Λουκάς Κοντοβίνης, παθολόγος - ογκολόγος.

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1 Λουκάς Κοντοβίνης, παθολόγος - ογκολόγος l.kontovinis@oncomedicare.com

4 Nuclear Medicine Review 2011, 14, 2:

5 N Engl J Med 2004;350:

6 Nuclear Medicine Review 2011, 14, 2:

7 N Engl J Med 2004;350:

8 Cancer-induced bone disease 25% pathologic fractures of vertebrae or other bones 8% spinal compression 25% hypercalcemia 4% surgical treatment 33% radiotherapy Treatment induced bone disease Antiandrogenic treatment etc. Radiotherapy Surgical treatment Nuclear Medicine Review 2011, 14, 2:

9 Cancer-induced bone disease 25% pathologic fractures of vertebrae or other bones 8% spinal compression 25% hypercalcemia 4% surgical treatment 33% radiotherapy > 70% pain in metastatic foci Bone tissue has rich neuration, mainly from the periosteum Recently found that the endings of nerve fibers also reach the medullary cavities in long bones (medullary membrane) and parts of cancellous bones Nuclear Medicine Review 2011, 14, 2:

10 Mechanical factors compression connected with bone remodeling and periosteum damage increased pressure inside bone bone deformation due to osteolysis direct compression of metastatic tissue on nerves or surrounding soft tissue; pathologic fractures that change bone compression distribution (e.g. vertebra compression fractures) Chemical mediators mediators activated or produced by neoplasm (e.g. TGF, TNF, IL) activation of arachidonic acid cascade (prostaglandin E). Nuclear Medicine Review 2011, 14, 2:

11 Nuclear Medicine Review 2011, 14, 2:

12 PROS Pain relief Easy CONS No tumor-only selectivity Large or multiple fields of irradiation Bone marrow suppression Repeatability G.I. toxicity? Clin Cancer Res 2006;12(20 Suppl) October 15, 2006

15 Radionuclides residing in family IIA of the periodic table carry the same divalent charge as elemental calcium and are incorporated into bone matrix directly

16 Radionuclides residing in family IIA of the periodic table carry the same divalent charge as elemental calcium and are incorporated into bone matrix directly

17 Most other radionuclides are not efficiently targeted to bone naturally and instead are chelated to organic phosphates, which are incorporated into the matrix

18 Microautoradiography from a dog injected with an a-emitting bone seeker. Distribution of a-particle tracks Normal spongious bone Osteoblastic zone Clin Cancer Res 2006;12(20 Suppl)

19 Cancer Control. 2012;19(2):

20 Indications Diffuse skeletal metastases visualized on nuclear medicine bone scan Painful skeletal metastases inadequately treated by analgesics Intolerance to prescribed analgesics Hormone-insensitive disease (for metastatic prostate cancer) Relative contraindications Uncontrolled extraskeletal disease burden Asymptomatic skeletal metastases Skeletal lesions limited to fewer than three sites Purely osteolytic lesions (no uptake on bone scan) Poor bone marrow reserve Life expectancy less than 60 days Cancer Control. 2012;19(2):

21 Absolute contraindications Presence of epidural spinal cord compression Pending or active pathological fracture of weight-bearing bone Renal failure Pregnancy Breast-feeding Cancer Control. 2012;19(2):

22 Half life Penetrance Daughters Production Safety Efficacy Repeatability

23 β-emitters Long half-life High penetration Bone marrow toxicity Usually no repeatability Conflicting data on delay of new foci α-emitters Enhanced relative biologic effectiveness : single knock out cell damage (as compared to gamma rays and β-particles)!!! If it is coupled with an unforgiving half life? N Engl J Med 2013; 369: July 18, 2013

24 1600 y!!!

29 Uptake in selected tissues

30 Effect of different treatment modalities Effect in prolonging symptoms free survivals

31 89 Sr 223 Ra J Nucl Med 2003; 44:

32 J Nucl Med 2003; 44:

34 Males (n = 15) Females (n = 10) Age, years 72.7 ± ± 6.0 ECOG status, n (%) (27) 8 (53) 3 (20) 2 (20) 7 (70) 1 (10) Number of hot spots 25.5 ± ± 25.7 Platelets 10 9 /L ± ± 84.1 WBC 10 9 /L 7.6 ± ± 1.5 Granulocytes 10 9 /L 5.6 ± ± 1.3 Hemoglobin (g/dl) 12.2 ± ± 1.4 Serum ALP (units/l) 1154 ± ± 117 QLQ pain, n (%) Not at all A little Quite a bit Very much 2 (13) 3 (20) 7 (47) 3 (20) 0 3 (30) 5 (50) 2 (20) Nilsson et al. Clin Cancer Res 2005;11:4451.

35 No dose-limiting hemotoxicities Some Grade 3 myelosuppression was observed within 2 to 4 weeks of dosing, with complete recovery during the 8-week follow-up Two patients experienced Grade 3 neutropenia and three patients (including the neutropenic patients) had Grade 3 leukopenia For thrombocytes, only Grade 1 toxicity was reported Mild, transient diarrhea was observed in 10 of the 25 patients Nausea and vomiting were more frequently observed in the highest dosage group Nilsson et al. Clin Cancer Res 2005;11:4451.

36 ADVERSE EVENT PROFILE Single-dose radium-223 dichloride ( kbq/kg) n (%) Patients 25 Any AE 22 (88) Any SAE 7 (28) Most frequent AE ( 5 patients) Diarrhea Bone pain (including flare ) Fatigue Nausea Vomiting 10 (40) 9 (36) 5 (20) 5 (20) 5 (20) Two patients SAEs were considered possibly treatment related (supraventricular arrhythmia and Grade 3 nausea/vomiting with Grade 3 leukopenia) Nausea/vomiting occurred in 4 out of 5 patients at the highest dose Patients reporting diarrhea responded well to remedial medication Nilsson et al. Clin Cancer Res 2005;11:4451.

Neutrophils ( 10 9 /L) Dose group 46 kbq/kg 93 kbq/kg 163 kbq/kg 213 kbq/kg 250 kbq/kg 9 8 7 6 5 4 3 2 1 0 Grade

37 Neutrophils ( 10 9 /L) Dose group 46 kbq/kg 93 kbq/kg 163 kbq/kg 213 kbq/kg 250 kbq/kg Grade 0 Grade 1 Grade 2 Grade Days Nilsson et al. Clin Cancer Res 2005;11:4451.

38 Nilsson et al. Clin Cancer Res 2005;11:4451.

39 Open-label, single-center, Phase I study Patients with progressive CRPC with 2 bone metastases MONITORING PHASE FOLLOW-UP PHASE Radium-223 dichloride 50, 100 or 200 kbq/kg Optional 2nd dose 50 kbq/kg Primary endpoints Safety and tolerability Cohort n Optional dose (n) kbq/kg kbq/kg kbq/kg 4 2 Total Months Biodistribution Dosimetry Pharmacokinetic profile Secondary endpoints PSA levels Bone markers (including bone-alp) Circulating tumor cells Morris et al. Presented at: ASCO Genitourinary Cancers Symposium 2010: Poster 211.

40 Body system Adverse event Grade 1 (n = 10) Grade 2 (n = 10) Grade 3 (n = 10) Grade 4 (n = 10) Blood/bone marrow Lymphopenia (20%) 1 (10%)* Constitutional Hemoglobin 2 (20%) 0 1 (10%) 0 Leukocytes (total WBC) 4 (40%) 0 1 (10%)* 1 (10%)* Neutrophils (ANC) 1 (10%) 1 (10%)* 1 (10%)* 0 Platelets 2 (20%) Fatigue (asthenia, lethargy, malaise) 2 (20%) 1 (10%) 0 0 Gastrointestinal Anorexia 3 (30%) Metabolic/ laboratory Diarrhea 4 (40%) 0 1 (10%)* 0 Nausea 1 (10%) 0 1 (10%)* 0 Vomiting 1 (10%) 1 (10%)* 0 0 Calcium, low (hypocalcemia) 2 (20%)* 2 (20%)* 1 (10%)* 0 Pain Pain: back 0 1 (10%)* 1 (10%)* 0 Morris et al. Presented at: ASCO Genitourinary Cancers Symposium 2010: Poster 211.

41 Body system Blood/bone Marrow Constitutional Death Adverse event Grade 1 (n = 10) Grade 2 (n = 10) Grade 3 (n = 10) Grade 4 (n = 10) Grade 5 (n = 10) Lymphopenia (20%) 1 (10%)* 0 Hemoglobin 2 (20%) 1 (10%) 1 (10%) 0 0 Leukocytes (total WBC) 4 (40%) 1 (10%)* 1 (10%)* 1 (10%)* 0 Neutrophils (ANC) 0 2 (20%)* 1 (10%)* 0 0 Platelets 2 (20%) 1 (10%) 1 (10%) 0 0 Fatigue (asthenia, lethargy, malaise) Disease progression NOS 3 (30%) 3 (30%) (10%) Gastrointestinal Anorexia 6 (60%) Diarrhea 4 (40%) 0 2 (20%)* 0 0 Nausea 3 (30%) 2 (20%)* 1 (10%)* 0 0 Vomiting 1 (10%) 1 (10%)* Morris et al. Presented at: ASCO Genitourinary Cancers Symposium 2010: Poster 211.

42 Changes in PSA from baseline (%) PSA RESPONSE Best PSA response through 12 weeks post first radium-223 dichloride injection (n = 10) kbq/kg 100 kbq/kg 200 kbq/kg Patient Morris et al. Presented at: ASCO Genitourinary Cancers Symposium 2010: Poster 211.

43 Change in bone-alp from baseline (%) BONE ALP RESPONSE Best bone alkaline phosphatase (ALP) response through 12 weeks post first radium-223 dichloride injection (n = 10) kbq/kg 100 kbq/kg 200 kbq/kg Patient Morris et al. Presented at: ASCO Genitourinary Cancers Symposium 2010: Poster 211.

45 Aim To investigate the painrelieving effect of single doses of radium-223 dichloride in patients with CRPC with painful bone metastases (n = 100) Primary endpoint Pain index from baseline to weeks 2, 4, 8, 12 and 16 Secondary endpoints included Change from baseline in Brief Pain Inventory (BPI) pain severity index Change in bone alkaline phosphatase Adverse events

46 Pain responders were those patients with Pain Index score 4 (i.e. decrease of 20% in diary pain rating and stable/reduced analgesic intake) Radium-223 dichloride single dose Nilsson et al. Eur J Cancer 2012;48(5):678.

47 Change in mean BPI score from baseline Decrease in BPI Pain Severity Mean Score at Week 8 Median Change from Baseline in Bone ALP Radium-223 dichloride single dose 0 5 kbq/kg 25 kbq/kg 50 kbq/kg 100 kbq/kg P = P = P = P = BPI, brief pain inventory. Nilsson et al. Eur J Cancer 2012;48(5):678.

48 Number (%) of patients experiencing adverse event during the post-treatment period (weeks 0 16) CTCAE Grade Hemoglobin 66 (66) 26 (26) 7 (7) 1 (1) White blood cells 87 (87) 12 (12) 1 (1) 0 (0) Platelets 92 (92) 2 (2) 4 (4) 2 (2) Neutrophils 85 (90) 6 (6) 1 (1) 2 (2) Safety set: all patients / dose levels Nilsson et al. Eur J Cancer 2012;48(5):678.

Dose group 5 kbq/kg 25 kbq/kg 50 kbq/kg 100 kbq/kg Overall n = 26 n = 25 n = 25 n = 24 n = 100 Nausea 13 (50.0) 9 (36.0) 9 (36.0) 12 (50.

0) Constipation 6 (23.1) 5 (20.0) 7 (28.0) 2 (8.3) 20 (20.0) Fatigue 8 (30.8) 6 (24.0) 4 (16.0) 8 (33.3) 26 (26.0) Peripheral edema 4 (15.

49 Dose group 5 kbq/kg 25 kbq/kg 50 kbq/kg 100 kbq/kg Overall n = 26 n = 25 n = 25 n = 24 n = 100 Nausea 13 (50.0) 9 (36.0) 9 (36.0) 12 (50.0) 43 (43.0) Vomiting 6 (23.1) 9 (36.0) 4 (16.0) 5 (20.8) 24 (24.0) Diarrhea 4 (15.4) 7 (28.0) 6 (24.0) 5 (20.8) 22 (22.0) Constipation 6 (23.1) 5 (20.0) 7 (28.0) 2 (8.3) 20 (20.0) Fatigue 8 (30.8) 6 (24.0) 4 (16.0) 8 (33.3) 26 (26.0) Peripheral edema 4 (15.4) 5 (20.0) 1 (4.0) 2 (8.3) 12 (12.0) Bone pain 2 (7.7) 5 (20.0) 2 (8.0) 2 (8.3) 11 (11.0) Urinary tract infection 4 (15.4) 4 (16.0) 2 (8.0) 4 (16.7) 14 (14.0) Adverse events reported by > 10% overall Number (%) of patients experiencing adverse event During 24 months follow-up, there were no new diagnoses of Acute myeloid leukemia (AML) Myelodysplastic syndrome (MDS) Aplastic anemia Primary bone cancer Nilsson et al. Eur J Cancer 2012;48(5):678.

50 Co-primary endpoints Change in bone ALP concentration Time to SRE Secondary endpoints Safety Serum markers of bone turnover Serum PSA Overall survival

51 Hematological toxicity Non hematological toxicity

53 Distribution of % change in serum PSA from baseline to 4 weeks after last study drug

Overall survival (OS) of patients in the radium-223 dichloride group of the BC1-02 study (ALP normalization) 100 80 60 Normalized ALP (n = 12) Median OS: 102.1 weeks P < 0.001 vs.

54 Overall survival (OS) of patients in the radium-223 dichloride group of the BC1-02 study (ALP normalization) Normalized ALP (n = 12) Median OS: weeks P < vs. non-normalized ALP Non-normalized ALP (n = 14) Median OS: 42.5 weeks Time from randomization (weeks) This confirms the significant OS improvement associated with ALP normalization observed in the BC1-04 study *Patients with elevated baseline total ALP were evaluated to determine whether total ALP was normalized ( 128 U/L) after treatment (week 12).ALP, alkaline phosphatase. Parker et al. Presented at: ASCO Genitourinary Cancers Symposium 2011: Abstract 49.

56 PATIENTS (N=921) Confirmed symptomatic CRPC 2 bone metastases No known visceral metastases Post-docetaxel, unfit for docetaxel, or refused docetaxel a STRATIFICATION Total ALP: <220 U/L vs 220 U/L Bisphosphonate use: Yes vs No Prior docetaxel: Yes vs No R 2:1 Radium-223 (50 kbq/kg IV) 6 injections at 4-week intervals + best standard of care b Placebo (saline) 6 injections at 4-week intervals + best standard of care b 136 centers in 19 countries Planned follow-up is 3 years ALSYMPCA was halted early after the positive efficacy results reported from a planned interim analysis of 809 patients with 314 deaths occurred. An updated analysis of efficacy and safety was performed from all 921 enrolled patients when 528 deaths had occurred. 56

57 Histologically confirmed, progressive CRPC with 2 bone metastases (on skeletal scintigraphy) and no known visceral metastases Patients were receiving best standard of care Patients had either received docetaxel, were not fit enough or willing to receive docetaxel, or did not have docetaxel available Symptomatic disease, defined as regular use of analgesic medication for cancerrelated bone pain or treatment with EBRT for bone pain within previous 12 weeks PSA 5 ng/ml with evidence of progressively rising PSA values ECOG PS score of 0 to 2 c Life expectancy of 6 months Adequate hematologic, renal, and liver function N Engl J Med 2013;369:213-23

58 Prior hemibody external radiation therapy Treatment with chemotherapy within the previous 4 weeks or failure to recover from AEs due to chemotherapy Systemic radiation therapy with radioisotopes within the previous 24 weeks Blood transfusion or erythropoietin-stimulating agents within the previous 4 weeks Malignant lymphadenopathy >3 cm in short-axis diameter History or presence of visceral metastases Imminent or established spinal cord compression N Engl J Med 2013;369:213-23

$Primary endpoint OS Whereas other trials included asymptomatic fractures detected by means of periodic radiologic review as skeletal events, ALSYMPCA had no radiographic review and so only$

59 Primary endpoint OS Whereas other trials included asymptomatic fractures detected by means of periodic radiologic review as skeletal events, ALSYMPCA had no radiographic review and so only symptomatic pathologic bone fractures were captured. Thus symptomatic skeletal event (SSE) was deemed a more clinically relevant term for this measurement. Secondary endpoints Time to total ALP progression Total ALP response Time to occurrence of first SSE Total ALP normalization Time to PSA progression Other secondary efficacy endpoints Safety Quality of life

60 Patients Enrolled (N=921) (radium-223, n=614; placebo, n=307) Patients Randomized, ITT Population (N=921 [100%]) (radium-223, n=614 [100%]; placebo, n=307 [100%]) Patients Who Withdrew From Study Before First Injection (n=20 [2%]) a (radium-223, n=13 [2%]; placebo, n=5 [2%]; missing, n=2 [0.2%]) Patients Treated (n= 901 [98%]) (Radium-223, n=599 [98%]; placebo, n=302 [98%]) Patients Who Discontinued Treatment b (n=387 [42%]) (radium-223, n=225 [37%]); placebo, n=162 [53%]) Patients Who Withdrew Early From Study d (n=582 [63%]) (radium-223, n=370 [60%]; placebo, n=212 [69%]) Patients Included in Safety Population (n=901 [98%]) (radium-223, n=600 [98%] c ; placebo, n=301 [98%]) ITT, intention-to-treat. a. 18 Patients who were not being treated were withdrawn from the study before the first injection of study drug; 2 patients received no treatment and had missing dates of withdrawal. b.patients who discontinued treatment but continued to participate through follow-up were not considered withdrawn from the study. c. 1 Patient was randomized to placebo but received radium-223 at week 0; this patient is included as randomized in the ITT population (placebo group) and is included in the radium-223 group for the safety population. d.patients who withdrew prior to their 3-year follow-up visit were considered to have withdrawn early from the study. SOURCE: Parker C, et al. N Engl J Med. 2013;369(3):

CHARACTERISTIC RADIUM-223 (n=614) PLACEBO (n=307) Age, years, Median (range) >75 years, n (%) 71 (49-90) 171 (28) 71 (44-94) 90 (29) Caucasian race, n (%) 575 (94) 290 (94) Total ALP, n (%) <220 U/L

61 CHARACTERISTIC RADIUM-223 (n=614) PLACEBO (n=307) Age, years, Median (range) >75 years, n (%) 71 (49-90) 171 (28) 71 (44-94) 90 (29) Caucasian race, n (%) 575 (94) 290 (94) Total ALP, n (%) <220 U/L 220 U/L Current use of bisphosphonates, n (%) Yes No Any prior use of docetaxel, n (%) Yes No ECOG PS, n (%) (57) 266 (43) 250 (41) 364 (59) 352 (57) 262 (43) 165 (27) 371 (60) 77 (13) 169 (55) 138 (45) 124 (40) 183 (60) 174 (57) 133 (43) 78 (25) 187 (61) 41 (13)

62 CHARACTERISTIC RADIUM-223 (n=614) PLACEBO (n=307) WHO ladder for cancer pain, n (%) (42) 151 (25) 194 (32) 137 (45) 78 (25) 90 (29) Extent of disease, n (%) <6 metastases 6-20 metastases >20 metastases Superscan EBRT within 12 weeks of screening, n (%) Yes No 100 (16) 262 (43) 195 (32) 54 (9) 99 (16) 515 (84) 38 (12) 147 (48) 91 (30) 30 (10) 48 (16) 259 (84) Hemoglobin (g/dl), Median (range) [normal range: g/dl] Albumin (g/l), Median (range) [normal range: g/l] Total ALP (U/L), Median (range) [normal range: U/L] 12.2 ( ) 12.1 ( ) 40 (24-53) 40 (23-50) 211 ( ) 223 ( ) LDH (U/L), Median (range) [normal range: U/L] 315 ( ) 336 ( ) PSA (μg/l), Median (range) [normal range: μg/l] 146 ( ) 173 ( )

63 The updated analysis confirmed the 30% reduction in risk of death (HR=0.70) for patients in the radium- 223 group compared with placebo

67 Vapiwala N, Glatstein E. N Engl J Med 2013;369:

SYSTEMIC THERAPIES FOR CRPC: Chemotherapy and Radium-223

SYSTEMIC THERAPIES FOR CRPC: Chemotherapy and Radium-223 ELENA CASTRO Spanish National Cancer Research Centre Prostate Preceptorship. Lugano 4-5 October 2018 Disclosures Participation in advisory boards: