Saad et al [12] Metastatic CRPC. Bhoopalam et al [14] M0 PCa on ADT <1 yr vs >1 yr ADT

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1 Evolution of Treatment Options for Patients with and Bone Metastases Trials of Treatments for Castration-Resistant Prostrate Cancer Mentioned in This Review Bisphosphonates (Zometa) 4 mg IV 8 mg IV ( to 4 mg) Placebo 4 mg IV every 3 mos Placebo every 3 mos 4 mg IV every 3 mos Doubleblind Open-label single-arm Human Monoclonal Antibodies Denosumab (Xgeva) vs bisphosphonates 180 mg D SC 180 mg D SC every 12 wks 4 mg BP SC Denosumab vs 60 mg SC every 6 mos Placebo every 6 mos Denosumab vs zoledronic acid 120 mg D SC + IV 4 mg Z IV + SC Denosumab 120 mg D SSC Placebo Open-label Doubleblind Saad [12] Metastatic Bhoopalam [14] <1 yr vs >1 yr ADT Campbell [13] Osteoporosis Fizazi [19] Bone metastasis Prostate, breast, other cancers Smith [20] Fizazi [23] Metastatic Saad [24] High-risk PCa 11% absolute risk reduction in SRE Median time to first SRE was 321 days for vs not reached for intervention arm 5.95% on zoledronic acid vs decreased 3.23% on (in patients < 1 yr ADT) 6.08% on zoledronic acid vs increased 1.57% on (in patients > 1 yr ADT) 4.17% 25% experienced increase in BMD beyond osteoporotic range Normalized untx 64% D vs 37% BP (OR, 3.0; P =.01) Fewer SREs: 8% D vs 17% BP (OR, 0.31) 5.6% increase vs 1.0% decrease in BMD of lumbar spine at 24 mos Decreased incidence of vertebral fractures at 36 mos (1.5% vs 3.9%; RR, 0.38; P =.006) Time to first SRE, 20.7 mos on D vs 17.1 mos on Z (HR, 0.82; P =.008) Median increase of 4.2 mos in bone metastasisfree survival, no difference in OS (HR, 0.85; P =.03) 1364 ONCOLOGY December 2011 cancernetwork.com

2 Beta-Emitting Radionuclides 89 Sr (Metastron) vs 89 Sr vs external beam radiation Sm (Quadramet) EDTMP 18.5 megabecquerel/ Sm-EDTMP 18.5 megabecquerel/ Sm-EDTMP vs 152 Sm-EDTMP kg Induction chemotherapy followed by doxorubicin vs doxorubicin + 89 Sr Sm-EDTMP + docetaxel External Beam Radiotherapy Local vs local + hemibody radiation Systemic Chemotherapy Mitoxantrone (Novantrone) + vs estramustine (Emcyt) vs + Docetaxel vs 75 mg/m 2 docetaxel Crossover (2nd and 3rd arms on next page) Lewington Quilty Resche Serafini Sartor [28] Metastatic PCa [29] Metastatic PCa [30] Metastatic cancer [31] Prostate, breast, or lung cancer to bone [32] Metastatic Tu [34] Fizazi Poulter Petrylak [35] Metastatic [37] Cancer to bone [41] [47] M0 [48] Metastatic Absolute risk reduction of pain 32.1% No difference in OS Higher dose more effective at reducing pain scores than lower dose, without significant increase in adverse events Higher dose more effective at reducing opioid use (absolute risk reduction, 25.6%) than lower dose Significant reductions in opioid use with Sm-EDTMP (P <.05) 9% with > 50% reduction in PSA Overall survival 27.7 mos for combination therapy vs 16.8 mos for chemotherapy alone (HR, 2.76; P =.0014) PSA response in 77%; pain response in 69%; PSA progression-free survival, 6.4 mos; overall survival, 29 mos Time to disease progression, 6.3 vs 12.6 mos 29% vs 12% (P =.01) had improved pain; duration of pain relief longer, 43 vs 18 wks (P <.0001) OS, 17.5 vs 15.6 mos (P =.02); time to progression, 6.3 vs 3.2 mos (P <.001); > 50% PSA declines in 50% vs 17% (P <.001) OS, 18.9 vs 17.4 vs 16.5 mos; > 50% PSA declines in 45% vs 48% vs 32% (P <.001 for both comparisons with ) cancernetwork.com ONCOLOGY December

3 Evolution of Treatment Options for Patients with and Bone Metastases Systemic Chemotherapy Docetaxel vs (1st arm on previous page) 30 mg/m 2 docetaxel every wk for 5 of 6 wks 12 mg/m 2 Final follow-up for previous study Cabazitaxel (Jevtana) vs All received 10 mg daily 75 mg/m 2 docetaxel 12 mg/m 2 Immunotherapies (Provenge) Src Inhibitors Dasatinib (Sprycel) Dasatinib + docetaxel Dasatinib + vs + Phase I-II Berthold de Bono Small Burch Small Kantoff [48] Metastatic [49] Metastatic [52] Docetaxelresistant [54] Metastatic [55] Metastatic [56] [57] Yu [66] Araujo Ongoing [68] OS, 18.9 vs 17.4 vs 16.5 mos; > 50% PSA declines in 45% vs 48% vs 32% (P <.001 for both comparisons with ) OS, 19.2 vs 17.8 vs 16.3 mos OS, 15.1 vs 12.7 mos (HR, 0.70; P <.0001); progression-free survival, 2.8 vs 1.4 mos (HR, 0.74; P <.0001) Only 3 experienced > 50% decline in PSA Radiological time to progression, 118 d Radiological/pain/SRE/time to progression showed no difference; OS, 25.9 vs 21.4 mos (HR, 1.70; P =.01) OS, 25.8 vs 21.7 mos (HR, 0.78; P =.03); of note, 109 in the arm were allowed to receive salvage sipuleucel-t therapy 43% achieved reductions in untx at 12 wks, 19% at 24 wks [67] 2009 Metastatic 41% had PSA reductions; objective tumor response in 57% 155 NCT ONCOLOGY December 2011 cancernetwork.com

4 Endothelin A Receptor Antagonists Atrasentan (Xinlay) Atrasentan Atrasentan Zibotentan Atrasentan + vs + Zibotentan + docetaxel vs docetaxel Zibotentan Clusterin Inhibitors + vs + vs vs Carducci Carducci Nelson James NCT [77] [73] [74] M0 [75] Metastatic [76] Chemotherapyresistant NCT [78] 1445 Completed August 2011, awaiting final results Chi [79] 848 asymptomatic [81] Saad [82] Chemotherapyresistant Ongoing [83] 800 Metastatic Time to progression, 155 vs 71 d (P =.002) No differences in time to progression No differences in time to progression OS, 23.5 vs 17.3 mos (HR, 0.65; P =.052) Study closed early based on negative results of interim analysis, announced in Southwest Oncology Group Apr 21, 2011 press release Study closed early based on negative results of interim analysis, announced in AstraZeneca Feb 7, 2011 press release NCT OS, 23.8 mos with vs 16.9 mos without (HR, 0.50; 95% CI, ) OS, 15.8 mos in the arm vs 11.5 mos in the + arm 70% reduction in hazard of death (HR, 0.3; P <.001) for low clusterin levels Median time to pain progression 10.0 vs 5.2 mos NCT cancernetwork.com ONCOLOGY December

5 Evolution of Treatment Options for Patients with and Bone Metastases Clusterin Inhibitors Docetaxel retreatment Ongoing [84] 292 NCT or cabazitaxel Metastatic with vs docetaxel retreatment or cabazitaxel with Alpha-Particle Emitters 223 Ra 223 Ra Nilsson Ended early, awaiting final results [88] Symptomatic [90] Symptomatic OS, 65 vs 46 wks (P =.02); time to PSA progression, 26 vs 9 wks; no difference seen in time to SRE 30% reduction in the odds of dying during follow-up in treatment arm; median increase in OS of 3 mos ADT = androgen-deprivation therapy; BMD = bone mineral density; BP = bisphosphonates; CI = confidence interval; = castration-resistant prostate cancer; D = denosumab; EDTMP = ethylenediaminetetramethylene phosphonic acid; HR = hazard ratio; OR = odds ratio; OS = overall survival; PCa = prostate cancer; PSA = prostate-specific antigen; = randomized-controlled trial; RR = relative risk; SRE = skeletal-related events; untx = urinary N-telopeptide; Z = zoledronic acid. postmenopausal women and in men with. It is currently FDAapproved for use in both postmenopausal women and men with advanced prostate cancer and bone metastase, to prevent bone loss and subsequent fracture.[17,18] The latter group presents a particular challenge with respect to potential loss in BMD and subsequent SREs for several reasons, including prolonged use of ADT and/or development of skeletal metastasis. Below we highlight several of the key studies of denosumab that have been published to date. In a phase II trial of denosumab in patients with bone metastases from prostate, breast, and other cancers who were noted to have persistently elevated bone turnover markers (urinary N-telopeptide [untx]) while receiving intravenous (IV) bisphosphonate treatment, patients were randomly assigned ADDRESS ALL CORRESPONDENCE TO: E. David Crawford, MD University of Colorado, Anschutz Medical Campus Mail Stop #F710, P.O. Box 6510 Aurora, CO david.crawford@ucdenver.edu to receive subcutaneous denosumab or continuation of the IV bisphosphonate. This study noted that more patients achieved normal levels of urinary bone turnover markers (about 64% vs 37%; P =.01) and that patients experienced fewer SREs (8% vs 17%; odds ratio [OR], 0.31; 95% confidence interval [CI], ) with denosumab than with bisphosphonate treatment. Similar numbers of patients suffered adverse events in the two arms.[19] In 2009, Smith published the results of a phase III randomized controlled trial comparing denosumab to in patients with non PCa who were receiving ADT. The key endpoints were percent change in BMD in the lumbar spine, total hip, and femoral neck at 24 and 36 months, and incidence of new vertebral fractures. [20] by 5.6% in the treatment group as opposed to a BMD decrease of 1.0% in the arm (P <.001). Patients who received denosumab also experienced a decreased incidence of new vertebral fractures at 36 months (1.5% vs 3.9% with ) (relative risk, 0.38; 95% CI, 0.19 to 0.78; P =.006). Subsequent analyses noted that patients with high baseline levels of turnover markers (serum C-telopeptide and tartrateresistant alkaline phosphatase 5b) had the greatest increases in BMD.[21] studies comparing denosumab to the bisphosphonate zoledronic acid with respect to time to development of a first SRE in patients with and at least one bone metastasis were published in 2010.[22,23] Denosumab improved the median time to development of a first SRE (20.7 months vs 17.1 months for zoledronic acid, a difference of 3.6 months). Rates of osteonecrosis of the jaw were not significantly different between the two study arms, at 2.3% and 1.3%, respectively (P =.09), but hypocalcemia was observed more frequently with denosumab than with zoledronic acid (13% vs 6%). This report showed no difference in overall survival between the two groups. Recently, results were presented regarding the ability of denosumab to prevent the development of bone metastasis.[24] Some have hypothesized that, by limiting bone turnover and resorption, denosumab may make bone an environment that is less amenable to cir ONCOLOGY December 2011 cancernetwork.com

Advanced Prostate Cancer. November Jose W. Avitia, M.D

Advanced Prostate Cancer. November Jose W. Avitia, M.D Advanced Prostate Cancer November 4 2017 Jose W. Avitia, M.D In 2017 161,000 new cases of prostate cancer diagnosed in US, mostly with elevated PSA 5-10% will present with metastatic disease In 2017: 26,000