1. CONVEGNO URO-ONCOLOGIA 7 Novembre 2015
Il controllo degli Eventi scheletrici
Nel paziente con tumore alla prostata
Metastatico alle ossa
Fabio Fulfaro
Ricercatore Universitario
Policlinico Paolo Giaccone
Palermo

2. METASTASI OSSEE epidemiologia
~30% dei pazienti con tumore metastatico sviluppa metastasi ossee clinicamente evidenti nel corso della malattia
Un ulteriore 50% di queste localizzazioni può essere osservato al tavolo autoptico
80% di tutti i casi derivano da primitività mammaria, prostatica e polmonare

3. METASTASI OSSEE Incidenza
Primary
Mieloma
Rene
Tiroide
Mammella
Polmone
Vescica
Melanoma
Prostata %
65 – 75 75 60
20 – 25
> LITICHE
> ADDENSANTI
Coleman RE. Cancer Treat Rev. 2001;27:

8. Bone Markers in Osteolytic and Osteosclerotic Metastatic Bone Disease60
500 50
400 40
300
Bone-specific alkaline phosphatase (ng/mL) 30
N-telopeptide (BCE/M Cr)
200 20
100 10
Lytic
Blastic
Mixed
Lytic
Blastic
Mixed
X-ray pattern
X-ray pattern
Lipton A. Semin Oncol. 2012;28:54-59.

11. Bone metastases can have serious and debilitating consequences  SREs
Skeletal-related events (SREs) are defined as:1,2
A composite SRE endpoint is commonly used in clinical trials to evaluate the efficacy of bone-targeted agents2
Pathological fractures may be symptomatic or identified by imaging assessments
Recently, symptomatic skeletal events (SSEs) has been used as an alternative study endpoint for skeletal complications3
Pathological fractures only included if clinically symptomatic
Hypercalcaemia of malignancy is an additional potential complication of bone metastases4
Radiation to bone
Pathological fracture
Spinal cord compression
Surgery to bone
Bone metastases can result in serious and debilitating SREs.1
Since the late 1990s, SREs have been defined as spinal cord compression, radiation to bone, pathological fracture or surgery to bone.2
Spinal cord compression is considered an oncological emergency and suspected cases require urgent evaluation and treatment3
Radiotherapy to bone is often administered as palliative therapy for bone pain4
Pathological fractures can result when metastases destruct bone and reduce the load-bearing capacity; painful microfractures may develop into full fractures3
Surgery to bone may be required to stabilise pathological fractures or pre-empt the occurrence of fractures in vulnerable areas.3
A composite SRE endpoint is often used in clinical trials to evaluate the efficacy of bone-targeted agents to prevent skeletal complications in patients with bone metastases.2
Symptomatic skeletal events (SSEs) was used as an alternative skeletal endpoint in a recently reported Phase III trial of radium-223 in men with castration-resistant prostate cancer (CRPC) and bone metastases.5
The definition of SSE differs from SRE in that pathological fractures are required to be clinically apparent (symptomatic) whereas they may be identified by periodic radiological review to be classified as an SRE.
Hypercalcaemia of malignancy is an additional potential complication of bone metastases.3
References
Saad F, Gleason DM, Murray R, et al. Long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer. J Natl Cancer Inst 2004;96:879–2.
(Accessed August 2014).
Coleman RE. Clinical features of metastatic bone disease and risk of skeletal morbidity. Clin Cancer Res 2006;12:6243s–9s.
Chow E, Harris K, Fan G, et al. Palliative radiotherapy trials for bone metastases: a systematic review. J Clin Oncol 2007;25:1423–36.
Sartor O, Coleman R, Nilsson S, et al. Effect of radium-223 dichloride on symptomatic skeletal events in patients with castration-resistant prostate cancer and bone metastases: results from a phase 3, double-blind, randomised trial. Lancet Oncol 2014;15:738−46.
1. Saad F, et al. J Natl Cancer Inst 2004;96:879–82; 2. (Accessed August 2014); 3. Sartor O, et al. Lancet Oncol 2014;15:738−46; 4. Coleman RE, et al. Clin Cancer Res 2006;12:6243s−9s. 11

12. Cumulative incidence of on-study SREs
SREs are a common complication in patients with solid tumours and bone metastases
Cumulative incidence of on-study SREs in patients with newly diagnosed bone metastases 1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1 6 12 18 24 30 36
Study month
Cumulative incidence of on-study SREs
Breast cancer (n = 621)
Lung cancer (n = 477)
Prostate cancer (n = 721)
SREs are a common complication in patients with solid tumours and bone metastases.1
A review of medical records from two large US health systems was conducted to assess the risk of SREs (spinal cord compression, pathological fracture, radiation to bone, bone surgery) in patients with solid tumours (breast cancer: n = 621; lung cancer: n = 477; prostate cancer: n = 721) in routine clinical practice.1
Cumulative incidence of SREs in patients with newly diagnosed bone metastases was estimated, accounting for death as a competing risk.1
Intravenous (IV) bisphosphonates were received by 55.8%, 14.8% and 20.2% of patients with breast cancer, lung cancer and prostate cancer, respectively.1
More than one half of patients with bone metastases had evidence of SREs (breast cancer: 62.6%; lung cancer: 58.7%; prostate cancer: 51.7%) either at diagnosis of bone metastases or subsequently.1
Reference
Oster G, Lamerato L, Glass AG, et al. Natural history of skeletal-related events in patients with breast, lung, or prostate cancer and metastases to bone: a 15-year study in two large US health systems. Support Care Cancer 2013;21:327986.
Use of intrvenous bisphosphonates: breast cancer, 55.8%; lung cancer, 14.8%; and prostate cancer 20.2%.
Oster G, et al. Support Care Cancer 2013;21:327986.

14. Skeletal Complications in Metastatic Bone Disease Are Significant
% of patients affected in PLACEBO arms of:
Pamidronate trials ZOMETA® trials
Disease Breast Myeloma Prostate Others Observation time 12 months 9 months 15 months 9 months
Radiation to bone
Fractures
Hypercalcaemia of malignancy
Surgery to bone
Spinal cord compression

15. SREs are a substantial burden to patients and healthcare systems
Direct consequences to patients
Pathological fracture1
Spinal cord compression1
Surgery to bone1
Radiation to bone for bone pain1
Indirect consequences to patients
Poorer physical, functional and emotional status2
Reduced HRQoL2
Hospital visits/stays3
Health resource utilisation
Increased treatment costs4
Increased hospital visits/stays3
SREs are a substantial burden to patients and healthcare systems.
Direct consequences to patients include: the need for radiation to bone for bone pain; pathological fracture; spinal cord compression; and surgery to bone.1
Additional, indirect consequences to patients include negative effects on physical, functional and emotional status;2 the requirement to undergo hospital visits and stays;3 and an overall reduction in health-related quality of life (HRQoL).2
SREs are also associated with substantial healthcare resource utilisation due to higher treatment costs vs advanced cancer without SREs4 and the need for hospital visits and inpatient stays.3
References
Costa L and Major PP. Effect of bisphosphonates on pain and quality of life in patients with bone metastases. Nat Clin Prac Oncol 2009;6:163–74.
DePuy V, Anstrom KJ, Castel LD, et al. Effects of skeletal morbidities on longitudinal patient-reported outcomes and survival in patients with metastatic prostate cancer. Support Care Cancer 2007;15:869–76.
Pocket RD, Castellano D, McEwan P, et al. The hospital burden of disease associated with bone metastases and skeletal-related events in patients with breast cancer, lung cancer, or prostate cancer in Spain. Eur J Cancer Care 2010;19:755–60.
Delea T, McKiernan J, Brandman J, et al. Retrospective study of the effect of skeletal complications on total medical care costs in patients with bone metastases of breast cancer seen in typical clinical practice. J Support Oncol 2006;4:341–7.
Impact on patients and healthcare systems
1. Costa L and Major PP. Nat Clin Prac Oncol 2009;6:163–74;
2. De Puy V, et al. Support Care Cancer 2007;15:869–76; 3. Pocket RD, et al. Eur J Cancer Care 2010;19:755–60;
4. Delea T, et al. J Support Oncol 2006;4:341–7.
HRQoL, health-related quality of life.

16. LA MALATTIA METASTATICA OSSEA Obiettivi del Trattamento
Obiettivi primari
Prevenire gli eventi scheletrici
Ridurre al minimo l’invalidità
Dare sollievo dal dolore
Migliorare la funzionalità
Migliorare la qualità di vita
Limitare gli eventi avversi
Migliorare l’accettabilità del paziente
Considerare il suo stile di vita
Ridurre i costi di gestione della terapia
Benché i bifosfonati attualmente disponibili siano efficaci nel trattare e prevenire alcuni eventi scheletrici, la loro utilità clinica è limitata da problematiche di tollerabilità (in particolare la tollerabilità renale) e modalità di somministrazione.
Recentemente, in pazienti trattati con alcuni bifosfonati è stato osservato un aumento del rischio di osteonecrosi mascellare/mandibolare.
Permane il bisogno clinico di un trattamento che unisca a un'efficacia e ad una tollerabilità superiori una maggiore flessibilità di somministrazione.

17. Opzioni terapeutiche nella malattia metastatica ossea
Terapia locoregionale
Terapia sistemica
Radioterapia
Chirurgia
Interventistica (vertebroplastica)
Ormonoterapia
Chemioterapia
Denosumab
Terapia radiometabolica
Terapia con bifosfonati

18. tra cellule neoplastiche e osteoclasti Liberazione di fattori
Interazioni tra cellule tumorali e osteoclasti: circolo vizioso o opportunità terapeutica?
METASTASI OSSEE
Interazioni
tra cellule neoplastiche e osteoclasti
Aumento del
riassorbimento
osseo
Stimolazione
degli
osteoclasti
Liberazione
di fattori solubili
ad azione attivante
sugli osteoclasti
(es. PTH-rP)
OSTEOCLASTA
Liberazione di fattori
di stimolazione della
crescita tumorale
(es. TGF-b)
Cell. Tumorale

19. Bifosfonati disponibili per la malattia metastatica ossea
1a generazione
- Clodronato orale
2a generazione
- Pamidronato endovena
3a generazione
- Acido zoledronico endovena
- Ibandronato endovena e orale
Cristofanilli M, Hortobagyi GN. Cancer Control 1999; 6 (3):

20. Bifosfonati Trattamento dell’ipercalcemia maligna
Riduzione degli eventi traumatici patologici o incremento del tempo mediano al primo evento patologico
Controllo del dolore osseo e riduzione
dell’uso di analgesici
Riduzione dei trattamenti radioterapici analgesici/preventivi
Miglioramento della qualità della vita

21. Ac zoledronico: la riduzione del dolore metastatico osseo nel ca prostatico
1.2
1.0
0.8
0.6
0.4
0.2
Variazione media rispetto al basale
Tempo trascorso nello studio (mesi)
Ac zoledronico 4 mg (n=214)
Placebo (n=208)
P<0,05
Saad F et al. J Nat Cancer Inst , 19:

22. Sicurezza dei bifosfonati nella malattia metastatica ossea
importanza di assicurare una tollerabilità ottimale
del trattamento con bifosfonati nella terapia palliativa
Differenti profili di sicurezza dei bifosfonati
Effetti indesiderati frequenti
- eventi legati all’infusione (reazione di fase acuta)
- tossicità /deterioramento funzione renale
- effetti indesiderati gastrointestinali (gastrite, diarrea)
- osteonecrosi della mandibola

23. Bone-targeted therapy was delayed in a substantial proportion of patients
Reasons for delaying treatment with bone-targeted agents † †
The audit also showed that bone-targeted therapy was delayed in a substantial proportion of patients.1
The main reason for delaying bone-targeted treatment was that bone metastases were thought to be responding to systemic anti-tumour therapies (56% of total patient population).1
Additionally, bone-targeted treatment was delayed in 31% of patients due to safety concerns; within this group, these concerns included existing renal impairment (61%), dental health issues (28%) and poor risk/benefit ratio (34%).1
Reference
1. Casas A, Lebret T, Cavo M, et al. 146 study: cost of skeletal-related events by country. Support Care Cancer 2012;20(Suppl 1):1–283:abstract 368 (and poster).
Data from a prospective, observational chart audit conducted in France, Germany, Italy, Spain and the UK in March 2010; data were available for 14,871 patients. Denosumab was not available at the time of the audit. †Includes poor life expectancy, poor performance status, etc
Casas A, et al. Support Care Cancer 2012;20(Suppl 1):1–283:abstract 368 (and poster).

24. A substantial proportion of patients with bone metastases never received bone-targeted therapy for prevention of SREs
Reasons why patients were expected never to receive bone-targeted agents
(N = 1351)
Despite the substantial burden of SREs to patients and healthcare systems, a substantial proportion of patients with bone metastases never receive bone-targeted therapy for the prevention of SREs.
This slide shows data from a prospective European chart audit including 881 physicians who completed brief and detailed questionnaires on a total of 17,193 patients during a 2–3-week observational period in March
It is important to note that denosumab was not available at the time of the audit.
Of the 14,871 patients for whom data were available from the brief questionnaire, 17% were expected never to receive bone-targeted agents despite 72% having a moderate-to-high risk of SREs.1
In further sub-set analyses of the 1351 patients who were expected never to receive bone-targeted agents, short life expectancy (38%), renal issues (37%) and poor risk/benefit ratio (34%) were identified as the most common reasons why treatment with bone-target therapy was not considered.1
Reference
1. Casas A, Lebret, T Cavo M, et al. 146 study: cost of skeletal-related events by country. Support Care Cancer 2012;20(Suppl 1):1–283:abstract 368 (and poster).
17% of patients were expected never to receive bone-targeted agents despite 72% having a moderate-to-high SRE risk†
Data from a prospective, observational chart audit conducted in France, Germany, Italy, Spain and the UK in March 2010; data were available for 14,871 patients. Denosumab was not available at the time of the audit. BM, bone metastases. †As determined by the treating physician.
Casas A, et al. Support Care Cancer 2012;20(Suppl 1):1–283:abstract 368 (and poster).

25. Prevention of skeletal morbidity in metastatic bone disease
New ESMO clinical practice guidelines on bone health in cancer patients
Prevention of skeletal morbidity in metastatic bone disease
Guidance on bone-targeted treatment (denosumab or zoledronic acid)
Initiation
Commence at diagnoses of metastatic bone disease
In all patients with breast cancer or CRPC, whether they are symptomatic or not
In selected patients with advanced lung cancer, renal cancer and other solid tumours if life expectancy > 3 months and considered at high risk of SREs
Continuation
Continue indefinitely throughout the course of the disease
Ongoing treatment is recommended for patients with progression of underlying bone metastases, a recent SRE and/or elevated bone resorption markers†
The European Society for Medical Oncology (ESMO) has set out new clinical practice guidelines on bone health in patients with cancer. These guidelines highlight the value of bone-targeted treatments (denosumab or zoledronic acid) for the prevention of skeletal morbidity in metastatic bone disease.1
The initiation of therapy is recommended on diagnosis of metastatic bone disease in all patients with breast cancer or CRPC, irrespective of the presence of symptoms, in order to delay the first SRE and reduce subsequent complications from metastatic bone disease. Bone-targeted therapy is also recommended in selected patients with advanced lung cancer, renal cancer, and other solid tumours, if they have a life expectancy of more than 3 months and there is a high risk of SREs.1
It is recommended that bone-targeted treatment be continued throughout the course of the disease, particularly in patients with progression of underlying bone metastases, recent SREs and/or elevated bone resorption markers.1
Results from clinical trials evaluating potential clinical applications of bone markers (e.g. helping to identify patients at high risk for bone metastasis or bone lesion progression) are awaited to clarify the value of bone markers in clinical practice.
Reference
Coleman R, Body JJ, Aapro M, et al. Bone health in cancer patients: ESMO Clinical Practice Guidelines. Ann Oncol 2014 [Epub ahead of print].
†Results from clinical trials evaluating potential clinical applications of bone markers (e.g. helping to identify patients at high risk for bone metastasis or bone lesion progression) are awaited to identify the true value of bone markers in clinical practice.
Coleman R, et al. Ann Oncol 2014 [Epub ahead of print].

26. Denosumab and prevention of skeletal-related events in adults with bone metastases
This slide set summarises key data on denosumab 120 mg subcutaneously (SC) every 4 weeks (Q4W) for skeletal-related event (SRE) prevention in adults with bone metastases from solid tumours.
*▼ This medicinal product is subject to additional monitoring. All suspected adverse reactions should be reported.
DMO-IHQ-AMG July-NP 26

27. Denosumab binds to RANK Ligand to block osteoclast differentiation and activation
‘Vicious cycle’
RANK Ligand
Denosumab
Osteoblasts
In healthy adult bone, receptor activator of NF-κB (RANK) Ligand activity is tightly regulated to balance bone formation and resorption.1
However, in the presence of tumour cells, a vicious cycle of bone destruction and tumour growth may develop.2,3
Tumour cells that have invaded bone secrete factors that increase the expression of RANK Ligand by osteoblasts
Increased expression of RANK Ligand upregulates osteoclast activity
Excessive osteoclast activity drives increased bone resorption; in turn, this releases growth factors from the bone matrix that may perpetuate tumour activity
This sequence of events drives a vicious cycle of bone destruction and tumour activity.
Denosumab is a fully human monoclonal antibody that precisely binds to and sequesters free RANK Ligand, thus preventing activation of the RANK receptor and blocking the development of activated osteoclasts. Inhibiting RANK Ligand in this way mimics the endogenous action of osteoprotegerin (OPG) on the RANK/RANK Ligand pathway in inhibiting the formation, function and survival of bone-resorbing osteoclasts.13
Because bone destruction may lead to SREs, it can be hypothesised that targeting RANK Ligand with denosumab could prevent or delay SREs in patients with bone metastases.
References
Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation. Nature 2003;423:337–42.
Roodman GD. Mechanisms of bone metastasis. N Engl J Med 2004;350:1655–64.
Mundy GR. Metastasis to bone: causes, consequences and therapeutic opportunities. Nat Rev Cancer 2002;2:584–93.
Osteoclast
Growth factors
Growth factors Ca2+
Tumour
Adapted from Roodman GD. N Engl J Med 2004;350:1655–64; Mundy GR. Nat Rev Cancer 2002;2:584–93; McClung MR, et al. N Engl J Med 2006;354:821–31.
RANK, receptor activator of NF-κB . 27

28. Pre-planned integrated analysis4 (N = 5723) Other solid tumours*/MM3
Three pivotal Phase III trials of denosumab vs zoledronic acid in patients with bone metastases from advanced cancer
Primary endpoint: time to first on-study SRE (non-inferiority)
Secondary endpoints: time to first on-study SRE (superiority); time to first and subsequent on-study SRE; safety and tolerability R A N D O M I S T
Breast cancer1
Denosumab 120 mg SC Q4W +
Placebo IV Q4W†
Prostate cancer2
Pre-planned integrated analysis4 (N = 5723)
Supplemental calcium and vitamin D
Zoledronic acid 4 mg IV Q4W†
+ Placebo SC Q4W
Other solid tumours*/MM3
Denosumab has been evaluated for SRE prevention in 3 large international, randomised, double-blind, double-dummy, active-controlled Phase III studies in patients with bone metastases (breast cancer, n = 2049; prostate cancer, n = 1904; other solid tumours or multiple myeloma, n = 1776).1−3
Patients were randomised to:1−3
Denosumab 120 mg SC and placebo IV Q4W or
Zoledronic acid 4 mg IV and placebo SC Q4W.
In line with the zoledronic acid prescribing information, agents administered IV (zoledronic acid or placebo) were dose-adjusted on the basis of baseline creatinine clearance ≤ 60 mL/min and held for renal function deterioration until serum creatinine returned to within 10% of baseline values. There was no requirement for dose adjustment with denosumab.1−3 Daily supplementation with calcium (≥ 500 mg) and vitamin D (≥ 400 IU) was strongly recommended.1−3
Key inclusion criteria were:1−3
Radiographic evidence of ≥ 1 bone metastasis or bone disease
Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2
Adequate organ function
Life expectancy ≥ 6 months.
Key exclusion criteria included the use of current or prior IV bisphosphonates for treatment of bone metastases.1−3
The primary endpoint was time to first on-study SRE (non-inferiority), with predefined secondary endpoints including time to first on-study SRE (superiority), time to first and subsequent on-study SRE, safety and tolerability. 1−3
Secondary endpoints were tested simultaneously with multiplicity adjustment (Hochberg procedure2) only after the primary endpoint was met (hierarchical order). This procedure is accepted by regulatory bodies
When the primary endpoint was met, a superiority test on time to first on-study SRE was performed as a secondary endpoint.1−3
References
Stopeck AT, Lipton A, Body JJ, et al. Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study. J Clin Oncol 2010;28:5132–9.
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;377:813–22.
Henry DH, Costa L, Goldwasser F, et al. Randomized, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma. J Clin Oncol 2011;29:1125−32.
†Per protocol and Zometa® label, IV product dose adjusted for baseline creatinine clearance and subsequent dose intervals determined by serum creatinine.
1. Stopeck AT, et al. J Clin Oncol 2010;28:5132–9; 2. Fizazi K, et al. Lancet 2011;377:813–22; 3. Henry DH, et al. J Clin Oncol 2011;29:112532; 4. Lipton A, et al. Eur J Cancer 2012;48:3082–92.
*Excluding breast and prostate. 28

29. Patients with a broad range of solid tumour types were enrolled
Baseline characteristic, n (%) or median
Zoledronic acid
(n = 2861)
Denosumab
(n = 2862)
Women
1349 (47.2)
1316 (46.0)
Age, years
63.0
ECOG status of 0 or 1
2546 (89.0)
2585 (90.3)
Tumour type*
Breast
1020 (35.7)
1026 (35.8)
Prostate
951 (33.2)
950 (33.2)
Non-small cell lung
352 (12.3)
350 (12.2)
Multiple myeloma
93 (3.3)
87 (3.0)
Renal
85 (3.0)
70 (2.4)
Small cell lung
48 (1.7)
61 (2.1)
Other
312 (10.9)
318 (11.1)
Time from first bone metastasis to randomisation, months
2.30
2.17
Previous SRE†
1157 (40.4)
1112 (38.9)
Patients with a broad range of solid tumour types were enrolled in the Phase III trials. In addition to the dedicated studies in breast and prostate cancer, the ‘other solid tumours and multiple myeloma’ study included a large number of patients with non-small cell lung cancer, renal carcinoma and small cell lung cancer, among others.1
Baseline characteristics, including age, sex, ECOG performance status, time from first bone metastasis to randomisation, and previous SRE were well balanced between the treatment groups.1
Approximately 40% of patients had experienced a previous SRE.1
Reference
Lipton A, Siena S, Rader M, et al. Superiority of denosumab to zoledronic acid for prevention of skeletal-related events: a combined analysis of 3 pivotal, randomised, phase 3 trials. Eur J Cancer 2012;48:308292.
Lipton A, et al. Eur J Cancer 2012;48:308292.
*ECOG, Eastern Cooperative Oncology Group; †Based on randomisation. 29

30. Patients without SRE (%)
Time to first on-study SRE reached almost 28 months in patients on denosumab
Time to first on-study SRE
HR = 0.83
(95% CI, 0.76–0.90)
P < (superiority)
Time (months)
Patients without SRE (%) 40 60 80
100 6 12 18 24 30
27.66 months
19.45 months 90 70 50 20 10
Time to first on-study SRE reached almost 28 months in patients on denosumab.1
The median time to first on-study SRE was months in patients on denosumab compared with months in patients on zoledronic acid − a difference of 8.21 months (P < 0.001, superiority).1
Denosumab was associated with a 17% risk reduction in first SRE over zoledronic acid (HR = 0.83; 95% CI, 0.76−0.90; P < 0.001, superiority).1
Reference
Lipton A, Siena S, Rader M, et al. Superiority of denosumab to zoledronic acid for prevention of skeletal-related events: a combined analysis of 3 pivotal, randomised, phase 3 trials. Eur J Cancer 2012;48:308292.
Denosumab
Zoledronic acid
(N = 5723)
Lipton A, et al. Eur J Cancer 2012;48:308292.
HR, hazard ratio. 30

31. Time to first and subsequent on-study SREs
Denosumab also significantly reduced the total number of SREs vs zoledronic acid
Time to first and subsequent on-study SREs
RR = 0.82
(95% CI, 0.75–0.89)
P < (superiority) 3 6 9 12 15 18 21 24 27 30 33 36
Cumulative mean number of SREs per patient
Time (months)
0.0
1.0
1.6
1.4
1.2
0.8
0.6
0.4
0.2
Total SREs
1360
1628
Denosumab
Zoledronic acid
(N = 5723)
There were significantly fewer on-study SREs with denosumab vs zoledronic acid (1360 vs 1628 in total).1
Denosumab treatment was associated with an 18% risk reduction in first and subsequent SREs over zoledronic acid (P < 0.001, superiority).
Reference
Lipton A, Siena S, Rader M, et al. Superiority of denosumab to zoledronic acid for prevention of skeletal-related events: a combined analysis of 3 pivotal, randomised, phase 3 trials. Eur J Cancer 2012;48:308292.
Lipton A, et al. Eur J Cancer 2012;48:308292.
Events occurring at least 21 days apart (multiple event analysis).
RR, rate ratio. 31

32. Denosumab delayed pain worsening by almost 2 months vs zoledronic acid
Time to moderate or severe pain (> 4 points) among patients with no or mild pain (0–4 points) at baseline (n = 2683)†
HR = 0.83 (95% CI, 0.760.92)
P < 0.001
mths
Median time from no or mild pain to moderate or severe pain (months)
2683 (52%) of 5198 patients included in a pooled pain analysis reported no or mild pain at baseline (Brief Pain Inventory-Short Form [BPI-SF] worst pain score 0−4 points).
Among these patients, denosumab delayed the median time to onset of moderate or severe pain (worst pain score > 4 points) by 1.8 months compared with zoledronic acid (6.5 vs 4.7 months) and reduced the risk of experiencing moderate or severe pain by 17% (HR, 0.83; 95% CI, 0.76–0.92; P < 0.001).1
Note that patients with multiple myeloma were excluded from the pooled pain analysis because denosumab is not indicated in patients with multiple myeloma.1
Reference
von Moos R, Body JJ, Egerdie B, et al. Pain and health-related quality of life in patients with advanced solid tumours and bone metastases: integrated results from three randomized, double-blind studies of denosumab and zoledronic acid. Support Care Cancer 2013;21:3497507.
von Moos R, et al. Support Care Cancer 2013;21:3497507.
†BPISF worst pain score. Patients with MM were not included in this analysis.

33. Safety results of interest
Patient incidence, n (%)
Zoledronic acid (n = 2836)
Denosumab (n = 2841)
Infectious AEs
1218 (42.9)
1233 (43.4)
Infectious serious AEs
309 (10.9)
329 (11.6)
Acute phase reactions (first 3 days)
572 (20.2)
246 (8.7)
Cumulative rate of ONJ
37 (1.3)
52 (1.8)
Year 1
15 (0.5)
22 (0.8)
Year 2
28 (1.0)
51 (1.8)
Hypocalcaemia
141 (5.0)
273 (9.6)
New primary malignancy
18 (0.6)
AEs leading to study discontinuation
280 (9.9)
270 (9.5)
572 (20.2)
246 (8.7)
37 (1.3)
52 (1.8)
This slide shows safety results of interest in the pivotal Phase III SRE prevention trials.
There were fewer acute phase reactions among patients on denosumab (8.7%) than zoledronic acid (20.2%).1
These were defined as a flu-like syndrome including pyrexia, chills, flushing, bone pain, arthralgias and myalgias, which have been associated with IV bisphosphonate use, as per the zoledronic acid prescribing information.
Hypocalcaemia (corrected serum calcium [CSC] levels < 9.0 mg/dL) was more frequent with denosumab (9.6%) than zoledronic acid (5.0%).1
There was no significant difference between the two treatment groups in the cumulative rate of osteonecrosis of the jaw (ONJ).1
There was no pattern in the type of new malignancies diagnosed on study.1
Reference
Lipton A, Siena S, Rader M, et al. Superiority of denosumab to zoledronic acid for prevention of skeletal-related events: a combined analysis of 3 pivotal, randomised, phase 3 trials. Eur J Cancer 2012;48:308292.
141 (5.0)
273 (9.6)
Lipton A, et al. Eur J Cancer 2012;48:308292.
ONJ, osteonecrosis of the jaw. 33

34. Higher rate of hypocalcaemia with denosumab vs zoledronic acid
In the pivotal Phase III trials most hypocalcaemia events were asymptomatic1,3−5
In the post-marketing setting, severe symptomatic hypocalcaemia (including fatal cases) has been reported, with most cases occurring in the first weeks of therapy2
The higher rate of hypocalcaemia with denosumab is consistent with the more potent antiresorptive effect vs zoledronic acid4
Hypocalcaemia1,2
Zoledronic acid (n = 2836)
Denosumab
(n = 2841)
Overall (integrated analysis), %
5.0
9.6
Grade 3, %†
1.2
2.5
Grade 4, %†
0.2
0.6
Hypocalcaemia is a known side effect of drugs that reduce bone remodelling.1
In the pivotal Phase III SRE prevention trials, hypocalcaemia occurred more frequently with denosumab than zoledronic acid.2,3
Overall, hypocalcaemia was reported in 9.6% of patients on denosumab and 5% of patients on zoledronic acid
Grade 3 or 4 hypocalcaemia was reported in 3.1% of patients on denosumab and 1.3% of patients on zoledronic acid
Most hypocalcaemia events in patients on denosumab were asymptomatic.1,2,4,5
Of note, in the post-marketing setting, severe symptomatic hypocalcaemia (including fatal cases) has been reported.3
The higher rate of hypocalcaemia observed with denosumab compared with zoledronic acid is consistent with its more potent antiresorptive effect.5
References
Fizazi K, Carducci M, Smith M, et al. A randomised, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in men with castration-resistant prostate cancer. Lancet 2011;377:813–22.
Lipton A, Fizazi K, Stopeck AT, et al. Superiority of denosumab to zoledronic acid for prevention of skeletal-related events: a combined analysis of 3 pivotal, randomized, phase 3 trials. Eur J Cancer 2012;48:3082–92.
XGEVA® (denosumab) Summary of Product Characteristics. Amgen.
Stopeck AT, Lipton A, Body JJ, et al. Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study. J Clin Oncol 2010;28:5132–9.
Henry DH, Costa L, Goldwasser F, et al. A randomized, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma. J Clin Oncol 2011;29:1125–32.
†Grade 3 defined as: CSC < 7.0– 6.0 mg/dL; Ionised calcium < 0.9–0.8 mmol/L; hospitalisation indicated; Grade 4 defined as: CSC < 6.0 mg/dL; Ionised calcium < 0.8 mmol/L; life-threatening consequences.
1. Lipton A, et al. Eur J Cancer 2012;48:3082–92;
2. Denosumab (XGEVA®) Summary of Product Characteristics, Amgen; 3. Stopeck AT, et al. J Clin Oncol 2010;28:5132–9; 4. Henry DH, et al. J Clin Oncol 2011;29:1125–32; 5. Fizazi K, et al. Lancet 2011;377:813–22. 34

35. Minimising the risk of ONJ
Before starting denosumab, a dental examination with appropriate preventative dentistry is recommended
Do not start denosumab in patients with an active dental jaw condition requiring surgery, or in patients who have not recovered following oral surgery
Tell patients receiving denosumab to maintain good oral hygiene practices, receive routine dental check-ups, and immediately report any oral symptoms such as dental mobility, pain or swelling
Risk factors include: invasive dental procedures, poor oral hygiene or other pre-existing dental disease, advanced malignancies, infections, older age, concomitant therapies (e.g. chemotherapy, corticosteroids, angiogenesis inhibitors, radiotherapy to the head and neck) smoking, and previous bisphosphonate therapy
In patients with risk factors for ONJ, an individual benefit-risk assessment should be performed before initiating therapy
This slide highlights guidance on minimising the risk of ONJ during denosumab treatment as outlined in the denosumab 120 mg Q4W SmPC.1
A dental examination with appropriate preventative dentistry is recommended before starting denosumab and treatment should not be initiated in patients with an active dental jaw condition requiring surgery, or in those who have not recovered following oral surgery.1
Routine dental check-ups should be performed.
Additionally, patients should be educated about good oral hygiene and on the signs and symptoms of ONJ; they should be informed to report any oral symptoms immediately.1
Risk factors for ONJ have been identified and an individual benefit-risk assessment should be performed before starting therapy in patients with know risk factors.1
Reference
1. Denosumab (XGEVA®) Summary of Product Characteristics, Amgen.
Denosumab (XGEVA®) Summary of Product Characteristics, Amgen.

36. Minimising the risk of hypocalcaemia
Pre-existing hypocalcaemia must be corrected prior to initiating therapy
Supplementation with calcium and vitamin D is required in all patients unless hypercalcaemia is present ( mg Ca UI Vit D)
Prior to the initial dose of denosumab
Within 2 weeks after the initial dose
If suspected symptoms of hypocalcaemia occur
Monitoring of calcium levels should be conducted:
Risk of hypocalcaemia increases with the degree of renal impairment
Consider monitoring calcium levels more frequently in patients with risk factors for hypocalcaemia (e.g. patients with severe renal impairment, creatinine clearance < 30 ml/min), or if otherwise indicated based on the clinical condition of the patient
Tell patients to report symptoms of hypocalcaemia
If hypocalcaemia occurs, additional calcium supplementation and monitoring may be necessary
This slide highlights guidance on minimising the risk of hypocalcaemia during denosumab treatment as outlined in the denosumab 120 mg Q4W Summary of Product Characteristics (SmPC).
Reference
1. Denosumab (XGEVA®) Summary of Product Characteristics, Amgen.
Denosumab (XGEVA®) Summary of Product Characteristics, Amgen.

37. Denosumab Versus Zoledronic Acid for Treatment of Bone Metastases in Men With Castration-Resistant Prostate Cancer: A Randomised, Double-Blind Study

38. 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
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:
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
*Per protocol and Zometa® label, IV product dose adjusted for baseline creatinine clearance and subsequent dose intervals determined by serum creatinine. No SC dose adjustments made due to increased serum creatinine.
Fizazi K, et al. Lancet. 2011;377:813–822.
Fizazi K, et al. Lancet 2011;377: 814,B,5; 815,A,1
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

39. Baseline Characteristics
Fizazi K, et al. Lancet 2011;377: 815,Table 1
Characteristic
Denosumab (N = 950)
Zoledronic Acid (N = 951)
Median age, years (IQR)
71 (64–77)
71 (66–77)
ECOG performance status of 0 or 1, n (%)
882 (93)
886 (93)
Stratification Factors
PSA at randomisation  10 g/L, n (%)
805 (85)
806 (85)
Recent chemotherapy ( 6 weeks before randomisation), n (%)
132 (14)
Previous SRE, n (%)
232 (24)
231 (24)
Median time from diagnosis of bone metastasis to randomisation, months (IQR)
3.94 (1.22–15.67)
5.19 (1.31–16.10)
Key Points
A total of 1901 patients were randomized to receive denosumab (n = 950) or zoledronic acid (n = 951)
Baseline age, race, and ECOG performance status variables were balanced between groups
Background
Randomization was stratified by previous SRE, PSA level ( 10 g/L vs  10 g/L), and chemotherapy for prostate cancer within 6 weeks before randomization
Patients in the zoledronic acid arm had a slightly longer median time from bone metastases diagnosis to study randomization (denosumab, 3.94 months; zoledronic acid, 5.19 months) although the quartiles were similar
Reference
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:
Fizazi K, et al. Lancet 2011;377: 815,Table 1
IQR = interquartile range.
ECOG = Eastern Cooperative Oncology Group.
PSA = prostate-specific antigen.
Fizazi K, et al. Lancet. 2011;377:813–822.

40. 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  (noninferiority)
P = (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:
Denosumab
Zoledronic acid
20.7
XGEVA™ PI, 2010: 11,Table 2
17.1
0.00 3 6 9 12 15 18 21 24 27
Fizazi K, et al. Lancet 2011;377: 816,Figure 2
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.

41. 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 = (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:
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
*Events occurring at least 21 days apart.
Fizazi K, et al. Lancet. 2011;377:813–822.

42. Summary of Adverse Events
Fizazi K, et al. Lancet 2011;377: 818,Table 4
Patient Incidence
Denosumab (N = 943) n (%)
Zoledronic Acid (N = 945)
n (%)
Infectious AEs*
402 (43)
375 (40)
Acute phase reactions (first 3 days)
79 (8)
168 (18)
Renal AEs†
139 (15)
153 (16)
Cumulative rate of osteonecrosis of the jaw (ONJ)‡
22 (2)
12 (1)
Year 1
10 (1)
5 (1)
Year 2
8 (1)
Hypocalcaemia
121 (13)
55 (6)
New primary malignancy
18 (2)
Fizazi K, et al. Lancet 2011;377: 819,A,3
Fizazi K, et al. Lancet 2011;377: 818,Table 4
Key Point
The incidence of AEs of interest was similar between the two study treatment groups
Background
During the first 3 days of treatment, AEs potentially associated with acute phase reactions occurred in 8% of denosumab and 18% of zoledronic acid patients
AEs potentially associated with renal impairment occurred in 15% of the denosumab group and 16% of the zoledronic acid group
Positively adjudicated ONJ occurred in 22 (2%) patients in the denosumab group and 12 (1%) patients in the zoledronic acid group (P = .09)
AEs of hypocalcemia were reported in 121 (13%) patients in the denosumab group and 55 (6%) patients in the zoledronic acid group
New primary malignancies were identified in 18 (2%) patients in the denosumab group and 10 (1%) patients in the zoledronic acid group
Reference
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:
Fizazi K, et al. Lancet 2011;377: 819,A,3
Fizazi K, et al. Lancet 2011;377: 818,Table 4
*Based on Medical Dictionary for Regulatory Activities (MedDRA; version 12.1) system organ class categorization of infections and infestations.
†Includes renal failure, increased blood creatinine, acute renal failure, renal impairment, increased blood urea, chronic renal failure, oliguria, hypercreatininaemia, anuria, azotemia, decreased creatinine renal clearance, decreased urine output, abnormal blood creatinine, proteinuria, decreased glomerular filtration rate, and nephritis.
‡P = 0.09.
Fizazi K, et al. Lancet. 2011;377:813–822.

43. Summary
Denosumab was superior to zoledronic acid in delaying the time to
First SRE
First and subsequent SRE(s)
Notable adverse events occurring in both treatment groups included ONJ and hypocalcaemia
Hypocalcaemia was more frequent in the denosumab arm
Incidence of ONJ was similar between arms and not statistically significantly different
Regarding Denosumab administration:
Administered as a 120 mg SC injection once every 4 weeks
No dose adjustment necessary for patients with renal impairment
Fewer acute phase reactions in the denosumab arm
Key Points
The results of this study demonstrated that denosumab was superior to zoledronic acid in delaying time to first and subsequent SRE(s) in advanced prostate cancer patients with bone metastases
Denosumab had several potentially beneficial characteristics

44. Radioisotopes Targets Bone Metastases
Naturally targets new bone growth in and around bone metastases
Most acts as a calcium mimic
Strontium-89
Samrarium-153
Radium-223 Ca Ra

45. Range of alpha-particle
Radium-223 (AlpharadinTM )
Based on alpha emitter Radium-223
ideal half-life of 11.4 days
Excreted via small bowel
Safe and easy to produce, deliver and handle
Alpha
Beta
Relative particle mass
7000 1
Initial energy (MeV)
3-8
Range in tissue (µm)
40-90
LET (KeV/µm)
60-230
Charge +2 -1
Ion pairs/µm
5-20
DNA hits to kill cell
1-5
Range of alpha-particle
Radium-223

46. ALSYMPCA (ALpharadin in SYMptomatic Prostate CAncer) Phase III Study Design
TREATMENT
6 injections at 4-week intervals
PATIENTS R
A N D
OM I S
E D
2:1
STRATIFICATION
Confirmed symptomatic CRPC
≥ 2 bone metastases
No known visceral metastases
Post-docetaxel or unfit for docetaxel
Radium-223 (50 kBq/kg) + Best standard of care
Total ALP: < 220 U/L vs ≥ 220 U/L
Bisphosphonate use: Yes vs No
Prior docetaxel: Yes vs No
Placebo (saline) + Best standard of care
N = 922
Planned follow-up is 3 years
Clinicaltrials.gov identifier: NCT

47. ALSYMPCA Overall Survival
100
HR 0.695; 95% CI, P = 90 80 70 60
Radium-223, n = 541
Median OS: 14.0 months % 50 40 30
Placebo, n = 268
Median OS: 11.2 months 20 10
Month 3 6 9 12 15 18 21 24 27
Radium- 223
541
450
330
213
120 72 30
Placebo
268
218
147 89 49 28 7
NEJM 2014

48. ALSYMPCA Secondary Endpoints: ALP and PSA
Hazard ratio 95% CI
P-value
Time to Total ALP progression
(0.121 – 0.221)
<
Time to PSA progression
(0.546 – 0.826)
Radium-223 n (%)
Placebo n (%)
P-value
Total ALP response (30% reduction)
165 (43)
4 (3)
< 0.001
Total ALP normalisation*
83 (33)
1 (1)
EORTC 2011
*In patients who had elevated total ALP at baseline.

49. ALSYMPCA Adverse Events
All Grades
Grades 3 or 4
Radium-223
(n = 509)
n (%)
Placebo
(n = 253)
Haematologic
Anaemia
136 (27)
69 (27)
54 (11)
29 (12)
Neutropenia
20 (4)
2 (1)
9 (2)
Thrombocytopenia
42 (8)
14 (6)
22 (4)
4 (2)
Non-Haematologic
Bone pain
217 (43)
147 (58)
89 (18)
59 (23)
Diarrhoea
112 (22)
34 (13)
6 (1)
3 (1)
Nausea
174 (34)
80 (32)
8 (2)
Vomiting
88 (17)
32 (13)
10 (2)
6 (2)
Constipation
46 (18)
EORTC 2011

50. METANALISI TERAPIA RADIOMETABOLICA
Drug Design Development Therapy
Tunio et al 2015

51. Tunio et al 2015

52. Tunio et al 2015

53. LINEE GUIDA AIOM 2014

54. GRAZIE PER L’ATTENZIONE