Antiresorptive therapy to reduce SRE risk in men with bone-metastatic CRPC.For the majority of men with CRPC and bone metastases

Bertrand Tombal, MD, PhDCliniques universitaires Saint-LucUniversité catholique de Louvain Brussels, Belgium

Credentials and conflict of interests

§ Professor and Chairman, Division of Urology, Cliniques universitaires Saint Luc, Brussels, BE

§ PInvestigator and paid advisor for Amgen, Astellas, Bayer, Janssen, Ferring, Pfizer, Sanofi, Myovant.

§ This presentation reflects the personal view of Bertrand TOMBAL

§ BPA (bone protecting agent): zoledronic acid or denosumab at the SRE prevention dose.

Advanced PCa landscape in 2019

Mottet N et al. EAU guidelines on prostate cancer, update 2015; http://uroweb.org/guideline/prostate-cancer/ (accessed

March 2016); ADT: androgen deprivation therapy; PSA: prostate-specific antigen; rPSA: PSA recurrence; pRX: progr.: radiological progression; SRE: skeletal-related events: T/: treatment; Sy; Symptoms, SRE and deterioration of HR-QoL

± 2-4 years

Newly diagnosed metastatic

pRX. Sy. rPSA.

± 7-15 yearsHigh-risk localized

Local T/ADT

± ADT

ADT

± Local T/

mCRPC

mCRPCnmCRPC

rPSA. rPSA. pRX. Sy.

± Abi.

± docetaxel

The concept of Skeletal-related events

Bone metastases Skeletal-related events (SREs)

Increased painDecreased HRQoL

Increasedhealth resource

utilisation

Increasedcancer burden

Radiationto bone

Pathologicalfracture

Spinal cordcompression

Surgeryto bone

Patients with bone metastases from CRPC are at high risk of developing SREs

1. Incidence of bone metastases in TAX327 trial, adapted from: Tannock I, et al. N Eng J Med 2004;351:1502–12;2. Incidence of SRE in placebo, adapted from: Saad F, et al. J Natl Cancer Inst 2004;96:879–82.

Bone metastases1

SRE2

Patie

nts (

%)

Patients (%)

Spinal cord compression

Surgery

Radiation therapy

Pathologic fracture

Any

20 40 600

Zoledronic acid delays the onset of first and subsequent SREs

Saad F, et al. JNCI 2002;94:1458–68 and 2004;96:879–82

Reduced proportion of patientswith ≥1 SRE

Increased time to first SRE

P=0.021

P=0.222

Patie

nts w

ith ≥

1 SR

E(%

)

33.238.5

44.2

0

10

20

30

40

50

Zoledronic acid 4 mg

(n=214)

Zoledronic acid 8/4 mg(n=221)

Placebo(n=208) Time after start of study drug (days)

Patie

nts w

ithou

t eve

nt, %

90

10

20

30

40

50

60

70

80

90

100

00 180 450270 540360

Zoledronic acid 4 mg (P=0.011 vs placebo)Zoledronic acid 8/4 mg (P=0.491 vs placebo)Placebo

HR=0.82 (95% CI, 0.71–0.95)P=0.008 (superiority)

Study month

Time to first SRE (primary endpoint) (n=1901)

0 3 6 9 12 15 18 21 24 27

17.1 months

20.7 months

Pat

ient

s w

ithou

t SR

E (%

)

0

100

90

80

70

60

50

40

Denosumab Zoledronic acid

No. at risk

3970115168259361472582758950476493140207299407544733951

DenosumabZoledronic acid

30

20

10

18% Risk Reduction

Denosumab vs. zoledronic acid for the prevention of SRE in men with mCRPC

Fizazi, et al. Lancet 2011;377:813–22

Benefit of BPA on the 1st on-study SRE

1. Saad, et al. J Natl Cancer Inst 2004;96:879–82 2. Fizazi, et al. Lancet 2011;377:813–22

Placebo Zoledronic acid

Zoledronic acid

Denosumab

10.7

16.317.1

20.7

Med

ian

time

to fi

rst S

RE

(mon

ths)

10

20

0

10

20

0

Time to first SRE1 Time to first SRE2

BPA are recommended by many guidelines.

EAU/EANM/ESTRO/ESUR/SIOG

§ Offer bone protective agents to patients with

mCRPC and skeletal metastases to prevent

osseous complications.

NCCN

§ Recommended in CRPC patients with bone

metastases

https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf

https://uroweb.org/wp-content/uploads/EAU-EANM-ESUR-ESTRO-SIOG-Guidelines-on-Prostate-Cancer-2019.pdf

But,...These we are mostly speaking of very late patients

Zoledronic Ac. Vs.Placebo(1)

Denosumab vs. Zoledronic Acid(2)

Average number of bone metastases

4,2

Previous SRE 30% 24%Time since first bone metastasis

23.8 months 5.19 months

Pain at baseline 72.5 %

1. Saad, et al. J Natl Cancer Inst 2004;96:879–82 2. Fizazi, et al. Lancet 2011;377:813–22

No abiraterone, enzalutamide, and others

Advanced PCa landscape in 2019

Mottet N et al. EAU guidelines on prostate cancer, update 2015; http://uroweb.org/guideline/prostate-cancer/ (accessed

March 2016); ADT: androgen deprivation therapy; PSA: prostate-specific antigen; rPSA: PSA recurrence; pRX: progr.: radiological progression; SRE: skeletal-related events: T/: treatment; Sy; Symptoms, SRE and deterioration of HR-QoL

± 2-4 years

Newly diagnosed metastatic

pRX. Sy. rPSA.

± 7-15 yearsHigh-risk localized

Local T/ADT

± ADT

ADT

± Local T/

mCRPC

mCRPCnmCRPC

rPSA. rPSA. pRX. Sy.

± Abi.

± docetaxel

When to start BPA acid at SRE protection dose ?

§ There is clear evidence that for advanced patients, with multiples bone metastases, having experience previous SRE, BPA are recommended at the SRE preventing dose

§ But what for PREVAIL and COU-AA-302 patients ? ü Patients have a low bone metastatic burden, are usually SRE

free, and low pain

Advanced PCa landscape in 2019

Mottet N et al. EAU guidelines on prostate cancer, update 2015; http://uroweb.org/guideline/prostate-cancer/ (accessed

March 2016); ADT: androgen deprivation therapy; PSA: prostate-specific antigen; rPSA: PSA recurrence; pRX: progr.: radiological progression; SRE: skeletal-related events: T/: treatment; Sy; Symptoms, SRE and deterioration of HR-QoL

± 2-4 years

Newly diagnosed metastatic

pRX. Sy. rPSA.

± 7-15 yearsHigh-risk localized

Local T/ADT

± ADT

ADT

± Local T/

mCRPC

mCRPCnmCRPC

rPSA. rPSA. pRX. Sy.

± Abi.

± docetaxel

SRE still happen on enzalutamide and abiraterone. § 278 (32%) have experienced SRE at the time of analysis on 28% of death.

Time to fi rst skeletal-related event among chemotherapy-naive patients with metastatic castration-resistant prostate cancer (intention-to-treat population)Loriot Y et al. Lancet Oncol 2015;16:509-21

Incidence of SRE in Patients with CRPC: An Observational Retrospective Cohort Study in the US.

§ Incidence rates of first SREs in a 2.234 men with CRPC in the SEER-Medicare database.

Kawai AT et al. Prostate Cancer. 2019 Jul 9;2019:5971615

SRE % of Total Cohort

Radiation therapy 27.3

Fracture 11.9

Spinal cord compression 1.7

Bone surgery 1.0

Total 40.1

Person-time Included Patients Incidence rate/100 person-months

All person-time 2,234 3.78 (3,53-4,03)

BTA use

Person-time before BTA use 1,021 4.16 (3.71-4.65)

Person-time after BTA use1,539 3.60 (3.32-3.91)

Role of BPA in combination with abiraterone (Sub-analysis of COU-AA-302)

Post-hoc Kaplan-Meier Estimates in Overall Study Population

Prior BTT UseMedian (95% CI)

No Prior BTT Use,Median (95% CI)

HR(95% CI) p Value

Primary end points

rPFS 11.1(10.8, 13.8)

11.1(10.8, 13.6)

0.95(0.81-1.12)

0.565

OS 34.7(30.2, N/E)

31.2(28.6, 35.3)

0.92(0.75-1.12)

0.409

Secondary end points

Time to opiate use (cancer-related pain) 32.6 (28.3, N/E)

27.2(22.9, 30.3)

0.81(0.67-0.99)

0.037

Time to chemotherapy initiation 22.8(18.9, 29.1)

21.0 (18.7, 22.8)

0.87(0.73-1.03) 0.108

Time to ECOG PS deterioration 12.9(11.1, 15.3)

11.1(10.1, 12.0)

0.79(0.69-0.91)

0.001

Saad C et al. Eur Urol. 2015 Oct;68(4):570-7.

Longer exposure to ADT, as a result of better treatment increases the risk of non-pathological fractures

ADT-induced bone loss ® fractures Bone metastases Skeletal-related

events (SREs)

Increased painDecreased HRQoL

Increasedhealth resource

utilisation

Increasedcancer burden

Radiationto bone

Pathologicalfracture

Spinal cordcompression

Surgeryto bone

Fractures in ERA 223

AAP

+ Ra223

AAP

+ placebo

Patients with ≥1 fracture, n 29% 11%

No bone metastasis

at site of fracture, n79% 74%

Type of fracture, n

Pathological 25% 6

Traumatic 36% 13

Osteoporotic 49% 4

Indeterminate 1% 0

*Independent review of fractures was based on patients with fractures and available image scans: n=80 in AAP + radium-223

group, n=27 in AAP + placebo group. AAP, abiraterone acetate and prednisone/prednisolone; BHA, bone health agent.

Smith M, Lancet Oncol. 2019 Mar;20(3):408-419.

• 40% of the patients were receiving bone protecting agent (BPA) at entry.

• In post-hoc analyses, BPA significantly

impacted the rate of fracture in both arm (37% vs. 15% in Ra-223/AAP without vs. with BPA)

Post-Hoc Subgroup Analysis of Fractures by Baseline BHA Use in the ERA223 (abiraterone vs. abiraterone + RA223)

Patients with ≥1 fracture (%)

29

15

37

117

15

0

5

10

15

20

25

30

35

40

Overall population Patients with BHAs atbaseline

Patients without BHAs atbaseline

AAP + placebo

AAP + radium-223

Presented by T.HIGANO at ESMO symposium 2017AAP, abiraterone acetate and prednisone/prednisolone; BHA, bone health agent.

Cumulative incidence of fracture in the PEACE III/EORTC GUCG 1333 enzalutamide vs. enzalutamide + Ra223

Small numbers beyond month 20

Tombal B. et al. J Clin Oncol 37, 2019 (suppl; abstr 5007)

Safety of long-term BPA therapy:Cumulative median dmab exposure 12.0 months PCa (n = 942); 295 patients received denosumab for >3 years.

Stopeck et al. Support Care Cancer (2016) 24:447–455

ONJ: 5-10%

Why most patients should received BPA when mCRPC

§ Bone is the most frequent site of metastasis in men with prostate cancer.§ Development of bone metastasis is associated with disease progression,

increased mortality, and risk of SREs and SSEs.§ Non pathological fractures are increasingly seem in patients treated for long

durations with ARpI§ BPA significantly reduce the incidence of fractures and SRE§ Caveat:§ We don’t know if the registered SRE dosage is required at earlier stage of

the disease.