Slide 1: Radiopharmaceutical Approaches To Skeletal Metastases from Prostate Cancer
“Radiopharmaceutical Approaches To Skeletal Metastases from Prostate Cancer” Howard I. Scher, MD Chief, Genitourinary Oncology Service Memorial Sloan-Kettering Cancer Center New York, NY
Slide 2: Therapeutic Objectives/Outcomes
Therapeutic Objectives/Outcomes Death From Other Causes 220,000 50,000 31,200 Death Of Disease Survival QOL Cure Risk Stratify Prevent Metastases Delay Progression
Slide 3: Castration Resistant Disease
Castration Resistant Disease Progression of Disease Despite Castrate Levels of Testosterone (<50 ng/ml – By Consensus) in the Blood Prostate Specific Antigen Prostate Specific Antigen (ng/ml) 2001 Apr Jul Oct Jan 2002 Apr Jul ng/ml
Slide 4: Clinical Management of Castration Resistant Prostate Cancer
Clinical Management of Castration Resistant Prostate Cancer 1. Therapeutic objectives: Why offer therapy – eliminate/relieve and/or prevent/delay 2. Chemotherapy for hormone-refractory prostate cancer 3. Radiopharmaceutical approaches to skeletal metastases from prostate cancer
Slide 5: Therapeutic Objectives
Therapeutic Objectives Death From Other Causes 1. If Present (Response): Eliminate, relieve or control. 2. If Absent (Progression): Prevent of delay it (them) from occurring in the future. 3. Objective and outcomes must be relevant clinically relevant and of tangible benefit. 4. The decision to offe
Slide 6: The Approved Drugs Support The Paradigm
The APPROVED Drugs SUPPORT The Paradigm of Eliminate/Relieve and/or Delay/Prevent Objectives and Outcomes Eliminate/Relieve: Bisphosphonates: Zometa, Radiopharmaceuticals: Metastron, Quadramet Chemotherapy: Mitoxantrone/prednisone, Taxotere/prednisone Prevent/Delay: Progression/Symptoms: Bisphosphon
Slide 7: Clinical Management of Castration Resistant Prostate Cancer
Clinical Management of Castration Resistant Prostate Cancer 1. Therapeutic objectives: Why offer therapy – eliminate/relieve and/or prevent/delay 2. Chemotherapy for hormone-refractory prostate cancer 3. Radiopharmaceutical approaches to skeletal metastases from prostate cancer
Slide 8: Activity In Castration-Resistant Prostate Cancer
Activity In Castration-Resistant Prostate Cancer Agents that Target the Cytoskeleton have Activity In Castration-Resistant Prostate Cancer Inhibition of Polymerization: Vinblastine + EMP Navelbine + EMP Tubulin Microtubule 20nm Inhibition of Depolymerization: Taxanes + EMP The importance of adequate
Slide 9: TAX327
TAX327 A Multicenter, Randomized Phase III Study of Docetaxel q 3 wks + Prednisone vs. Docetaxel q wk + Prednisone vs. Mitoxantrone + Prednisone in Patients with Hormone-Refractory Prostate Cancer Taxotere 75mg/m2 q3 wks + Prednisone 5 mg po bid Hormone Refractory Prostate Cancer RANDOMIZE Taxotere
Slide 10: Secondary Objectives Response Rates
Secondary Objectives Response Rates Docetaxel Docetaxel 3 wkly wkly Mltoxantrone Pain Response Rate* n, evaluable 153 154 157 Response rate (%) 35 31 22 P-value (vs. mitoxantrone) 0.01 0.07 PSA Response Rate* n, evaluable 291 282 300 PSA response rate (%) 45 48 32 P-value (vs. mitoxantrone) 0.0005 <
Slide 11: TAX 327: Overall Survival
TAX 327: Overall Survival Docetaxel 3 wkly Docetaxel wkly Mitoxantrone Probability of Surviving 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Median survival Hazard (mos) ratio P-value D 3 wkly: 18.9 0.76 0.009 D wkly: 17.3 0.91 0.3 Mitoxantrone 16.4 - - 0 6 12 18 24 30 Months Slide # 11
Slide 12: Summary
Summary Good news: TAX 327 and 9916 establish that chemotherapy can prolong life in patients with castration resistant prostate cancer Bad news: Activity of tubulin targeting approach identified 10 years ago Shows the importance of designing, accruing and completing trials of adequate size and power
Slide 13: Clinical Management of Castration Resistant Prostate Cancer
Clinical Management of Castration Resistant Prostate Cancer 1. Therapeutic objectives: Why offer therapy – eliminate/relieve and/or prevent/delay 2. Chemotherapy for hormone-refractory prostate cancer 3. Radiopharmaceutical approaches to skeletal metastases from prostate cancer
Slide 14: Mechanism of Bone Disease
Mechanism of Bone Disease Metastatic Bone Disease Bone Derived Growth Factors Unknown Growth Factors Tumor Osteoblast Stimulating Factors Osteolytic Factors Osteoclast Osteoblasts Bone Old bone matrix (OB) showing resorption pits with multinucleated osteoclasts (green arrows) is being destroyed whil
Slide 15: Questions in Development of Radiopharmaceuticals
Questions in Development of Radiopharmaceuticals Do they provide clinical benefit(s) and for how long? Can they be used more than once? Can effects be enhanced if used BEFORE a patient demonstrates progressive/resistant disease? Can effects be enhanced if combined with an effective chemotherapy that
Slide 16: Radiopharmaceuticals
Radiopharmaceuticals Samarium Sm-153 Strontium-89 Emission beta/gamma beta Beta energy (max/avg) MeV 0.81/0.29 1.46/0.58 Gamma energy (KeV) — Physical half-life (days) 1.9 50.6 Recommended dose 1 mCi/kg 37 mBq/kg mCi 148 mBq Average depth of penetration in tissue 1.7 mm 8 mm Targeting mechanism Tetr
Slide 17: Samarium-153-EDTMP (Quadramet)
Samarium-153-EDTMP (Quadramet®) Radioactive samarium + tetraphosphonate chelator (EDTMP) Accumulates in areas of bone tumors, associates with hydroxyapatite Accumulates in osteoblastic lesions Lesion to normal bone ratio 5:1 Excreted intact in urine 35% excreted in urine within 6 hrs
Slide 18: Safety Summary
Safety Summary at 1.0 mCi/kg Toxicity Grade Placebo (n=85) 1.0 mCi/kg (n=185)* Hemoglobin 0-2 78 (92%) 6 (7%) 1 (1%) 162 (88%) 20 (11%) 3 (2%) WBC’s 0-2 85 (100%) 169 (92%) (8%) Platelets 0-2 85 (100%) 173 (94%) 10 (5%) 2 (1%) * N=184 for WBC’s
Slide 19: Samarium-153-EDTMP Conclusions
Samarium-153-EDTMP Conclusions Three controlled studies: Single IV injection of 1.0 mCi/kg provided pain relief Pain relief within 1 week of administration Pain palliation persisted at least to Week 16 in the majority of responding patients Pain relief correlated with decreased use of opioids Mild,
Slide 20: Radiopharmaceuticals Summary
Radiopharmaceuticals Summary Bone-targeted radioisotopes provide long-lasting pain relief PSA declines are observed in 10% of patients Cell kill appears not to be a prerequisite for palliation of pain No trial of any one bone-targeted radioisotope alone has been shown to prolong life
Slide 21: Questions in Development of Radiopharmaceuticals
Questions in Development of Radiopharmaceuticals Do they provide clinical benefit(s) and for how long? Can they be used more than once? Can effects be enhanced if used BEFORE a patient demonstrates progressive/resistant disease? Can effects be enhanced if combined with an effective chemotherapy that
Slide 22: Patients Receiving Multiple Doses in Compassionate Use Study
Patients Receiving Multiple Doses in Compassionate Use Study 424Sm12 Additional Quadramet® doses administered based on recurrence of pain 48 prostate cancer, 5 breast cancer, 1 unknown primary 132 doses administered to 54 patients (2 to 11 doses per patient) 54 patients: 2 doses 11 patients: 3 doses
Slide 23: No Cumulative Myelosuppression
No Cumulative Myelosuppression WBC and Platelet Nadirs Dose 1 Dose 2 Doses >3 3.6±1.1 [54%] 3.6±1.1 [49%] WBC Nadir [% of baseline] 3.5±0.9 [57%] 93±38 [50%] 105±49 [48%] 129±37 [50%] Platelet Nadir [% of baseline]
Slide 24: Questions in Development of Radiopharmaceuticals
Questions in Development of Radiopharmaceuticals Do they provide clinical benefit(s) and for how long? Can they be used more than once? Can effects be enhanced if used BEFORE a patient demonstrates progressive/resistant disease? Can effects be enhanced if combined with an effective chemotherapy that
Slide 25: Bone Consolidation with Sr-89
Bone Consolidation with Sr-89 Source: Tu SM, et al. Lancet. 2001;357(9253):336-341.
Slide 26: Bone Consolidation with Sr-89
Bone Consolidation with Sr-89 62 patients had a > 50% reduction in PSA that was maintained for at least 8 weeks The median survival for all patients was 17.5 months For the 36 patients randomly assigned to receive Sr-89 and doxorubicin, the median survival 27.7 months The hazard ratio was 2.76 (95%
Slide 27: Questions in Development of Radiopharmaceuticals
Questions in Development of Radiopharmaceuticals Do they provide clinical benefit(s) and for how long? Can they be used more than once? Can effects be enhanced if used BEFORE a patient demonstrates progressive/resistant disease? Can effects be enhanced if combined with an effective chemotherapy that
Slide 28: Rationale
Rationale Both chemotherapy and bone-targeted radioisotopes do not eliminate disease in bone The combination of the two modalities has shown promising results in a randomized Phase II trial The approved chemotherapy for prostate cancer is a radiosensitizer The combination of chemotherapy and bone-ta
Slide 29: MSKCC Combination Study
MSKCC Combination Study Approach Use the approved dosing schedule for docetaxel (q3wk) Administer Quadramet® with the first cycle and again at 12 weeks Study Design Dose escalate docetaxel from 65®75 mg/m2 (2 steps) at a Quadramet dose of 0.5 mCi/kg, then Dose escalate Quadramet from 0.5®1.0 mCi/kg