Università Campus Bio-Medico Daniele Santini Università Campus Bio-Medico Roma

> 3 Bone Lesions associated With Shorter Survival Curatio PowerPoint Template Zoledronic Acid (ZOMETA®) in Breast Cancer 3/27/2017 5:32 AM > 3 Bone Lesions associated With Shorter Survival Baseline (n = 376) P < .0001 3 6 9 12 15 18 21 24 Time since randomization, months Proportion died 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 < 3 > 3 Shirina N, et al. Presented at ASCO 2006. Poster 8529.

> 3 Bone Lesions Associated with Shorter Time to SRE Curatio PowerPoint Template Zoledronic Acid (ZOMETA®) in Breast Cancer 3/27/2017 5:32 AM > 3 Bone Lesions Associated with Shorter Time to SRE Baseline (n = 376) P < .0001 < 3 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 3 6 9 12 15 18 21 24 Time since randomization, months Proportion with SRE > 3 Shirina N, et al. Presented at ASCO 2006. Poster 8529.

Patients With Bone Metastases From Pca Are at High Risk for Developing SREs Any Pathologic fracture Radiation therapy Surgical intervention Spinal cord compression Patients With SRE, % 24 months Saad F, et al. JNCI. 2002;94(19):1458-1468; Saad F, et al. Eur Urol Suppl. 2007;6(11):683-688. 4 4

Change/Standard Deviation Skeletal Complications Reduce Quality of Life in Prostate Cancer Patients Total Physical Functional Emotional a Change/Standard Deviation a a a a a Change in FACT-G score for patients with an event vs patients without an event a P < .05. Data from Weinfurt KP, et al. Ann Oncol. 2005;16(4):579-584. 5

SREs Are Associated With Lower Survival in Prostate Cancer 360 Days Survival No SRE: 49.7% ≥ 1 SRE: 28.2% P = .02 Median Survival Times No SRE: 338 days (95% CI = 189, 460) ≥ 1 SRE: 248 days (95% CI = 181, 296) No SRE (n = 355) ≥ 1 SRE (n = 116) 1 0.9 0.8 0.7 0.6 Probability 0.5 0.4 0.3 0.2 0.1 90 180 270 360 Survival, days Abbreviations: CI, confidence interval; SRE, skeletal-related event. DePuy V, et al. Support Care Cancer. 2007;15:869-876. 6

FISIOPATOLOGIA DELLA METASTASI ADDENSANTE Osteocalcina ALP TGF-b1 IGF1 TGFb-1 IGF1 TGFb-1 ET1 uPA Wnt DDK-1 >RANKL/<OPG PTHrP IL-6 OPG Bertoldo F, Santini D Textbook of Osteoncology 2010

Skeletal complications according to types and number of bone lesions p=n.s. % of patients undergoing SRE p=0.01

Skeletal Related Event (SRE) free survival according to types and number of bone lesions < 3 bone lesions 4-6 bone lesions > 6 bone lesions Mixed bone lesions Blastic bone lesions Cumulative proportion SRE free surviving Cumulative proportion SRE free surviving Months Months

Target therapies and potential applications in prostate cancer CTIBL Bone met prevention in castration resistant prostate cancer patients SREs in castration resistant metastatic disease

Prevention of Bone Metastases in PC: Phase III Denosumab Trial (AMG 147) Primary endpoint: Time to development of bone metastasis or death Secondary endpoint: Time to development of bone metastasis (excluding death) R A N D O M I Z T N = 1.435 Prostate cancer (non metastatic) Hormone-refractory disease High risk of bone metastases (PSA at least 8 and/or PSA doubling time less than 10 months Adequate organ function Denosumab 120 mg SC every 4 weeks Placebo Event-driven study: time to bone metastasis or death Smith MR, et al. Lancet. 2012. 11 11 11

Sopravvivenza libera da metastasi ossee in pazienti con PSADT ≤4 mesi F. Saad, ASCO 2012

Target therapies and potential applications in prostate cancer CTIBL Bone met prevention in castration resistant prostate cancer patients SREs in castration resistant metastatic disease

ZOL Reduced All Types of SREs vs Placebo at 2 Years in Patients With Bone Metastases From PC 38 26 17 4 6 2 49 33 25 8 7 1 10 20 30 40 50 60 Any SRE Radiation to Bone Fractures Spinal Cord Compression Change in Antineoplastic Therapy Surgery to Bone HCM Zoledronic acid 4 mg (n = 214) Placebo (n = 208) Patients With SRE, % Abbreviations: HCM, hypercalcemia of malignancy; SRE, skeletal-related event. Adapted from Saad F, et al. Eur Urol Suppl. 2007;6(11):683-688. 14 14 14

Study Design: International, Randomised, Double-Blind, Active-Controlled Study XGEVA™ PI 2010: 9,14 Fizazi K, et al. Lancet 2011;377: 815,Table 1 Key Inclusion Criteria Castration-resistant prostate cancer and 1 bone metastases Key Exclusion Criteria Current or prior IV bisphosphonate treatment N = 950 denosumab 120 mg SC and placebo IV Q4W XGEVA™ PI 2010: 2,2.1 Fizazi K, et al. Lancet 2011;377: 815,A,1 Fizazi K, et al. Lancet 2011;377: 814,B,1-2 Supplemental calcium and vitamin D strongly recommended Fizazi K, et al. Lancet 2011;377: 815,A,2 N = 951 zoledronic acid 4 mg IV* and placebo SC Q4W XGEVA™ PI 2010: 9,14 Fizazi K, et al. Lancet 2011;377: 813,Methods Key Points This was an international, randomized, double-blind, active-controlled trial comparing denosumab with zoledronic acid for the treatment of bone metastases in patients with castration-resistant prostate cancer The primary endpoint was time to first on-study SRE comparing denosumab with zoledronic acid for noninferiority Secondary efficacy endpoints, evaluated only if noninferiority was demonstrated, were superiority tests comparing denosumab and zoledronic acid for time to first on-study SRE and time to first and subsequent SRE(s) (multiple-event analysis) Background Eligible patients were men  18 years old with histologically confirmed prostate cancer and current or prior radiographic evidence of at least one bone metastasis and documented failure of at least 1 hormonal therapy Patients were randomized 1:1 to receive either SC injections of denosumab 120 mg and an IV placebo Q4W, or an IV infusion (lasting no less than 15 minutes) of zoledronic acid 4 mg and an SC injection of placebo Q4W Daily supplementation with calcium and vitamin D was strongly recommended Key exclusion criteria included current or prior IV bisphosphonate or oral bisphosphonate administration to treat bone metastasis References XGEVA™ (denosumab) prescribing information, Amgen. Fizazi K, Carducci M, Smith M, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet. 2011;377:813-822. Primary Endpoint Time to first on-study skeletal-related event (SRE) (noninferiority) Secondary Endpoints Time to first on-study SRE (superiority) Time to first and subsequent on-study SRE(s) (superiority) Fizazi K, et al. Lancet 2011;377: 815,A,2 XGEVA™ PI 2010: 9,14 Fizazi K, et al. Lancet 2011;377: 814,A,2;B,1 Fizazi K, et al. Lancet 2011;377: 814,B,5; 815,A,1 Fizazi K, et al. Lancet. 2011;377:813–822. XGEVA™ PI 2010: 2,2.1 Fizazi K, et al. Lancet 2011;377: 815,A,1 XGEVA™ PI 2010: 3,6.1 Fizazi K, et al. Lancet 2011;377: 814,B,1-2 15

Primary Endpoint: Time to First On-Study SRE XGEVA™ PI, 2010: 11,Table 2 Fizazi K, et al. Lancet 2011;377: 816,Figure 2 HR = 0.82 (95% CI, 0.71–0.95) P  0.001 (noninferiority) P = 0.008 (superiority) 1.00 0.75 Proportion of Subjects Without SRE 0.50 Kaplan-Meier Estimate of Median Months 0.25 Key Points Denosumab significantly delayed the time to first on-study SRE by 18% compared with zoledronic acid (HR = 0.82; 95% CI, 0.71–0.95; P  .001 for noninferiority and P = .008 for superiority)1 The median (95% CI) time to first on-study SRE was 20.7 months in the denosumab group and 17.1 months in the zoledronic acid group, a difference of 3.6 months1 Between-group divergence is evident beginning at 3 months after initiation of treatment2 References XGEVA™ (denosumab) prescribing information, Amgen. Fizazi K, Carducci M, Smith M, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet. 2011;377:813-822. Denosumab Zoledronic acid 20.7 XGEVA™ PI, 2010: 11,Table 2 17.1 0.00 Fizazi K, et al. Lancet 2011;377: 816,Figure 2 3 6 9 12 15 18 21 24 27 Study Month Patients 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 Fizazi K, et al. Lancet. 2011;377:813–822. 16

Cumulative Mean Number of SREs per Patient Secondary Endpoint: Time to First and Subsequent On-Study SRE(s) (Multiple-Event Analysis) XGEVA™ PI, 2010: 11,Table 2 Fizazi K, et al. Lancet 2011;377: 816,Figure 3 2.0 Rate ratio = 0.82 (95% CI, 0.71–0.94) P = 0.009 (superiority) 1.8 1.6 1.4 1.2 Cumulative Mean Number of SREs per Patient 1.0 0.8 0.6 Key Points Denosumab significantly delayed the time to first and subsequent on-study SREs (rate ratio = 0.82; 95% CI, 0.71–0.94; adjusted P = .009)1 A total of 1078 events occurred, 494 in the denosumab treatment group, and 584 in the zoledronic acid treatment group2 References XGEVA™ (denosumab) prescribing information, Amgen. Fizazi K, Carducci M, Smith M, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet. 2011;377:813-822. XGEVA™ PI, 2010: 11,Table 2 Events 0.4 Denosumab 494 Fizazi K, et al. Lancet 2011;377: 816,Figure 3 0.2 Zoledronic acid 584 0.0 3 6 9 12 15 18 21 24 27 30 33 36 Study Month Fizazi K, et al. Lancet. 2011;377:813–822. 17

Exploratory Endpoint: Overall Survival Fizazi K, et al. Lancet 2011;377: 817,Figure 4,A HR = 1.03 (95% CI, 0.91–1.17) P = 0.65 1.00 0.75 Proportion of Patients Survived 0.50 0.25 Fizazi K, et al. Lancet 2011;377: 817,Figure 4,A Key Points Overall survival (HR = 1.03; 95% CI, 0.91–1.17; P = .65) was similar between study groups1 Overall survival and progression-free survival were similar between arms in all three trials1 Mortality was higher with denosumab in a subgroup analysis of patients with multiple myeloma (HR = 2.26; 95% CI, 1.13–4.50; n = 180)2 References Fizazi K, Carducci M, Smith M, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet. 2011;377:813-822. XGEVA™ (denosumab) prescribing information, Amgen. Denosumab Zoledronic acid XGEVA™ PI, 2010: 10-14 0.00 3 6 9 12 15 18 21 24 27 30 Study Month Patients at Risk: Zoledronic acid 951 864 745 635 519 401 297 207 143 98 Denosumab 950 872 746 645 552 427 310 233 156 99 55 54 Fizazi K, et al. Lancet. 2011;377:813–822. 18

J Brown EAU, 2011

Skeletal Complication Risk: Incremental Benefits in Prostate Cancer Zoledronic ~ 20% risk reduction No bisphosphonate 49% risk at 2 yrs Denosumab Additional 18% time to first SRE increase Denosumab Additional ~ 12% risk reduction + Saad F, JNCI, 2004, Fizazi K, Lancet, 2011 20

Why should we use CT/HT to delay skeletal related events? To improve overal survival To improve quality of life To delay SRE To delay bone metastases

Abiraterone post-docetaxel does improve Overall Survival Fizazi K et al. Lancet Oncology, 2012

Abiraterone pre-docetaxel does improve Overall Survival 546 542 538 534 482 465 452 437 27 25 524 509 503 493 2 120 106 258 237 412 387 100 80 60 40 20 Survival (%) 3 12 15 Time to Death (Months) 33 Abiraterone Prednisone 6 9 30 24 21 18 Abiraterone (median, mos): NR Prednisone (median, mos): 27.2 HR (95% CI): 0.75 (0.61-0.93) P value: 0.0097 Ryan et al. NEJM, 2013 23

Enzalutamide post-docetaxel does improve Overall Survival Scher HI et al, NEJM, 2012

Radium-223 does improve Overall Survival S Nilsson et al, Clinical Genitourinary Cancer, 2013

Cabazitaxel does improve Overall Survival De Bono JS et al. Lancet 2010

Why should we use CT/HT to delay skeletal related events? To improve overal survival To improve quality of life To delay SRE To delay bone progression

Abiraterone post-docetaxel improve quality of life Abiraterone + Prednisone (n = 797) Placebo + Prednisone (n = 398) P Value Palliation, n (%) 132/223 (59.2) 38/100 (38.0) 0.0004 Median Time to palliation (months) (95% CI) 1.02 (0.92-1.91) 3.71 (2.69-4.44) 0.0009 When comparing self-reported pain interference in AA-treated patients with placebo-treated patients, there is an increased proportion of palliation, greater duration of palliation and a longer time to symptom progression  all favored the AA arm Curves of time to palliation and time to progression of pain interference are similar to those shown for pain intensity Logothetis et al. Lancet Oncology, 2012

Abiraterone pre-docetaxel improve quality of life AA + P (months) Placebo + P (months) P Value Hazard Ratio (95% CI) FACT-G 16.6 11.1 0.002 0.76 (0.63-0.91) PCS 5.8 < 0.001 0.70 (0.60-0.83) Physical well- being 14.8 0.76 (0.64-0.90) Functional well-being 13.3 8.4 0.001 Emotional well-being 22.1 14.2 0.71 (0.59-0.87) Social/Family well-being 18.4 0.528 0.94 (0.78-1.14) Ryan et al. NEJM, 2013 29

Enzalutamide post-docetaxel improve quality of life JS De Bono, ASCO, 2012

Radium-223 improve quality of life Parker CC et al. Eur Urology, 2012

Cabazitaxel improve quality of life Tombal B, EAU, 2011

Why should we use CT/HT to delay skeletal related events? To improve overal survival To improve quality of life To delay SRE To delay bone progression

Abiraterone post-docetaxel does delay SREs 4.7 months of difference SRE defined as: pathological fracture, spinal cord compression, palliative radiation to bone, or bone surgery Convergence between additional outcomes and Pain/SRE data: AA not only delayed pain progression, but also provided pain palliation, associated with delayed time to SRE, increased overall survival, and greater progression free survival Logothetis et al. Lancet Oncology, 2012

Abiraterone post-docetaxel does delay SREs SRE defined as: pathological fracture, spinal cord compression, palliative radiation to bone, or bone surgery Convergence between additional outcomes and Pain/SRE data: AA not only delayed pain progression, but also provided pain palliation, associated with delayed time to SRE, increased overall survival, and greater progression free survival Logothetis et al. Lancet Oncology, 2012

Enzalutamide post-docetaxel does delay SREs 3.4 months of difference Pre-planned analysis JS De Bono, ASCO, 2012

Enzalutamide post-docetaxel does reduce SREs

Radium-223 does delay SREs 5.5 months of difference Pre-planned analysis C Parker et al, ASCO, 2012

Cabazitaxel No data on SREs

Why should we use CT/HT to delay skeletal related events? To improve overal survival To improve quality of life To delay SRE To delay bone progression

Abiraterone post-docetaxel does delay bone progression Abiraterone + Prednisone (n = 797) Placebo + Prednisone (n = 398) P Value Time to progression (months) 25th percentile (95% CI) 9.27 (7.39-12.88) 4.57 (2.79-6.47) 0.0019 When comparing self-reported pain interference in AA-treated patients with placebo-treated patients, there is an increased proportion of palliation, greater duration of palliation and a longer time to symptom progression  all favored the AA arm Curves of time to palliation and time to progression of pain interference are similar to those shown for pain intensity Logothetis et al. J Clin Oncol 2011; 29 (Suppl): Abstract 4520 (oral presentation)

Abiraterone pre-docetaxel does delay bone progression 100 80 60 40 20 Progression-Free (%) 3 6 9 15 18 12 546 542 489 400 340 204 164 90 46 30 Time to Progression or Death (Months) Abiraterone Prednisone Abiraterone (median, mos): NR Prednisone (median, mos): 8.3 HR (95% CI): 0.43 (0.35-0.52) P value: < 0.0001 Abiraterone Prednisone Ryan et al. NEJM, 2013 43

Enzalutamide post-docetaxel does delay bone progression Scher HI et al, NEJM, 2012

Cabazitaxel does delay disease progression De Bono JS et al., Lancet, 2010

Abstract 4513 Cabozantinib (XL184) in chemotherapy-pretreated metastatic castration resistant prostate cancer (mCRPC): Results from a phase II nonrandomized expansion cohort (NRE). Autori, Matthew Raymond Smith, Christopher Sweeney, Dana E. Rathkopf, Howard I. Scher, Christopher Logothetis, Daniel J. George, Celestia S. Higano, Evan Y. Yu, Andrea Lynne Harzstark, Eric Jay Small, A. Oliver Sartor, Michael S. Gordon, Nicholas J. Vogelzang, David C. Smith, Maha Hussain, Johann Sebastian De Bono, Naomi B. Haas, Christian Scheffold, Yihua Lee, Paul G. Corn; ASCO 2012

Risposta sulle lesioni ossee (revisione indipendente)

What about bisphosphonate and denosumab? To improve overal survival NO To improve quality of life YES To delay SRE YES To delay bone progression NO

What about new HT/CT agents in CRPC? To improve overal survival YES To improve quality of life YES To delay SRE YES To delay bone progression YES

Open Issues 1 Nello studio AA post-docetaxel il 42% circa dei pazienti avevano ricevuto bisfosfonati in ciascun braccio di trattamento: come sono andati i pazienti non trattati con BPs? Nello studio MDV-3100 post-docetaxel il 30% circa dei pazienti avevano ricevuto bisfosfonati in ciascun braccio di trattamento: come sono andati i pazienti non trattati con BPs? Necessità di studi mirati a valutare l’effetto di AA e MDV-3100 sui marker di riassorbimento osseo (CTX, NTX, BALP): cosa succederebbe se scoprissimo una modulazione degli stessi?

Open Issues 2 Necessità di studiare le modificazioni del metabolismo osseo in corso di terapia combinata tra bone target therapies e nuovi farmaci ormonali Necessità di comprendere meglio quando e per chi usare le bone target therapies INSIEME ai nuovi farmaci: Al momento della comparsa delle metastasi ossee Al momento dell’introduzione della nuova terapia ormonale Al momento dell’incremento dei marker di riassorbimento osseo A tutti i pazienti con metastasi ossee? Esiste un effetto antitumorale sinergico?

Skeletal Complication Risk: Incremental Benefits in Prostate Cancer Zoledronic ~ 20% risk reduction No bisphosphonate 49% risk at 2 yrs Denosumab Additional 18% time to first SRE increase Denosumab Additional ~ 12% risk reduction + Questi dati sono pre-era nuovi farmaci…. ora la storia deve essere riscritta Saad F, JNCI, 2004, Fizazi K, Lancet, 2011 52

Thank you very much for your attention d.santini@unicampus.it