established bone metastases

0

1.00

Prop

ortio

n of

Sub

ject

s With

out S

RE

0 3 6 9 12 15 18 21 24 27

0.25

0.50

0.75

KM Estimate ofMedian Months

DenosumabZoledronic acid

20.717.1

HR 0.82 (95% CI: 0.71, 0.95)P = 0.0002 (Non-inferiority)P = 0.008 (Superiority)

Study Month

18% Risk Reduction

Fizazi et al. Lancet 2011; 377: 811-822

Denosumab: time to first symptomatic event (SSE)

Smith M et al., Ann Oncol 2015; 26: 368-74

0

1

2

3

4

5

6

7

8

9

%

Spinal cord compression

Preventing the onset of the worst enemy:

Placebo Zoledronicacid

Dmab

103 trialZA pivotal trial

8% 4% 2.7%

Zoledronicacid

Saad, et al. J Natl Cancer Inst 2004;96:879–82; Fizazi et al. Lancet 2011; 377: 811-822

Fractures are commonly reported in the investigational arm of phase III studies with new AR

pathways inhibitors

16USPI, U.S. prescribing information.1. Smith MR et al. N Engl J Med 2018; doi:10.1056/NEJMoa1715546 [Epub ahead of print]. 2. Xtandi (enzalutamide) [prescribing information]. Astellas Pharma US, Inc., Northbrook, IL. July 2018. 3. Zytiga (abiraterone acetate) [prescribing information]. Janssen Biotech, Inc., Horsham, PA. February 2018. 4. Erleada (apalutamide) [prescribing information]. Janssen Products, LP, Horsham, PA. February 2018.

11.7%

6.5%

0%

2%

4%

6%

8%

10%

12%

14%

Apalutamide

Placebo

SPARTAN fractures1

8.8%

3.0%

0%

2%

4%

6%

8%

10%

12%

14%

Enzalutamide

Placebo

PREVAIL fractures2

(excluding pathologic fractures)

4.0%

0.8%

0%

2%

4%

6%

8%

10%

12%

14%

Enzalutamide

Placebo

AFFIRM fractures2

(excluding pathologic fractures)

5.9%

2.3%

0%

2%

4%

6%

8%

10%

12%

14%

Abi + Pred

Placebo

COU-301 fractures3

(excluding pathologic fractures)

9.8%

4.9%

0%

2%

4%

6%

8%

10%

12%

14%

Enzalutamide

Placebo

PROSPER fractures2

Use of bone-targeted agents withabiraterone (COU-302)

OS TT deterioration in PS

Saad F, Eur Urol 2016; 68: 570-7

EORTC GUCG 1333 (PEACE III) original design

PFS2

Bone health agents (denosumab or bisphosphonates) only permitted in patients receiving them at baseline;Initiation during study was prohibited to prevent confounding effects.

Target AccrualN=560

Study population

• Patients with bone-predominant mCRPC (≥2 bone metastases)

• Asymptomatic or mildly symptomatic

• WHO PS of 0 or 1 • No prior treatment

with, cyp17 inhibitors, enzalutamide, Ra233, other radionucleotides, hemibodyradiotherapy

• No known brain or visceral metastases

1:1R

Primary endpoint• rPFS

Secondary endpoints• OS• DSS• SSE• Time to initiation

of next systemic anti-neoplastic therapy

• PFS2• Brief Pain

Inventory (BPI),• (EQ-5D-5L)

Enzalutamide 160 mg qdRadium-223

55 kBq/kg IV every 4 weeks for 6 cycles

Enzalutamide 160 mg qd

Stratification factors • Country• Baseline pain (BPI worst pain 0-1 vs 2-3)• Prior docetaxel (yes vs no)• Use of bone health agents*

Tombal B, ASCO 2019

Cumulative incidence function of the fractures by treatment arm and use of bone protecting

agents

Small numbers beyond month 20

Tombal B, ASCO 2019

Bone-targeted agents: Are they worth using?

• Morbidity reduced ++• Prevention vs treatment• Overall good tolerance• Cheaper than most new

cancer drugs

• No demonstrated role in survival

• ONJ (1-2%), hypocalcemia

Osteonecrosis of the jaw• Data from 3 randomized trials (n=5723)• ONJ in 89 (1.6%) pts

– 37 (1.3%) zoledronic acid – 52 (1.8%) denosumab (p = 0.13)

• Tooth extraction in 62% of pts with ONJ– Discontinuation of denosumab recommended– Antibiotics recommended

• ONJ conservative treatment in >95% • ONJ resolution in 36%

Saad F, Ann Oncol 2012; 23: 1341-7

No benefit of zoledronic acid in pts withcastrate-sensitive metastatic CaP

n= 645 pts with HSPC and bone mets

RImmediate Zoledronic Acid

Zoledronic Acid when CRPC

Median time to SRE:32 mo vs 30 mo (HR=0.97)

Smith MR, J Clin Oncol 2014; 32: 1143-50

Zoledronic acid in hormone-sensitive CaP: Survival (Stampede)

SOC 405 deathsSOC+ZA 197 deaths

HR (95%CI) 0.93 (0.79, 1.11)P-value 0.44

Non-PH p-value 0.83

Median OS (95% CI)SOC 67m (60, 91m)SOC+ZA 80m (70, NR)

Restricted mean OS timeSOC 58.5m SOC+Doc 59.5mDiff (95%CI) 1.0m (-1.4, 3.4m)

James N, ASCO 2015

Zoledronic acid 4 mg Q3 monthsNo zoledronic acid*

1433 patientsProstate cancer, M0

+/- local treatment, +/- ADTHigh-risk PCa with at least one of the following criteria:• Gleason Score 8-10• pN+• PSA ≥20 at diagnosis Treatment duration 4 years

R

Does Zoledronic Acid prevent the onset of bone metastases? The ZEUS trial

Wirth M, EAU 2013

Primary endpoint: Bone metastases

Zoledronate 13.7%Control 13%

p=0.72

Median follow-up: 4.8 years Overall survival

Should Denosumab be used to preventthe onset of bone metastases in CRPC?

The « 147 » trial

0.0

0.2

0.4

0.6

0.8

1.0

0 6 12 18 24 30 36

HR = 0.77 (95% CI, 0.64−0.93)P = 0.0064

Prop

ortio

n of

pat

ient

s with

bone

met

asta

sis-fr

ee s

urvi

val

Study month

Placebo Denosumab

18.725.9

7.2

Median months

Delay(months)

23%

Risk reduction

Study month

0.0

0.2

0.4

0.6

0.8

1.0

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42

Median:25.2 months

29.5 months

Events:370

335

HR = 0.85 (95% CI, 0.73−0.98)P = 0.028

Prop

ortio

n of

pat

ient

s

Placebo (n = 716)

Denosumab (n = 716)

Pts with PSA DT ≤ 6 monthsOverall population

Smith MR, et al. Lancet 2012;379:39–46Smith MR, et al. J Clin Oncol 2013

Should we use bone-targetedagents to prevent bone loss in men

receiving ADT?

Annual Zoledronic Acid Increases BMD During GnRH Agonist Therapy

LumbarSpine

TotalHip

Final 12-mo data

BMD

Perc

ent C

hang

e

-6

-4

-2

0

2

4

6Placebo

Zoledronic acid 4 mg/y

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

Denosumab Fracture Prevention Study

• Primary endpoint: BMD • Secondary endpoint: new vertebral fractures

ClinicalTrials.gov. NCT00089674.

Current androgen deprivation therapy for patients with

prostate cancer who are older than 70 yrs of age or with T

score < -1.0

(N = 1468)

Denosumab 60 mg q6mfor 3 yrs

Placebo q6mfor 3 yrs

Denosumab Increased BMD at All Skeletal Sites

1086420

-2-4-6

01 3 6 12 24 36Month

Chan

ge in

BM

D Fr

om B

asel

ine

(%)

C. Femoral Neck

Denosumab

Placebo

Difference at 24 mos,3.9 percentage points

1086420

-2-4-6

01 3 6 12 24 36Month

Chan

ge in

BM

D Fr

om B

asel

ine

(%) 8

6420

-2-4-6

01 3 6 12 24 36Month

Chan

ge in

BM

D Fr

om B

asel

ine

(%)

A. Lumbar Spine

Denosumab

Placebo

Difference at 24 mos,6.7 percentage points

Denosumab

Placebo

Difference at 24 mos,4.8 percentage points

B. Total Hip

86420

-2-4-6

01 3 6 12 24 36Month

Chan

ge in

BM

D Fr

om B

asel

ine

(%)

Placebo

Difference at 24 mos,5.5 percentage points

D. Distal Third of Radius

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

Denosumab

10

10

Denosumab

Placebo

Denosumab to Prevent Fractures

12Mos

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

(%)

PlaceboDenosumab

13 2 22 7 26 10Patients, n

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

Conclusion: Bone-targeted agents in advanced prostate cancer

• In metastatic CRPC:– Zoledronic acid: SRE improved– Denosumab: SRE improved (>ZA)– SSE also improved

• No current role in hormone-sensitive metastaticprostate cancer (except for prevention of boneloss)

• Not approved in non-metastatic CRPC (unfavorablerisk/benefit balance)