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Bone Directed Therapy in Prostate Cancer Matthew R. Smith, M.D., Ph.D. Program Director, Genitourinary Oncology Massachusetts General Hospital Cancer Center Associate Professor of Medicine Harvard Medical School Spectrum of Bone Disease in Prostate Cancer Castrate-sensitive nonmetastatic Castrate-resistant nonmetastatic Castrate-resistant metastatic Spectrum of Bone Disease in Prostate Cancer Treatment-Related Fractures Castrate-sensitive nonmetastatic Castrate-resistant nonmetastatic Castrate-resistant metastatic Spectrum of Bone Disease in Prostate Cancer Disease-Related Skeletal Complications Treatment-Related Fractures Castrate-sensitive nonmetastatic Castrate-resistant nonmetastatic Castrate-resistant metastatic Clinical Complications of Osteoblastic Metastases pain fractures spinal cord compression myelophthisis Markers of Osteoblast (BAP) and Osteoclast (NTx) Activity in Men with Metastatic Prostate Cancer BAP (U/L) Correlation coefficient = 0.67 Normal NTx (nmol/mmol creatinine) Adapted and reprinted by permission from the American Association for Cancer Research: Cook RJ et al. Markers of bone metabolism and survival in men with hormone-refractory metastatic prostate cancer. Clin Cancer Res 2006;12(11 Pt 1):3361-7. Bisphosphonates: Contemporary Phase 3 Trials in Castration-Resistant Metastatic Prostate Cancer STUDY POPULATION TREATMENT ENDPOINT NCIC Pr06 (n= 204) Symptomatic Mitoxantrone/prednisone ±clodronate Palliative response 032/INT 05 (n= 350) Symptomatic IV pamidronate vs placebo Pain score Analgesic use Zoledronic acid 039 (n= 643) Asymptomatic IV zoledronic acid vs placebo SRE Zoledronic Acid Study 039 randomize placebo q3w Castrate-resistant, bone metastases (n=643) zoledronic acid q3w Primary Endpoint: Skeletal Related Events (SRE) Saad F et al. J Natl Cancer Inst 2002;94(19):1458-68. Cumulative Incidence of Skeletal-Related Events Placebo Events/100 patients 100 P = 0.002 50 Zoledronic acid Skeletal Related Events Radiation to bone Pathologic fracture Spinal cord compression Surgery to bone Change in antineoplastic therapy 0 0 12 24 Time (months) With permission from Cook RJ and Lawless JF. Proc ASCO 2003;Abstract 3062. Denosumab–Targeting RANKL • • • • Fully human monoclonal antibody to RANKL IgG2 High affinity for human RANKL (Kd 3x10–12 M) Does not bind to human TNFα, TNFß, TRAIL, or CD40L • Approved to treat osteoporosis • In development to treat and prevent bone metastases Bekker PJ et al. J Bone Miner Res 2004;19:1059–66. Boyle WJ et al. Nature 2003;423:337–42. Phase 3 RCT of Denosumab versus Zoledronic Acid to Prevent Skeletal Related Events Castrate-resistant, Bone metastases, No prior bisphosphonate (n=1870) R A N D O M I Z E Primary Endpoint: Skeletal-related events Fizazi K et al. Proc ASCO 2010;Abstract LBA4507. Denosumab monthly Zoledronic acid monthly Phase 3 RCT of Denosumab versus Zoledronic Acid to Prevent Skeletal Related Events Castrate-resistant, Bone metastases, No prior bisphosphonate (n=1870) R A N D O M I Z E Denosumab monthly Zoledronic acid monthly Primary Endpoint: Skeletal-related events Accrual complete 2008 Q4 Final analyses 2010 Fizazi K et al. Proc ASCO 2010;Abstract LBA4507. Proportion of Subjects Without SRE Time to First On-Study SRE HR 0.82 (95% CI: 0.71, 0.95) P = 0.0002 (Non-inferiority) P = 0.008 (Superiority) 18% Risk Reduction KM Estimate of Median Months Denosumab Zoledronic acid 20.7 17.1 Study Month Subjects at risk: Zoledronic Acid 951 733 544 407 299 207 140 93 64 47 Denosumab 950 758 582 472 361 259 168 115 70 39 With permission from Fizazi K et al. Proc ASCO 2010;Abstract LBA4507. Cumulative Mean Number of SREs per Patient Time to First and Subsequent On-Study SRE* (Multiple Event Analysis) Rate Ratio = 0.82 (95% CI: 0.71, 0.94) P = 0.008 *Events occurring at least 21 days apart 18% Risk Reduction Events Denosumab Zoledronic acid Study Month With permission from Fizazi et al. Proc ASCO 2010;Abstract LBA4507. 494 584 Conclusions–Treatment of Bone Metastases • Disease-related skeletal complications are common in men with metastatic prostate cancer • Zoledronic acid decreases risk of SRE in men with castrate-resistant disease and bone metastases • Denosumab, a human monoclonal antibody targeting RANKL, is superior to zoledronic acid for prevention of SRE • Role of bone-targeted therapy in castrate-sensitive disease has not been established Natural History of Castration-Resistant Nonmetastatic Prostate Cancer Originally published by the American Society of Clinical Oncology. [Smith MR et al: 23(13), 2005: 2918-25]. PSA and PSA Doubling Time (PSADT) Are Associated with Shorter Bone Metastasis-Free Survival Originally published by the American Society of Clinical Oncology. [Smith MR et al: 23(13), 2005: 2918-25]. Denosumab to Prevent Metastases Castrate-resistant No bone metastases PSA≥8 or PSADT ≤10 mos (n~1500) Primary Endpoint: Bone metastasis-free survival www.clinicaltrials.gov. R A N D O M I Z E Denosumab monthly Placebo monthly Denosumab to Prevent Metastases Castrate-resistant No bone metastases PSA≥8 or PSADT ≤10 mos (n~1500) R A N D O M I Z E Denosumab monthly Placebo monthly Primary Endpoint: Bone metastasis-free survival Accrual complete 2008 Q2 Final analyses 2010 www.clinicaltrials.gov. ZEUS–Zoledronic Acid to Prevent Metastases High risk disease: Gleason sum 8-10, pN+, or PSA>20 ng/mL at diagnosis No bone metastases (n=1433) R A N D O M I Z E Primary Endpoint: First bone metastasis http://www.controlled-trials.com/ISRCTN66626762/zeus. Zoledronic acid q3 months for 48 months Placebo q3 months ZEUS–Zoledronic Acid to Prevent Metastases High risk disease: Gleason sum 8-10, pN+, or PSA>20 ng/mL at diagnosis No bone metastases (n=1433) R A N D O M I Z E Zoledronic acid q3 months for 48 months Placebo q3 months Primary Endpoint: First bone metastasis Anticipated completion date 2011 http://rand.dnsalias.com. ZEUS–Zoledronic Acid to Prevent Metastases High risk disease: Gleason sum 8-10, pN+, or PSA>20 ng/mL at diagnosis No bone metastases (n=1433) Primary Endpoint: First bone metastasis http://rand.dnsalias.com. R A N D O M I Z E Zoledronic acid q3 months for 48 months Placebo q3 months Study does not control for ADT 1. Some men will develop bone metastases prior to ADT 2. Dramatic variation in duration of response to ADT Conclusions–Metastasis Prevention • Prevention of bone metastases is an important unmet clinical need • Failure of prior studies is related, at least in part, to poorly defined natural history of castrate resistant nonmetastatic disease • The results of an aborted RCT of zoledronic acid have helped define the natural history of this disease state • An ongoing RCT in high-risk subjects will evaluate whether denosumab prevents metastases Consequences of Vertebral Fractures Pain • Kyphosis • Loss of height • Respiratory problems • Netter illustration used with permission of Elsevier, Inc. All rights reserved. www.netterimages.com. Proportion of Patients with Fractures 1-5 Years After Cancer Diagnosis +6.8%; P < 0.001 21 ADT (n = 6650) 18 19.4 15 12 No ADT (n = 20,035) 12.6 +2.8%; P < 0.001 9 6 5.2 3 2.4 0 Any Fracture Shahinian VB et al. N Engl J Med 2005;352:154-64. Fracture Resulting in Hospitalization Denosumab Fracture Prevention Study Current androgen deprivation therapy for prostate cancer; Age >70 or T score <-1.0 (n=1,468) R A N D O M I Z E Denosumab q6 months for 3 years Placebo q6 months for 3 years Primary Endpoint: change in lumbar spine BMD Key Secondary Endpoint: new vertebral fractures Smith MR et al. N Engl J Med 2009;361:745-55. Denosumab Increased BMD at All Skeletal Sites Smith MR et al. N Engl J Med 2009;361:745-55. © [2009] Massachusetts Medical Society. All rights reserved. Denosumab Decreased New Vertebral Fractures Smith MR et al. N Engl J Med 2009;361:745-55. © [2009] Massachusetts Medical Society. All rights reserved. Conclusions–Fracture Prevention • Androgen deprivation therapy increases fracture risk in prostate cancer survivors • A variety of drugs increase bone mineral density during androgen deprivation therapy • Toremifene, a SERM, increases bone mineral density and decreases incidence of new vertebral fractures • Denosumab increases bone mineral density and decreases incidence of new vertebral fractures