Advances in the management of skeletal related events

January 30, 2018 | Author: Anonymous | Category: Science, Health Science, Urology
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Advances in the Management of Skeletal Related Events/Bone Metastases in Prostate Cancer Robert Dreicer, M.D., M.S., FACP, FASCO Chair Dept of Solid Tumor Oncology Taussig Cancer Institute Cleveland Clinic Professor of Medicine Cleveland Clinic Lerner College of Medicine

Clinical States In Prostate Cancer (circa Winter 2014) Sipuleucel-T Organ Confined

Denosumab

Rising PSA Hormone Naive

Locally Advanced Disease

Metastatic Disease (De novo)

Metastases Castrate Resistant Asymptomatic

Cabazitaxel

Metastases Castrate Resistant Symptomatic

Metastases Castrate Resistant Post Docetaxel

Rising PSA Castrate

Metastases Castrate Resistant Post Cabazitaxel

Enzalutamide Abiraterone Radium 223

Modified from Scher H, et al. Urology 2000

Bone Issues in Prostate Cancer   

A major bone tropic neoplasm Bone issues vary along the disease spectrum Impact of ADT  

 

Osteoporosis Increase in osteoporotic related fx

Prevention/delay of bone metastases Castration resistant metastatic disease 

SRE (SSE) prevention

Bone Events Defined 

Skeletal Related Event (SRE)   

 



Radiation to bone Pathologic fracture Surgery to bone Spinal cord compression Hypercalcemia of malignancy

Symptomatic Skeletal Event (SSE)    

EBRT to relieve skeletal symptoms New symptomatic pathologic bone fracture Occurrence of spinal cord compression Tumor-related orthopedic surgical intervention

Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study 





1904 men with metastatic CRPC were randomized to receive denosumab (human monoclonal antibody against RANKL) or zolendronic acid The primary endpoint was time to first on-study SRE (pathological fracture, radiation therapy, surgery to bone, or spinal cord compression), and was assessed for non-inferiority The same outcome was further assessed for superiority as a secondary endpoint Fizazi K, et al. Lancet. 2011 377:813-22

Fizazi K, et al. Lancet. 2011 377:813-22

COU-AA-301: Abiraterone Acetate Improves Overall Survival in mCRPC HR = 0.646 (0.54-0.77) P< 0.0001

100

Abiraterone acetate: 14.8 months (95%CI: 14.1, 15.4)

Survival (%)

80

60

40 Placebo: 10.9 months (95%CI: 10.2, 12.0) 20 2 Prior Chemo OS: 14.0 mos AA vs 10.3 mos placebo

1 Prior Chemo OS 15.4 mos AA vs 11.5 mos placebo

0 0

100

200

300

400

500

Days from Randomization

de Bono J et al: N Engl J Med 364:19952005, 2011

600

700

Ryan CJ, et al. N Engl J Med 2013;368:138-48

Logothetis CJ, et al. Lancet Oncol 2012; 13: 1210–17

Scher H, et al. n engl j med 367:1187 2012

Impact of Enzalutamide, an androgen receptor signaling inhibitor, on time to first skeletal related event (SRE) and pain in the phase 3 AFFIRM Study

• Median time to first SRE for enzalumatide treated patients: 16.7 months versus 13.3 months for patients receiving placebo (hazard ratio [HR] = 0.69; P = .0001) 9 • Pain palliation: as > 30% reduction in mean pain score at week 13 versus baseline without a > 30% increase in analgesic use was achieved by 45% of patients on enzalutamide compared with only 7% of patients in the placebo group (P = .0079) Fizazi K, et al. ESMO 2012 Abstract 896O

ALSYMPCA (ALpharadin in SYMptomatic Prostate CAncer) Phase III Study Design TREATMENT PATIENTS • Confirmed symptomatic CRPC • ≥ 2 bone metastases • No known visceral metastases

• Postdocetaxel or unfit for docetaxel

6 injections at 4-week intervals

STRATIFICATION

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

R A N D O M I S E D 2:1

N = 922

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

Placebo (saline) + Best standard of care

Parker C, et al. N Engl J Med 2013;369:213-23

Questions 





Does the addition of “standard” bone targeted agents to next generation therapies “add”, “synergize” or “add nothing” to more effective therapies ? Does the introduction of more potent agents earlier mitigate the effect of older agents? Pharmacoeconomics 

Bone targeted agent with drugs that already impact on SRE?

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