Matthew Raymond Smith, MD, PhD Professor of Medicine Harvard Medical School Program Director, Genitourinary Oncology Massachusetts General Hospital Cancer Center Boston, Massachusetts Bone-Modifying Agents to Prevent Bone Metastases in Men With Prostate Cancer This program is supported by an educational donation from

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clinicaloptions.com/oncology Maximizing Skeletal Integrity in Patients With Cancer Disclosure Matthew Raymond Smith, MD, PhD, has disclosed that he has received consulting fees from Amgen.

clinicaloptions.com/oncology Maximizing Skeletal Integrity in Patients With Cancer Case Presentation  66-yr-old man with clinical stage T3bNx prostate cancer, Gleason 4+3 in multiple cores, PSA 14  Treated with IMRT + combined ADT for 24 mos  PSA < 0.1 at completion of therapy  2 yrs later, resumed ADT for progressive PSA rise to 23.6; PSA nadir < 0.1  Now, 3 yrs after initiation of salvage ADT, PSA is elevated at 18; estimated PSADT is 6 mos  No detectable metastases by bone scan and abdominal- pelvic CT

clinicaloptions.com/oncology Maximizing Skeletal Integrity in Patients With Cancer What is your best estimate for median time to detectable bone metastases? A.< 6 mos B.9 mos C.18 mos D.> 30 mos

clinicaloptions.com/oncology Maximizing Skeletal Integrity in Patients With Cancer Natural History of Castration-Resistant Nonmetastatic Prostate Cancer Smith MR, et al. J Clin Oncol. 2005;23: Death Bone metastasis Bone metastasis or death Yrs Since Random Assignment Proportion With Event

clinicaloptions.com/oncology Maximizing Skeletal Integrity in Patients With Cancer Smith MR, et al. J Clin Oncol. 2005;23: PSA and PSADT Are Associated With Shorter Bone Metastasis–Free Survival Proportion of Patients With Bone Metastases or Died Yrs Since Random Assignment PSA 24.0 ng/mL Yrs Since Random Assignment PSADT 18.8 mos

clinicaloptions.com/oncology Maximizing Skeletal Integrity in Patients With Cancer Case  Patient received secondary hormonal therapy with bicalutamide 50 mg PO QD  Best response was PD  PSA is now 33  No detectable metastases on repeat bone scan and abdominal-pelvic CT

clinicaloptions.com/oncology Maximizing Skeletal Integrity in Patients With Cancer What do you recommend for bone- targeted therapy? A.Monthly zoledronic acid to prevent metastases B.Monthly denosumab to prevent metastases C.Observation until detectable bone metastases D.Other

clinicaloptions.com/oncology Maximizing Skeletal Integrity in Patients With Cancer Smith MR, et al. Lancet. 2012;379: Patients with M0 CRPC at high risk for bone metastases: PSA ≥ 8.0 ng/mL or PSADT ≤ 10.0 mos (N = 1432) Double-blind randomization Calcium and vitamin D supplementation Off investigational product Denosumab 120 mg SC q4w (n = 716) Placebo 120 mg SC q4w (n = 716) Survival follow-up Bone metastasis or death Phase III Study: BMFS With Denosumab in M0 CRPC With Aggressive PSA Kinetics  Primary endpoint: BMFS  Secondary endpoints: time to first bone metastasis (either symptomatic or asymptomatic), OS

clinicaloptions.com/oncology Maximizing Skeletal Integrity in Patients With Cancer Smith MR, et al. Lancet. 2012;379: Denosumab Increases Bone Metastasis– Free Survival Proportion of Patients Mos HR: 0.85 (95% CI: ; P =.028) Denosumab Placebo Median Survival, Mos Events, n Pts at Risk, n Denosumab Placebo

clinicaloptions.com/oncology Maximizing Skeletal Integrity in Patients With Cancer Time to First Bone Metastasis With Denosumab Smith MR, et al. Lancet. 2012;379: Proportion of Patients Mos HR: 0.84 (95% CI: ; P =.032) Denosumab Placebo Median Time, Mos Events, n

clinicaloptions.com/oncology Maximizing Skeletal Integrity in Patients With Cancer Smith MR, et al, Lancet. 2012;379: Denosumab in High-Risk M0 CRPC: Secondary Endpoints  OS: no improvement with denosumab vs placebo  Time to first bone metastasis prolonged with denosumab vs placebo  Fewer symptomatic bone metastases with denosumab vs placebo Study Month 0.2 Study Month Proportion of Patients Survived Placebo Denosumab HR: 1.01 (95% CI: ; P =.91) OS Proportion of Patients Without Symptomatic Bone Metastases Placebo Denosumab HR: 0.67 (95% CI: ; P =.013) Time to Symptomatic Bone Metastasis risk reduction Events, n (%) 96 (13) 69 (10) 33%

clinicaloptions.com/oncology Maximizing Skeletal Integrity in Patients With Cancer Denosumab and Adverse Events Smith MR, et al, Lancet. 2012;379: Adverse Events, n (%)Placebo (n = 705)Denosumab (n = 720) Any adverse event655 (93)676 (94) Most common adverse events  Back pain156 (22)168 (23)  Constipation119 (17)127 (18)  Arthralgia112 (16)123 (17)  Diarrhea102 (14)111 (15)  Urinary tract infection96 (14)108 (15) Serious adverse events323 (46)329 (46) Most common serious adverse events  Urinary retention31 (4)54 (8)  Hematuria24 (3)35 (5)  Prostate cancer21 (3)15 (2)  Anemia12 (2)22 (3)  Urinary tract infection14 (2)15 (2) Grade 3, 4, or 5 adverse events353 (50)381 (53) Adjudicated positive osteonecrosis of the jaw033 (5) Hypocalcaemia2 (< 1)12 (2)

clinicaloptions.com/oncology Maximizing Skeletal Integrity in Patients With Cancer Relationship Btwn PSADT & Risk for Bone Metastasis or Death: Placebo Arm of 147 Relative Risk for Bone Metastasis or Death PSADT in Mos Shorter PSADT Increasing Risk Smith MR, et al. ASCO GU Abstract 6.

clinicaloptions.com/oncology Maximizing Skeletal Integrity in Patients With Cancer Bone Metastasis-Free Survival in Patients with PSADT ≤ 10 Months HR = 0.84 (95% CI 0.72, 0.99) P = % Risk Reduction Smith MR, et al. ASCO GU Abstract 6. Proportion of Patients With Bone Metastasis-Free Survival Study Month Placebo Denosumab Median Months Events Delay (Months)

clinicaloptions.com/oncology Maximizing Skeletal Integrity in Patients With Cancer Bone Metastasis–Free Survival in Patients With PSADT ≤ 6 Mos HR: 0.77 (95% CI: ; P =.006) 23% risk reduction Smith MR, et al. ASCO GU Abstract 6. Proportion of Patients With Bone Metastasis–Free Survival Study Mo Placebo Denosumab Median Mos Events, n Delay, Mos

clinicaloptions.com/oncology Maximizing Skeletal Integrity in Patients With Cancer Bone Metastasis–Free Survival in Patients With PSADT ≤ 4 Mos HR = 0.71 (95% CI 0.56, 0.90) P = % Risk Reduction Proportion of Patients With Bone Metastasis–Free Survival Study Mo Placebo Denosumab Smith MR, et al. ASCO GU Abstract 6. Median Mos Events, n Delay, Mos

clinicaloptions.com/oncology Maximizing Skeletal Integrity in Patients With Cancer Conclusions  Bone metastases are a major cause of prostate cancer morbidity  Denosumab is the first bone-targeted therapy to delay bone metastases in men with prostate cancer  In men with high-risk nonmetastatic CRPC, denosumab increases bone metastasis–free survival, time to first bone metastasis, and time to symptomatic bone metastasis  Effects of denosumab on bone metastasis–free survival were maintained in men at particularly high risk

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