Incorporating Xofigo (radium Ra 223 dichloride) into Clinical Practice

Transcription

1 Incorporating Xofigo (radium Ra 223 dichloride) into Clinical Practice Please see Important Safety Information throughout this presentation and full Prescribing Information available at this 2014 Bayer Healthcare Pharmaceuticals. All rights reserved. BAYER, the Bayer Cross, Xofigo, and Xofigo Access Services logo are registered trademarks of Bayer. PP 600 US 0615 Objectives Review the metastatic castration resistant prostate cancer (mcrpc) disease state and the impact of bone metastases Describe the Xofigo (radium Ra 223 dichloride) mechanism of action Highlight key data from the phase III ALSYMPCA study Describe the Xofigo safety profile Discuss the integration of Xofigo into clinical practice 2 Bone Predominant Disease Is Common in CRPC 233,000 ~14% ~90% new cases of prostate cancer expected in of patients achieving surgical or medical castration will develop CRPC 2 of men with mcrpc have metastases in the bone year survival is reduced to 4% once CRPC metastasizes to bone 6 CRPC=castration resistant prostate cancer. 1. SEER Prostate Cancer Fact Sheet. Accessed July 30, Alemayehu B, et al. J Med Econ. 2010;13: Tannock IF, et al. N Engl J Med. 2004;351(15): de Bono J, et al. N Engl J Med. 2011;364: Scher H, et al. N Engl J Med. 2012;367: , supplementary appendix. 6. SEER Prostate Cancer Fact Sheet. Accessed July 30,

2 Progression to mcrpc 1,2 Tumor volume & activity Local Disease (M0) Rising PSA (M0) Biochemical Relapse (M0) CRPC (failed ADT) Newly Diagnosed Metastases (M1) mcrpc Nonmetastatic Metastatic, Chemo naive Asymptomatic Symptomatic a Chemo Metastatic Post chemo 4% of patients with prostate cancer present with M1 hormone sensitive disease 3 a For the purposes of these slides, symptomatic refers to any level of symptoms (including minimally symptomatic). 1. Higano CS. Sipuleucel T: autologous cellular immunotherapy for metastatic castration resistant prostate cancer. In: Figg W, et al (eds). Drug Management of Prostate Cancer. New York: Springer; 2010: NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Prostate Cancer. v Available at: Accessed November 11, SEER Prostate Cancer Fact Sheet. Available at: Accessed July 30, Progression of Metastatic Disease to Bone in CRPC No metastases Metastases Low-volume metastases; minimal or no symptoms Progressive, symptomatic metastases High-volume or symptomatic metastases Death What do you do in your practice to facilitate earliest detection of bone metastases? What do you do in your practice to facilitate earliest detection of symptoms related to bone metastases? Antonarakis ES, Eisenberger MA. N Engl J Med. 2011;364(21): Copyright 2011 Massachusetts Medical Society. 5 Prostate Tumor Cells May Colonize the Bone In vitro data show that colonization of bone tissue may be driven by chemoattraction and preferential attachment 1 3 Prostate cancer metastases are associated with osteoblastic activity 4 6 Balance shifts from bone destruction to bone deposition Correlates with higher levels of alkaline phosphatase (ALP) and osteocalcin Prostate Cancer Cells Bone 1. Tsingotjidou AS, et al. Anticancer Res. 2001;21: Jacob K, et al. Cancer Res. 1999;59: Taichman RS, et al. Cancer Res. 2002;62: Urwin GH, et al. Br J Urol. 1985;57: Jung K, et al. Int J Cancer. 2004;111: Yang J, et al. Cancer Res. 2001;61:

3 Bone Metastases Associated With Shortened Survival a Probability of Survival (%) Time After Initial Prostate Cancer Diagnosis (years) a Of the 23,087 patients with initial diagnosis of prostate cancer, 22,404 had no bone metastases and 569 presented with bone metastases. 1 CI=confidence interval. 1. Nørgaard M, et al. J Urol. 2010;184: Noguchi M, et al. Br J Cancer. 2003;88: % alive at 5 years (95% CI: ) 1 3% alive at 5 years (95% CI: ) 1 No bone metastases Bone metastases Skeletal tumor burden is an independent predictor of death in patients with advanced prostate cancer 2 7 XOFIGO (radium Ra 223 dichloride) CLINICAL PROFILE, EFFICACY, AND SAFETY Xofigo (Radium Ra 223 Dichloride) Indication Xofigo is indicated for the treatment of patients with CRPC, symptomatic bone metastases and no known visceral metastatic disease 1 Important safety information 1 Contraindications: Xofigo is contraindicated in women who are or may become pregnant. Xofigo can cause fetal harm when administered to a pregnant woman Please see additional Important Safety Information throughout this presentation and full Prescribing Information available at this 9 3

4 Xofigo (Radium Ra 223 Dichloride) Mechanism of Action Mimics Calcium Short Range High Linear Energy Xofigo mimics calcium, forming complexes with the bone mineral hydroxyapatite at areas of increased bone turnover such as bone metastases 1 The short range of alpha particles emitted by Xofigo (<10 cell diameters) limits damage to surrounding normal tissue 1 Xofigo emits alpha particles that predominantly cause double strand DNA breaks in adjacent cells, resulting in an antitumor effect on bone metastases 1 Xofigo can be absorbed by organs other than bone, primarily the bone marrow and gastrointestinal system, which can result in side effects in those healthy tissues. Please see additional Important Safety Information throughout this presentation and full Prescribing Information available at this 10 Phase III ALSYMPCA Study Design, Patient Eligibility Patients 1,2 Stratification 2 Treatment 1,2 N=921 CRPC with 2 symptomatic bone metastases No known visceral metastases Lymphadenopathy 3 cm only Prior docetaxel: Yes vs no Current bisphosphonate use: Yes vs no Total ALP: <220 U/L vs 220 U/L 2:1 Xofigo (radium Ra 223 dichloride) (50 kbq/kg) + Best standard of care (BSoC) (n=614) 6 injections at 4 week intervals Placebo (saline) + BSoC (n=307) 136 centers in 19 countries Primary Endpoint 2 Overall survival Best standard of care included local external beam radiation therapy (EBRT), corticosteroids, antiandrogens, estrogens, estramustine or ketoconazole 2. Parker C, et al. N Engl J Med. 2013;369: Phase III ALSYMPCA Best Standard of Care (BSoC) In the ALSYMPCA trial, BSoC was defined as treatment with 1 Local external beam radiation therapy (EBRT) Glucocorticoids Antiandrogens Ketoconazole Estrogens (eg, diethylstilbestrol, estramustine) 1. Parker C, et al. N Engl J Med. 2013;369:

5 Phase III ALSYMPCA Other Endpoints Secondary Endpoints 1 Median time to first SSE Median time to ALP progression Median time to ALP normalization Median time to PSA progression Other Exploratory Secondary Endpoints 1 Safety Quality of life Symptomatic skeletal event (SSE) was defined as the first use of external beam radiation therapy to relieve skeletal symptoms, new symptomatic pathologic vertebral or non vertebral bone fractures, spinal cord compression, or tumor related orthopedic surgical intervention ALP= Alkaline phosphatase 1. Parker C, et al. N Engl J Med. 2013;369: Phase III ALSYMPCA Definition of Symptomatic and Patient Demographics In the ALSYMPCA trial, patients were required to have symptomatic disease, with regular use of analgesic medication or EBRT for cancerrelated bone pain 1 Xofigo (Radium Ra 223 dichloride), n=614 Placebo, n=307 Median age (years) ECOG PS (%) Opiate pain medications (%) Nonopiate pain medications (%) No pain medications (%) 2 1 Prior docetaxel (%) Yes No Current bisphosphonate use (%) Yes No Total ALP (%) <220 U/L U/L Median PSA Parker C, et al. N Engl J Med. 2013;369: OS Benefit Consistent Across Planned Interim and Exploratory Updated Analyses An exploratory updated OS analysis was performed before patient crossover, incorporating an additional 214 events, resulting in findings consistent with the interim analysis. Xofigo (radium P Value Ra 223 dichloride) a Placebo a (2 sided) HR=hazard ratio; OS=overall survival. a Plus BSoC. HR (95% CI) Planned interim analysis n=541 n=268 Number of deaths (%) 191 (35.3) 123 (45.9) Censored 350 (64.7%) 145 (54.1%) Median OS (months) (95% CI) ( ) ( ) ( ) Exploratory updated analysis b n=614 n=307 Number of deaths (%) 333 (54.2) 195 (63.5) Censored 281 (45.8%) 112 (36.5%) Median OS (months) (95% CI) 14.9 ( ) 11.3 ( ) ( ) 15 5

6 Xofigo (Radium Ra 223 Dichloride) Is First Agent to Extend OS by Treating Bone Metastases in CRPC Probability of Survival (%) Xofigo + BSoC Placebo + BSoC Median OS Extended by 3.6 Months vs Placebo in the Exploratory Updated Analysis Xofigo median OS: months Xofigo + BSoC (n=614) (95% CI: ) 70 Placebo a + BSoC (n=307) 60 HR= (95% CI: ) Placebo median OS: 11.3 months 20 (95% CI: ) Time (months) % reduction in the risk of death vs placebo (HR=0.695 b ) a 95% CI: for the exploratory updated analysis. 16 Overall Survival Benefit Supported by Delay in Time to First SSE 1 EBRT to relieve skeletal symptoms SSEs were symptom driven a New symptomatic broken bone caused by disease Occurrence of spinal cord compression Tumor related orthopedic surgical intervention The majority of events consisted of EBRT to bone metastases to relieve skeletal symptoms 1 a There were no scheduled radiographic assessments performed in the study. 2. Parker C, et al. N Engl J Med. 2013;369: Xofigo (Radium Ra 223 Dichloride) Improves Key Biomarkers of Disease Progression Exploratory Updated Analysis of Select Secondary Endpoints Secondary Efficacy Endpoints Xofigo (n=614) Placebo (n=307) HR (95% CI) Median time to total ALP progression (months) ( ) Total ALP response ( 30% reduction) a 47% 3% Total ALP normalization ab 34% 1% Median time to PSA progression (months) ( ) a Number of patients without missing values. b In patients who had elevated total ALP at baseline. 1. Parker C, et al. N Engl J Med. 2013;369(3):

7 Hematologic Laboratory Abnormalities Occurring in 10% of Patients a The most common hematologic laboratory abnormalities (all grades) in the Xofigo arm ( 10%) verus the placebo arm, respectively, were anemia (93% vs 88%), lymphocytopenia (72% vs 53%), leukopenia (35% vs 10%), thrombocytopenia (31% vs 22%) and neutropenia (18% vs 5%) Xofigo (radium Ra 223 dichloride) b (n=600) Grades 3 4 (%) Placebo b (n=301) Anemia 6 6 Lymphocytopenia 20 7 Leukopenia 3 <1 Thrombocytopenia 3 <1 Neutropenia 2 <1 a For which the rates for Xofigo exceed the rates for placebo. b Plus BSoC. 19 Hematologic Events Stratified by Docetaxel Exposure 1 Frequency of Events Among Patients Receiving Xofigo (radium Ra 223 dichloride) a Grade 3 4 thrombocytopenia (laboratory abnormality) Patients Without Prior Docetaxel Exposure Patients With Prior Docetaxel Exposure 1% 4% Grade 3 4 neutropenia 1% 3% a Plus BSoC. 20 Important Safety Information Bone Marrow Suppression 1 : In the randomized trial, 2% of patients in the Xofigo (radium Ra 223 dichloride) arm experienced bone marrow failure or ongoing pancytopenia, compared to no patients treated with placebo Two deaths due to bone marrow failure. For 7 of 13 patients treated with Xofigo, bone marrow failure was ongoing at the time of death Among the 13 patients who experienced bone marrow failure, 54% required blood transfusions. Four percent (4%) of patients in the Xofigo arm and 2% in the placebo arm permanently discontinued therapy due to bone marrow suppression Deaths related to vascular hemorrhage in association with myelosuppression were observed in 1% of Xofigo (radium 223 dichloride) treated patients compared to 0.3% of patients treated with placebo 21 7

8 Important Safety Information (cont d) Bone Marrow Suppression (continued) 1 : Incidence of infection related deaths (2%), serious infections (10%), and febrile neutropenia (<1%) was similar for patients treated with Xofigo (radium Ra 223 dichloride) and placebo Myelosuppression notably thrombocytopenia, neutropenia, pancytopenia, and leukopenia, has been reported in patients treated with Xofigo Monitor patients with evidence of compromised bone marrow reserve closely and provide supportive care measures when clinically indicated. Discontinue Xofigo in patients who experience life threatening complications despite supportive care for bone marrow failure 22 Important Safety Information (cont d) Hematological Evaluation: Monitor blood counts at baseline and prior to every dose of Xofigo (radium Ra 223 dichloride) Prior to first administering Xofigo, the absolute neutrophil count (ANC) should be /L, the platelet count /L, and hemoglobin 10 g/dl Prior to subsequent administrations, the ANC should be /L and the platelet count /L Discontinue Xofigo if hematologic values do not recover within 6 8 weeks after last administration despite receiving supportive care 23 Important Safety Information (cont d) Concomitant Use With Chemotherapy: Safety and efficacy of concomitant chemotherapy with Xofigo (radium Ra 223 dichloride) have not been established Outside of a clinical trial, concomitant use of Xofigo in patients on chemotherapy is not recommended due to the potential for additive myelosuppression If chemotherapy, other systemic radioisotopes, or hemibody external radiotherapy are administered during the treatment period, Xofigo should be discontinued 24 8

9 Safety Profile Established in ALSYMPCA Study Adverse Reactions Occurring in 2% of Patients a All Grades (%) Grades 3 4(%) Xofigo (radium Ra 223 dichloride) b (n=600) Placebo b (n=301) Xofigo (radium Ra 223 dichloride) b (n=600) Placebo b (n=301) Pancytopenia Nausea Diarrhea Vomiting Peripheral edema Renal failure and impairment a For which the rates for Xofigo exceed the rates for placebo. b Plus BSoC. 25 Overall Grade 3 4 AEs and Discontinuations Due to AEs Grades 3 4 AEs 57% 63% Discontinuation Due to AEs 17% 21% a Xofigo (radium Ra 223 dichloride) a Placebo 0% 20% 40% 60% 80% 100% Patients (%) The most common hematologic laboratory abnormalities leading to discontinuation of Xofigo were anemia (2%) and thrombocytopenia (2%) AE=adverse event. a Plus BSoC. 26 Important Safety Information Administration and Radiation Protection 1 Xofigo should be received, used and administered only by authorized persons in designated clinical settings The administration of Xofigo is associated with potential risks to other persons from radiation or contamination from spills of bodily fluids such as urine, feces, or vomit. Therefore, radiation protection precautions must be taken in accordance with national and local regulations 27 9

10 Important Safety Information Fluid status 1 Dehydration occurred in 3% of patients on Xofigo (radium Ra 223 dichloride) and 1% of patients on placebo Xofigo increases adverse reactions such as diarrhea, nausea, and vomiting, which may result in dehydration Monitor patients oral intake and fluid status carefully and promptly treat patients who display signs or symptoms of dehydration or hypovolemia Injection site reactions (reported in 1% Xofigo patients) 1 Erythema Pain Edema 28 Important Safety Information (cont d) Secondary malignant neoplasms 1 Xofigo (radium Ra 223 dichloride) contributes to a patient s overall long term cumulative radiation exposure Long term cumulative radiation exposure may be associated with an increased risk of cancer and hereditary defects Xofigo may increase the risk of osteosarcoma or other secondary malignant neoplasms due to its MOA and neoplastic changes However, the overall incidence of new malignancies in the randomized trial was lower on the Xofigo arm compared to placebo (<1% vs 2%, respectively), but the expected latency period for development of secondary malignancies exceeded the duration of follow up for patients on the trial MOA=mechanism of action. 29 Important Safety Information (cont d) Subsequent treatment with cytotoxic chemotherapy 1 In the randomized clinical trial, 16% patients in the Xofigo (radium Ra 223 dichloride) group and 18% patients in the placebo group received cytotoxic chemotherapy after completion of study treatments Adequate safety monitoring and laboratory testing was not performed to assess how patients treated with Xofigo will tolerate subsequent cytotoxic chemotherapy MOA=mechanism of action

11 Currently Approved Therapies for Advanced Prostate Cancer National Comprehensive Cancer Network (NCCN ) category 1 evidence Hormone Sensitive CRPC Asymptomatic mcrpc Symptomatic mcrpc Increasing symptoms Hormone therapy Radium Ra 223 dichloride a Abiraterone Sipuleucel T Enzalutamide Abiraterone Enzalutamide Cabazitaxel Docetaxel Supportive Care (denosumab/bisphosphonates/β emitters/ebrt) EBRT=external beam radiation therapy. This illustration does not represent all possible treatment options in the various stages of mcrpc treatment paradigm. Distance is not proportional to time. a For patients with symptomatic bone metastases with no known visceral metastatic disease. Adapted with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) for Prostate Cancer V Available at: Accessed November 11, National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines and illustrations herein may not be reproduced in any form for any purpose without the express written permission of the NCCN. To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK, NCCN, NCCN GUIDELINES, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. 31 When Is It the Right Time to Administer Xofigo (Radium Ra 223 Dichloride)? Xofigo is indicated for the treatment of patients with CRPC, symptomatic bone metastases and no known visceral metastatic disease 1 At the earliest onset of symptoms from bone metastases Bone metastases 1 Symptoms 1 Administer Xofigo 1,2 Patients in the phase III ALSYMPCA trial had 2 or more bone metastases Regular OTC analgesic use (42% patients in ALSYMPCA were on non opiate pain medications, 57% were on opiate pain medications) Use of EBRT to treat bone pain Added to BSoC (EBRT, glucocorticoids, antiandrogens, ketoconazole, estrogens (eg, estramustine) 6 injections at 4 week intervals (the median number of injections was 6 in the Xofigo arm and 5in the placebo arm) Xofigo is not recommended in combination with chemotherapy. OTC=over the counter. 1. Parker C, et al. N Engl J Med. 2013;369: Xofigo (radium Ra 223 dichloride) injection [prescribing information]. Wayne, NJ: Bayer HealthCare Pharmaceuticals Inc.; May Summary (1 of 2) Xofigo (radium Ra 223 dichloride) is an alpha particle emitting pharmaceutical that exerts an antitumor effect on bone metastases 30% reduction in risk of death vs placebo (HR=0.695) Exploratory updated analysis a : 3.6 month increase in median OS vs placebo (HR=0.695; 95% CI: ) 14.9 months for Xofigo b (95% CI: ) vs 11.3 months for placebo b (95% CI: ) Prespecified interim analysis: 2.8 month increase in median OS vs placebo, P= (HR=0.695; 95% CI: ) 14.0 months for Xofigo b (95% CI: ) vs 11.2 months for placebo b (95% CI: ) a An exploratory updated OS analysis was performed before patient crossover, incorporating an additional 214 events, resulting in findings consistent with the interim analysis. b Plus BSoC

12 Summary (2 of 2) OS benefit supported by delay in time to first SSE, favoring Xofigo a The majority of events consisted of EBRT to bone metastases Xofigo (radium Ra 223 dichloride) is contraindicated in women who are or may become pregnant. Xofigo can cause fetal harm when administered to a pregnant woman The most common adverse reactions ( 10%) in the Xofigo b arm vs the placebo b arm, respectively, were nausea (36% vs 35%), diarrhea (25% vs 15%), vomiting (19% vs 14%), and peripheral edema (13% vs 10%) a An exploratory updated OS analysis was performed before patient crossover, incorporating an additional 214 events, resulting in findings consistent with the interim analysis. b Plus BSoC