Bone-targeted therapies in Prostate cancer: updating the...

Luís Costa, MD, PhDHospital de Santa MariaInstituto de Medicina MolecularFaculdade de Medicina de LisboaPresident of ASPIC

Bone-targeted therapies in Prostate cancer: updating the landscape

Luís Costa, MD, PhDHospital de Santa MariaInstituto de Medicina MolecularFaculdade de Medicina de LisboaPresident of ASPIC

Disclosures

Research Grants: Amgen; Novartis; Roche.

Consultant: Novartis; Amgen.

Speaker Honoraria: Amgen; Bayer; Janssen.

Cancer treatment-

induced bone loss

Treatment of

bone metastases

What is the role of Bone-targeted therapy in Prostate Cancer at all stages of disease ?

Early cancer Advanced cancer

Prevention/delay

of bone metastases

HSPC / CRPC mHSPC / mCRPC

HSP, hormone-sensitive prostate cancer; CRPC, castration-resistant prostate cancer; mHSPC, metastatic hormone-sensitive prostate cancer; mCRPC, metastatic castration-resistant prostate cancer

Ann Intern Med. 2017;167:341-350. doi:10.7326/M16-2577.

One in 2 receive androgen deprivation therapy (ADT) at some point after diagnosis (1).

The greatest loss in bone mineral density (BMD) occurs within the first year of ADT use.

Continued use is associated with increased risk for fractures (2).

1- Gilbert SM, et al. Urol Oncol. 2011;29:647-53; 2- Shahinian VB, et al. N Engl J Med. 2005; 352:154-64.

The Genitourinary Cancer Disease Site Group ofthe Program in Evidence-Based Care/Cancer Care Ontario

Improvements in BMD were observed at 24 months with risedronateand alendronate and at 36 months with Zoledronic acid.

No ≠ in Fracture Rate

• Primary endpoint: percentage change from baseline at Month 24in lumbar spine BMD

• Secondary endpoints included: incidence of new vertebral fractures

Denosumab pivotal Phase III trial in men receiving ADT for prostate cancer

36 months

Supplemental calcium and vitamin D

Baseline

N = 1468

Smith MR, et al. N Engl J Med 2009;361:745–55.

Key eligibility criteria• Non-metastatic disease• Continuous ADT• Age ≥ 70 years or• Age < 70 years with either:

• History of osteoporotic fracture• Baseline BMD T-score < -1.0

at lumbar spine, total hip orfemoral neck

Denosumab60 mg SC Q6M

Placebo SC Q6M

RA ND O MISA TIO N

Total hipLumbar spine

*

Study month

1 3 6 12 24 36

Placebo (n = 734)Denosumab (n = 734)

0

** * *

*

4.8% difference

at 24 months

Study month

1 3 6 12 24 36

Placebo (n = 734)Denosumab (n = 734)

0

**

**

6.7% difference

at 24 months

10

8

6

4

2

0

-2

-4

-6

Perc

enta

ge c

han

ge (±

95

% C

I)fr

om

bas

elin

e in

BM

D

Perc

enta

ge c

han

ge (±

95

% C

I)fr

om

bas

elin

e in

BM

D

**

10

8

6

4

2

0

-2

-4

-6*P = 0.001

• Increase in BMD was rapid

• Increase in BMD was significant at all measured sites(lumbar spine, total hip, femoral neck and distal 1/3 radius P ≤ 0.001)

Denosumab significantly increased BMD compared with placebo at all measured sites


Denosumab significantly reduced incidence of new vertebral fractures compared with placebo

0

2

4

6

P = 0.004

P = 0.004P = 0.006

Perc

enta

ge o

f su

bje

cts

No. of pts

Month 12 Month 24 Month 36

- 84%

- 70% - 62%

13 2 22 7 26 10

8

Denosumab (n = 679)Placebo (n = 673)


Cancer treatment-

induced bone loss

Treatment of

bone metastases



Prevention/delay

of bone metastases



Time to bone metastasis and overall survival

Study month

PlaceboDenosumab

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

Median months

29.533.2

Events

319286

HR = 0.84 (95% CI, 0.71–0.98)P = 0.032

Pro

po

rtio

n o

f p

atie

nts

Study month

PlaceboDenosumab

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

HR = 1.01 (95% CI, 0.85–1.20)P = 0.91

Pro

po

rtio

n o

f p

atie

nts

42 45

Smith MR, et al. Lancet 2012;379:39–46.

*Patients were withdrawn from study on development of bone metastases; 80% of deaths occurred during study follow-up. Median survival was

19 months after development of bone metastases.

Denosumab (120 mg Q4W) is currently not approved for prevention of bone metastases.

Denosumab is investigational in that setting.

Time to bone metastasis Overall survival*

Cancer treatment-

induced bone loss

Treatment of

bone metastases



Prevention/delay

of bone metastases



Prostate Cancer Develops a Phenotype That Allows for Migration to the Bone

• The bone matrix is rich in factors that stimulate the growth of tumor cells and promote a vicious cycle of metastases and bone pathology1

• Physical factors in the bone microenvironment may also enhance tumor growth2

• Cross talk between prostate cancer and the bone drives continued disease progression3,4

References: 1. Yin JJ et al. Cell Res. 2005;15(1):57-62. 2. Zheng J et al. J Bone Oncol. 2012;2(1):47-57. 3. Mundy GR. Nat Rev. 2002;2:584-593.

4. Kingsley LA et al. Mol Cancer Ther. 2007;6:2609-2617.

Cancer cells

Host cells

Soluble factors(eg, exosomes,

cytokines, hormones)

HOMELAND

MIGRATION

HOSTLANDImage courtesy of Kenneth Pienta, MD.

Most Patients With mCRPC Develop Visceral Metastases in the Final Stages of the Disease

Increased visceralinvolvement

100

90

80

70

60

50

40

% o

f P

atie

nts

30

20

10

0>24 15-24 12-15 9-12 6-9 3-6 <3

Time Prior to Death, months

Visceral involvement Bone involvement

~90%~95%

Minimal visceral involvement

Reference: Pezaro CJ et al. Eur Urol. 2014;65:270-273.

The Androgen Axis Is Not the Only Driver of Advanced Prostate Cancer Disease Progression1-5

References: 1. Yin JJ et al. Cell Res. 2005;15(1):57-62. 2. Mundy GR. Nat Rev. 2002;2:584-593. 3. Kingsley LA et al. Mol Cancer Ther. 2007;6:2609-2617. 4. Gundem G et al. Nature. 2015;520(7547):353-357.

5. Nemeth JA et al. J Natl Cancer Inst. 2002;94(1):17-25..

Androgen Bone

Course of mCRPC

Metastases

CRPC

Initial diagnosis and therapy ADT

SRE/SSE

Death

SRE/SSE

Death

PS

A /

Tu

mo

r B

urd

en

1. Adapted from Scher H, et al. Urology. 2000;55(3):323-327. 2. Dennis E, et al. J Clin Oncol. 2012;30(5):519-524.

Time

Hormone dependence

Tumor Heterogeneity

…Course of CRPC and goals of new therapies

Pockett RD, et al. Eur J Cancer Care 2010;19:75560.Review of hospital admission data for patients admitted to Spanish hospitals, January 2000

to March 2006, including 7,546 patients with prostatecancer

SREs increase the hospital burden ofProstate cancer

Mean length of hospital stay by disease type and admission status

Prostate cancerLung cancerBreast cancer

Can

cer

on

ly

Can

cer

on

ly

Can

cer

on

ly

+ b

on

em

etas

tase

s

+ b

on

em

etas

tase

s

+ b

on

em

etas

tase

s

+ SR

E

+ SR

E

+ SR

E

Mea

n le

ngt

h o

f st

ay (

day

s)

15

10

5

0

20

25

1211

6

9 9 9

13

19

16

11

21

14

10

8

12

910

15

Elective

Emergency

The Vicious Cycle of Bone Metastases: Targeting osteoclasts

Bisphosphonates

Denosumab

Cancer treatment-

induced bone loss

Treatment of

bone metastases



Prevention/delay

of bone metastases



CALGB 90202 (ALLIANCE)1

STAMPEDE

BONE-TARGETED AGENTS IN HORMONE -SENSITIVE

PROSTATE CANCER

1-Smith MR, Halabi S, Ryan CJ, et al. Randomized controlled trial of early zoledronic acid in men with castration-sensitive prostate cancer and bonemetastases: results of CALGB 90202 (alliance). J Clin Oncol 2014; 32:1143–1150.

“This trial was closed prematurely due to a low eventrate and termination of sponsor support…”

+ZA

+Doc

+ZA+Doc

Pre-planned analysis

Overall survival by metastatic status

James, N et al. Eur J Cancer 2015;51(S3): abstract 19LBA (presented at ECC 2015)

STAMPEDE

SOC 328 SSE eventsSOC+ZA 153 SSE events

HR (95%CI) = 0.89 (0.73, 1.07)P-value 0.221

Zoledronic Acid: skeletal events(all patients)

Excluding ONJSOC 0 reportsSOC+ZA 10 reports

James, N et al. Eur J Cancer 2015;51(S3): abstract 19LBA (presented at ECC 2015)

Cancer treatment-

induced bone loss

Treatment of

bone metastases



Prevention/delay

of bone metastases



Time to first SRE

P = 0.021

Pat

ien

ts w

ith

≥ 1

SR

E (%

)

33.2

44.2

0

10

20

30

40

50

Zoledronicacid 4 mg(n = 214)

Placebo(n = 208)

Time after start of study drug (days)

Pat

ien

ts w

ith

ou

t ev

en

t (%

)

90

10

20

30

40

50

60

70

80

90

100

00 180 450270 540360

Zoledronic acid 4 mg (P = 0.011 vs placebo)

Placebo

Proportion of patientswith ≥ 1 SRE (primary endpoint)

Saad F, et al. J Natl Cancer Inst. 2002;94:1458-1468.

Zoledronic Acid Was Superior to Placebo in CRPC

CI = confidence interval; HR = hazard ratio; SRE = skeletal related events.Fizazi K, et al. Lancet. 2011;377:813-22.

Significantly Longer Time Without an SRE With Denosumab vs Zoledronic Acid

18% risk reduction

HR = 0.82 (95% CI, 0.71–0.95)

P = 0.008 (superiority)

Time to first SRE

Study month

Pat

ien

ts w

ith

ou

t SR

E (%

)

0

40

60

80

100

20.7 months

17.1 months

90

70

50

30

20

10(N = 1901)

Denosumab

Zoledronic acid

0 3 6 9 12 15 18 21 24 27

*Events occurring at least 21 days apart (multiple event analysis).CI = confidence interval; RR = rate ratio; SRE = skeletal related events.Fizazi K, et al. Lancet. 2011;377:813-22.

Significantly Fewer SREs With Denosumab vs Zoledronic Acid

18% risk reduction

RR = 0.82 (95% CI, 0.71–0.94)

P = 0.008 (superiority)

Time to first andsubsequent SREs*

3 6 9 12 15 18 21 24 27 30

1.8

1.6

1.4

1.2

1.0

0.8

0.6

0.4

0.2

0.0

2.0

0 33Cu

mu

lati

ve m

ean

nu

mb

er

of

SREs

pe

r p

atie

nt

Study month

(N = 1901)

494

584

Denosumab

Zoledronic acid

Total SREs:

Patient incidence, n (%)Zoledronic acid

(n = 945)Denosumab

(n = 943)

Infectious adverse events (AEs) 375 (39.7) 402 (42.6)

Infectious serious AEs 108 (11.4) 130 (13.8)

Acute phase reactions (first 3 days) 168 (17.8) 79 (8.4)

Renal AEs* 153 (16.2) 139 (14.7)

Cumulative rate of osteonecrosis of the jaw (ONJ)† 12 (1.3) 22 (2.3)

Hypocalcemia 55 (5.8) 121 (12.8)

New primary malignancy 10 (1.1) 18 (1.9)

*Includes renal failure, increased blood creatinine, acute renal failure, renal impairment, increased blood urea, chronic renal failure, oliguria, hypercreatininemia, anuria, azotemia, decreased creatinine renal clearance, decreased urine output, abnormal blood creatinine, proteinuria, decreased glomerular filtration rate, and nephritis. †P = 0.09

Denosumab (120 mg Q4W) is investigational (not approved) for use in patients with advanced cancer to delay SREs.Fizazi K, et al. J Clin Oncol. 2010;28(suppl 18). Poster.

Safety Results of Interest

BTA No BTA HR (95% CI) P value

Median overall survival (months) NE 30.3 0.75 (0.60–0.94) 0.012

Median time to opiate use for CaRP (months) NE 27.9 0.80 (0.65–0.99) 0.036

Median time to ECOG PS deterioration (months) 14.3 11.1 0.75 (0.64–0.87) <0.001

Clinical outcomes for patients with and without concomitant bone-targeted agents (BTA) in the COU-AA-302 study ofabiraterone in the chemo-naive setting.1

BTA, bone-targeted agent; CaRP, cancer-related pain; CI, confidence interval; ECOG PS, Eastern Cooperative Oncology Group performance status; HR, hazardratio; NE, not estimable.

1-Saad F, et al. Eur Urol 2015; 68:570–577.

Radium-223 is a bone targeted therapy: targets cancers cells and the microenvironment

References: 1. Body, J.-J. Casimiro, S. And Costa L. Nat. Rev. Urol. 12, 340–356 (2015)

• Radium-223 is a targeted alphatherapy, that affects the cancercells and the tumormicroenvironment and thusdisrupts the vicious cycle oftumor growth and abnormalbone formation

Role of Bone-Targeted therapy when Current treatment paradigm is evolving

Local therapy

Androgen deprivation therapy (ADT)

Therapies after ADT

Death

ADT

Bone –targeted agents: denosumab / zoledronic acid)

mCRPCpost-

docetaxel

mCRPCsymptomatic

mCRPCmildly

symptomatic

mCRPCasymptomatic

(failed ADT)

Hormonesensitive

Sipuleucel-T

Enzalutamide

Abiraterone Abiraterone

Docetaxel Cabazitaxel

Radium 223 (bone-targeted agent)

Enzalutamide

Abiraterone

Bone-targeted agent: denosumab ; zoledronic acid

mCRPC Treatment Rationale

AR Inhibitors

Targeted Alpha Therapy

QTImmuno-therapy

Supportive Therapy

Traditional ADT

Abiraterone

Enzalutamide

Radium-223 dichloride

Docetaxel

CabazitaxelSipuleucel-T

Strontium-89

Samarium-153

Rhenium-186

Zoledronic acid

Denosumab

Steroids

Drugs with proven survival benefitSupportive

drug

References: 1 Crawford E.David at al. Prostate Cancer Radiographic Assessments for Detection of Advanced Recurrence (RADAR II) Group. Urology 2017

ALSYMPCA: Study Design

Radium-223 (50 kBq/kg* IV) 6 injections at 4-week intervals

+ best standard of careb

Placebo (saline)6 injections at 4-week intervals

+ best standard of careb

• 136 centers in 19 countries• Planned follow-up is 3 years

PATIENTS (N=921)• Confirmed symptomatic CRPC• ≥2 bone metastases• No known visceral metastases• Post-docetaxel, unfit for docetaxel, or

refused docetaxela

STRATIFICATION• Total ALP: <<220 U/L vs ≥220 U/L• Bisphosphonate use: Yes vs No• Prior docetaxel: Yes vs No

R 2:1

ALP, alkaline phosphatase; ALSYMPCA, ALpharadin in SYMptomatic Prostate CAncer; CRPC, castration-resistant prostate cancer.

*Value is based on data assessed by previously used NIST standard. Updated nominal value of Xofigo is 55 kBq/kg body weight and not 50 kBq/kg body weight. Please see: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002653/WC500156172.pdf.

a. Unfit for docetaxel includes patients who were ineligible for docetaxel, refused docetaxel, or lived where docetaxel was unavailable.

b. Best standard of care defined as a routine standard of care at each center, e.g., local external beam radiation therapy, corticosteroids, antiandrogens, estrogens (e.g., stilbestrol), estramustine, or ketoconazole.

Parker C, et al. N Engl J Med. 2013;369(3):213–223

Radium-223 Improved OS Across All Patient Subgroups

Variable Subgroup n HR (95% CI)

All patients 921 0.70 (0.58-0.83)

Total ALP< 220 U/L 517 0.82 (0.64-1.07)

≥ 220 U/L 404 0.62 (0.49-0.79)

Current bisphosphonates Yes 374 0.70 (0.52-0.93)

No 547 0.74 (0.59-0.92)

Prior docetaxelYes 526 0.71 (0.56-0.89)

No 395 0.74 (0.56-0.99)

Baseline ECOG score0 or 1 801 0.68 (0.56-0.82)

≥ 2 118 0.82 (0.50-1.35)

Favours placeboFavours

223Ra

0.5 2.01.0

Parker C. N Engl J Med. 2013;369:213-223

Radium 223 SSE impact

CI, confidence interval. CRPC, castration-resistant prostate cancer. NE, not estimable.

a. Number of patients.

b. Median time to first event.

c. P values are for descriptive purpose only and not adjusted for multiplicity; the hazard ratio is the best interpretation of radium-223 effect.

Sartor O, et al. Lancet Oncol. 2014;15(7):738–746

RADIUM-223 (N=614) PLACEBO (N=307)

INDIVIDUAL SSE COMPONENTS na (%)

MEDIAN,b

MONTHS na (%)MEDIAN,b

MONTHS HR

(95% CI) P VALUEc

External beam radiation therapy

186 (30) 17.1 105 (34) 17.5E0.67

(0.53-0.85)0.00117

Symptomatic pathologic bone fracture

32 (5) NE 20 (7) NE0.62

(0.35-1.09)0.10

Spinal cordcompression

25 (4) NE 21 (7) NE0.52

(0.29-0.93)0.03

Tumor-related orthopedic surgical intervention

12 (2) NE 7 (2) NE0.72

(0.28-1.82)0.48

FavoursRadium-223

FavoursPlacebo

0 21

Adverse events aPatients With Treatment-Related AEs

Radium-223 + BSoC (n=600) Placebo + BSoC (n=301)

All Grades, n (%) Grades 3/4, n (%) All Grades, n (%) Grades 3/4, n (%)

Anaemia 187 (31) 79 (13) 93 (31) 39 (13)

Neutropaenia 30 (5) 13 (2) 3 (1) 2 (1)

Thrombocytopaenia 69 (12) 39 (7) 17 (6) 6 (2)

Bone pain 310 (52) 132 (22) 192 (64) 79 (26)

Diarrhoea 154 (26) 8 (1) 45 (15) 6 (2)

Nausea 215 (36) 10 (2) 102 (34) 6 (2)

Vomiting 116 (19) 10 (2) 41 (14) 7 (2)

Constipation 109 (18) 7 (1) 64 (21) 4 (1)

Fatigue 160 (27) 27 (5) 79 (26) 18 (6)

No AML, MDS, or primary bone cancer

No major safety issues identified up to 3 years after the last injection

aAEs on or after the first injection and up to 12 weeks after the last injection

AML, acute myelogenous leukaemia; MDS, myelodysplastic syndrome

Parker C et al. J Clin Oncol 33, 2015 (suppl 7; abstr 195)Parker C, et al. J Clin Oncol. 33, 2015 (suppl 7; abstr 195

ALSYMPCA: 3 Year Safety Follow-up

Treatment goal: prolong symptom-free AND overall survival

Symptom-free survival

Overall survival

+

SREs

How do you Classify Radium-223?

mCRPC Treatment Rationale

Anti-tumourtherapy

Bone-targeted therapy

Why?

Radium-223 prolongs survival with the added

clinical benefit of decreasing risk of SSEs

associated with skeletal disease progression,

when compared to placebo.

• Reduction of osteoblast number (72 h post dosing)

• Decline of serum PSA levels upon Ra-223 treatment (significant difference 72 h post dosing)

Number of osteoblasts Serum-PSA

Radium-223 is a bone targeted therapy

MoA in LuCaP-58 osteoblastic prostate PDX- Autoradiography upon a single dose of Ra-223 -

Suominen et al, EORTC-NCI-AACR 2014 posterECTS-IBMS 2015 poster 139, oral poster CABS OP4.3

━ Radium-223 (n=614)━ Placebo (n=307)End of cycleFollow-up visit

P <0.001

0

-40

40

80

120

140

Mea

n (

Stan

dar

d E

rro

r)P

erce

nt

Ch

ange

Fro

m B

asel

ine

100

60

20

-20

Week

0 20 28 40 4844363224124 168

Sartor O, et al. J Clin Oncol. 31, 2013 (suppl; abstr 5080). Annals of Oncol (28): 1090-1097, 2017.

1 2 3 4 5 6 1 2

━ Radium-223 614 582 561 517 465 413 353 336 252━ Placebo 307 286 260 231 193 159 130 136 100

ALSYMPCA: ALP dynamics

38

12 week tALP decline vs overall survival

*Confirmed tALP decline was defined as any decrease from baseline at week 12, confirmed ≥3 weeks later

.

Sartor O, et al. J Clin Oncol. 31, 2013 (suppl; abstr 5080). Annals of Oncol (28): 1090-1097, 2017.

20

0

40

60

80

100P

atie

nts

, %

Months

0 32 4024168

MEDIAN OS (months)━ Confirmed tALP decline (n=400) 17.8━ No confirmed tALP decline (n=97) 10.4HR (95% CI): 0.45 (0.34-0.61)P <0.0001

39

The Vicious Cycle of Bone Metastases: can we target both the cancer cell and the microenvironment (osteoclasts and osteoblasts)?

Bisphosphonates

Denosumab

Ra223

A phase 3b, international, prospective, interventional, open-label, single-arm, multicenter EAP

• Eligibility criteria were generally similar to those of ALSYMPCA, with the exception that asymptomatic patients were allowed

• Concomitant treatment with abiraterone, enzalutamide or denosumab was permitted

International Expanded Access Program (iEAP) for radium-223

*Value is based on data assessed by previously used NIST standard. Updated nominal value of Xofigo is 55 kBq/kg body weight and not 50 kBq/kg body weight. Please see: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002653/WC500156172.pdf.

§BSoC according to local clinical practice. If chemotherapy/radiotherapy is considered BSoC, Ra-223 must be discontinued. ‡473 patients entered active follow-up.†Adverse events were coded according to MedDRA version 17.1 and graded by NCI-CTCAE version 4.03.

SOURCE: Saad F, et al. Lancet Oncol. 2016 Sep;17(9):1306-16.

TREATMENT (N=696)

Radium-223 (50 kBq/kg*) q 4 wk × 6 injections + best standard of care§

PATIENTS (N=839)

• CRPC/HRPC with bone metastasis

• ≥2 skeletal mets on imaging

• No lung/liver/brain mets(lymph node metastases allowed)

TREATMENT ASSESSMENTS(each cycle)

Variables: SREs, TEAEs, ECOG PS, lab tests, QoL (BPI-SF), OS

Exploratory: SREs, ALP, PSA (changes in levels and time to event data)

FOLLOW-UP‡

Safety† TEAEs, SAEs, secondary malignancies

PRIMARY ENDPOINTS

• Safety

• OS

EXPLORATORY ENDPOINTS

• Time to first SRE

• Changes in total ALP activity and PSA levels from baseline

• Time to ALP/PSA progression

• QoL

POST HOC ANALYSES INCLUDED OS IN SUBGROUPS BASED ON:

• Previous use of docetaxel, abiraterone or enzalutamide

• Concomitant use of abiraterone, enzalutamide or denosumab

• Baseline total ALP values

• Baseline ECOG PS

• Baseline hemoglobin

• Baseline pain

OS by concomitant treatment – novel endocrine agents and denosumab*

NA = not available.

*Concomitant use is defined as an agent started after the first injection of radium-223 (concomitant), or any agent administered before the provision of patient informed consent and continued after the first injection of radium-223 (continuous).

SOURCE: Saad F, et al. Lancet Oncol. 2016 Sep;17(9):1306-16.

Median duration of treatment with concomitant abiraterone or enzalutamide, which included all abiraterone or enzalutamide exposure on or after the first injection of radium-223, was 24.9 weeks (IQR 12.6–37.9) for abiraterone and 15.5 weeks (IQR 6.7–29.1) for enzalutamide.

MEDIAN OS, months (95% CI)

━ Yes (n=189): NA (16-NA)━ No (n=507): 13 (12-16)

CONCOMITANT USE OF NOVEL ENDOCRINE AGENTS

80

100

Ove

rall

Surv

ival

(%

)

20

0

60

40

2460 12 18

Time from Start of Treatment (months)

80

100

Ove

rall

Surv

ival

(%

)

20

0

60

40

2460 12 18

Time from Start of Treatment (months)

MEDIAN OS, months (95% CI)

━ Yes (n=136): NA (15-NA)━ No (n=560): 13 (12-NA)

CONCOMITANT USE OF DENOSUMAB

Cancer treatment-

induced bone loss

Treatment of

bone metastases

Bone-targeted therapies in Prostate cancer: updating the landscape


Prevention/delay

of bone metastases

???↑ ↑ ↑: mCRPC

Currently, there is no role for bisphosphonates and denosumab for the prevention of bone metastases in patients with PCa.

Anti-osteoclastic agents such as zoledronic acid and denosumab have a significant impact in bone metastases associated morbidity (Skeletal–events).

Radium-223 is a bone-targeted agent with significant impact in Overall Survival and in symptomatic skeletal-events incidence.

The association of Radium-223 with anti-osteoclastic agents seems to be beneficial to improve outcomes in mCRPC.

The majority of patients with mCRPC to bone should receive BTAs. Special attention should be given to patient’s comorbidities before starting BTAs and to the risk of ONJ in prolonged therapy with BTAs.

Summary

Integrate forefront scientific research

with medical teaching, medical training and patient care

Lisbon Academic Medical Center

Thank you for your attention,

Luís Costa

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