Management of Hormone Refractory Prostate Cancer: Old Dog, New Tricks

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1 Management of Hormone Refractory Prostate Cancer: ld Dog, New Tricks Kim N. Chi, MD FRCPC BC Cancer Agency - Vancouver Centre Vancouver Hospital Prostate Centre University of British Columbia Agenda Defining the patient population Current management Second line hormonal maneuvers Chemotherapy Bisphosphonates New tricks Novel therapies

2 HRPC - Defining the Population: The Past Symptomatic Metastases Death 6-0 Months HRPC - Defining the Population: The Present PSA Rise Biochemical C linical Metastases Symptomatic Metastases 4+ Months 8-4 Months -8 Months Serial rise in PSA with castrate level testosterone Heterogenous Biochemical Clinical metastases Asymptomatic Symptomatic Larger population of patients demanding more effective treatment Effects interpretation of single arm clinical trials Death

3 Mechanisms of Androgen Independence nd Line Hormone Maneuvers Feldman and Feldman. Nature Reviews 00 nd Line Hormonal Maneuvers: RCT ERTC: Flutamide vs Prednisone N = 0, symptomatic patients PSA Response Rate: Prednisone: % Flutamide: % Palliative Response Rate Prednisone: 56% Flutamide: 45% Fossa JC 9:6 00

4 ther NSAA Bicalutamide 50 mg: Phase II trial, no prior NSAA (SWG 95) PSA RR = 0% Nilutamide: Retrospective, selected consecutive patients, all had prior NSAA PSA RR: 50% Kucuk Urology 58:5 00; Vogelzang Urology 58:06 00 nd Line Hormonal Maneuvers: RCT CALGB: AAWD Alone vs AAWD plus Keto/HC PSA Response Rate AAWD Alone AAWD + Keto AAWD -> Keto (Crossover) % 7% 0% bjective Response Rate AAWD Alone AAWD + Keto AAWD -> Keto (Crossover) 5% 4% 7% Lower doses of ketoconazole may also be as effective (600 mg/day) Effect of corticosteroids alone? Small, JC : 05, 004; Harris, J Urol 68:

5 Summary: nd Line Hormonal Maneuvers Many options: Initiate maximum androgen blockade Corticosteroids Antiandrogen withdrawal Ketoconazole and hydrocortisone Switching antiandrogens Clinical Impact? Impact on survival has never been well defined for populations of patients - are we changing natural history? But... Well tolerated Some very good biochemical and symptomatic responses Appropriate for asymptomatic or chemotherapy ineligible patients Mechanisms of Androgen Independence nd Line Hormone Maneuver Feldman and Feldman. Nature Reviews 00 5

6 Chemotherapy in Prostate Cancer Drug Class Agents bjective Response Anthracyclines Doxorubicin Mitoxantrone Epirubicin 0-0% 0-0% 0-0% Alkylating Agents Cyclophosphamide CCNU Ifosfamide 0-0% 0-0% 0-0% Vinca Alkaloids Vinblastine Vincristine 0-0% <0% Antibiotics Mitomycin 0-0% Antimicrotubule Agents Estramustine Paclitaxel 0-0% 0-0% Platinum Complexes Cisplatin Carboplatin 0-0% <0% Antimetabolites Methotrexate 5-FU 0-0% <0% Topoisomerase Inhibitors Etoposide Topotecan <0% <0% Chemotherapy as a Palliative Treatment Mitoxantrone as First Line Chemotherapy for Metastatic Prostate Cancer: Phase II results patients / PR ( objective disease, with >75% in PAP) 5/ symptomatic response: pain, PS, wt N. Murray, C. Coppin, T MacDermaid, Proc of the 4th Int Congress of Chemo, Kyoto, 985 6

7 Chemotherapy: Mitoxantrone as Standard M+P N=80 P N=8 No. % No. % Palliative Response 9 0 Tannock, J Clin ncol, 4:756, 996; soba, J Clin ncol, 7:654, 999 Mitoxantrone Kantoff, J Clin ncol, 7:506, 999 7

8 Time to Progression Mitoxantrone verall Survival Kantoff, J Clin ncol, 7:506, 999 Docetaxel N Regimen PSA RR RR 5 75 mg/m qw 46% 8% 75 mg/m qw 8% 60% 60 6 mg/m /wk q6/8w 4% % 5 6 mg/m /wk q6/8w 4% NR Picus, Semin ncol 999; Friedland, Semin ncol 999; Beer, Proc ASC 000; Berry, Proc ASC 999 8

9 Mr. T.G. Pre-Docetaxel Post-Docetaxel Docetaxel: The New Standard? Tax 7 00 Patients HRPC with Metastases RANDMIZATIN Docetaxel 75 mg/m qw Docetaxel 0 mg/m qw Mitoxantrone mg/m qw Plenary session at ASC 004 9

10 Docetaxel and Estramustine N Regimen PSA RR RR 46 D 70 mg/m d 68% 50% E 0 mg/kg/d d-5 qw 7 D 70 mg/m d 68% 55% E 80 mg tid d-5 qw 7 Arm A: D 0-0 mg/m /wk 8% 7% E 40 mg tid d-4 q6/8w Arm B: D 0-40 mg/m d,9 + E tid (40 mg 4;80 mg 5) d-, d8-0; qw D 4 mg/m d E 40 mg/d d-5 q/4w 7% % Savarese, JC 00; Petrylak, Proc ASC, 000; Natale, Proc ASC 999; Kosty, Proc ASC 00 SWG Patients HRPC with Metastases RANDMIZATIN Docetaxel 60 mg/m Estramustine 80 mg TID d-5 qw Mitoxantrone mg/m qw Plenary session at ASC 004 0

11 Summary: Chemotherapy Mitoxantrone Demonstrated palliative patient benefit Well tolerated Still useful Docetaxel Single agent q weekly current standard for appropriate patients with HRPC at BCCA Basis for future trials in HRPC Bisphosphonates Stable analogues of Pyrophosphate Decrease depth and rate of formation of bone remodeling units Inhibit bone resorption by osteoclasts Promote apoptosis of osteoclasts A number of bisphosphonates are active in other cancers Rationale in prostate cancer Increased activity of BRU steoporosis from androgen withdrawal therapy Trials with bisphosphonates have all been negative except for the one trial which used skeletal related event as the primary endpoint...

12 Zoledronic Acid vs Placebo in Prostate Cancer Patients with Hormone-refractory Metastatic Bone Lesions Primary endpoint: skeletal related events Pathological fractures Spinal cord compression Radiation for bone pain or to treat or prevent pathologic fractures or spinal cord compression Surgery to bone Change of antineoplastic therapy for bone pain Hypercalcemia of malignancy (HCM) Saad, JNCI, 94:458, 00 q weeks x 5 months q weeks x 5 months q weeks x 5 months

13 Toxicity Skeletal Related Events Zometa 4mg Placebo Zometa 8mg % of patients P=0.0 P=0. 44% % 8% N = 4 08

14 SRE ver Time A Positive Trial Patient Benefit? Pain Scale out of 0 - not a clinically significant difference Analgesics and quality of life not different Survival not different statistically Cost effectiveness Number needed to treat = in 9 An additional $,000 per event avoided An additional $59,000 for each man in whom an event is avoided PEC proposal under review Available under the palliative drug benefit program Reed, J Urology, 7:57, 004 4

15 New Tricks: Targeted Therapy Bevacizumab Iressa BAY49006 Calcitriol Bcl- Clusterin Enhancing Apoptosis: Targeting Bcl- B-cell lymphoma/leukemia associated gene Encodes a 6kd mitochondrial membrane associated protein with anti-apoptotic regulatory function First recognized member of a growing family of apoptosis regulatory gene products that function as death antagonists or agonists 5

16 Bcl- in Prostate Cancer Localized Disease correlated with high Gleason score, N+ independent negative predictive/prognostic factor Relapsed Disease poorer response to androgen withdrawal therapy Hormone Refractory Disease expression of Bcl- implicated in the development of androgen independence and mechanism of treatment resistance taxanes phosphorylate Bcl- (D>P by 0 - ) McDonnell, J Urol, 997; Colombel, Am J Path, 99; Bubendorf, Am J Path, 996; Scherr, J Urol, 999; Haldar, Cancer Res, 997. Targeting Bcl-: G9/Genasense (Genta Inc) st generation antisense oligonucleotide with a phosphorothioate backbone Complimentary to the first six codons of the human bcl- open reading frame Active in pre-clinical models in inhibiting expression of Bcl- and enhancing apoptosis In Phase I, II and III trials H B NH N N P S N N n NH N P S da dc N N NH P S N N NH CH NH P S N H dg T 6

17 Does Antisense Bcl- Work in People?: Phase III Melanoma Trial Genasense + DTIC (N = 86) DTIC (N = 85) P value Progression-free survival 78 d 49 d Time-to-progression 78 d 49 d verall response (CR + PR) 45 (.7%) 6 (6.8%) Complete response 5 (.%) (0.5%) Partial response 40 (0.4%) 4 (6.%) Stable disease 6 (0.%) 06 (7.5%) Total Progressive disease 6 5 (4.7%) (9.4%) 78 (4.%) (46.%) 0.04 Durable response (6 mo.) (.4%) 5 (.%) ngoing response (6.0%) 4 (.6%) Primary Endpoint: verall Survival Intent-to-Treat (n = 77) Proportion Surviving Estimated Median Survival Genasense + DTIC = 9. mos DTIC alone = 7.9 mos Hazard ratio = 0.89 P= Days 7

18 verall Survival Patients with > Months Follow-Up Proportion Surviving Per-protocol treatment: n = 480 Median Survival Genasense + DTIC = 0. mos DTIC alone = 8. mos Hazard ratio = 0.8 P= Days A Phase II Pharmacokinetic and Biologic Correlative Study of G9 and Docetaxel in Hormone-Refractory Prostate Carcinoma Institute for Drug Development and BC Cancer Agency Genasense Day 6 Taxotere Genasense Day 7 Taxotere Day Day 8 Day Day 9 Cycle Cycle Genasense 7 mg/kg/4 hours CIVI D-D8 D8 Taxotere 75 mg/m IV on D6 Growth factors not used routinely Chi, Proc of ASC, 00 8

19 Patient Characteristics Characteristic Median (Range) No. of Patients (%) N= Age 66 (44-8) Years since diagnosis 5.9 ( ) ECG PS 0 8 (6) 9 (6) 4 () Baseline Fatigue Grade (6) Grade 4 () Sites of Disease Bone (4) Lymph Node 9 (9) ther 9 (9) PSA 7.6 (0.-,77) Hemoglobin.7 (9.-5.) Alkaline Phosphatase 66 (6-,78) Prior Therapy rchiectomy 4 () LHRH Agonist 7 (87) Non-Steroidal Antiandrogen 0 (97) Steroidal antiandrogen (4) Estrogen 8 (6) Corticosteroids (4) Ketoconazole (0) Radiotherapy (prostate) (4) Radiotherapy (other sites) 7 (55) Chemotherapy 6 (9) ther () Toxicity ADVERSE EVENTS Grade Grade Grade Grade 4 Total Patients HEMATLGICAL Neutropenia Neutropenia (on day 6 pre-docetaxel) Febrile Neutropenia Anemia 0 7 Thrombocytopenia 0 0 NN-HEMATLGICAL Alopecia Fatigue Non-Neutropenic Fever Diarrhea Nausea Vomiting 0 0 Myalgia Arthralgia Edema Peripheral Hypotension Hypophosphatemia Dehydration Hypoalbuminemia 0 4 G-CSF use: 6 pts/ cycles 9

20 Responses PSA Response No. of Patients (%) N=9 > 50% reductions in PSA 4 (48) > 75% reductions in PSA 6 () > 90% reductions in PSA (7) bjective Response No. of Patients (%) N= Complete Response (CR) 0 Partial Response (PR) 4 () Stable/No Response (SD) (5) Progression of Disease (PD) 7 (54) PSA Progression Free Survival 0

21 verall Survival Correlative Studies Percent Decrement in Bcl- Protein Genasense Css (ug/ml) N = 5 N = 5

22 Conclusions: Docetaxel + G9 for HRPC Interesting activity PSA response rate reasonable considering the patient population Time to progression, overall survival Not a home run Drug - need more? Target - not that important? Population - Bcl- expression not assessed Phase III trial rd quarter 004 by Aventis/Genta Enhancing Apoptosis: Targeting Clusterin Clusterin associated processes Tissue remodeling, lipid transport, membrane protection, complement defense and apoptosis Anti-apoptotic In malignancy Prostate Low expression in normal prostatic tissue Increased expression correlates with higher Gleason Grade Increased expression after neo-adjuvant hormone therapy Also expressed in renal, bladder, ovary, lung and breast cancers verexpression in pre-clinical models confers resistance to hormone, chemo and radiation therapy Poon, FEBS 00; Lakins, Biochemistry 00; Michel, Biochem J, 997; Steinberg, Clin Cancer Res, 997

23 Clusterin AS Delay Androgen Independent Progression In Vivo (Shionogi) Tumour Volume (mm ) Castration + mismatch TRPM- DN Castration + antisense TRPM- DN antisense mismatch TRPM- GPDH PARP Fragments Days Post-Castration Clusterin AS Enhance Chemosensitivity In Vivo (PC) A. B..8 AS TRPM- + Taxol MM TRPM- + Taxol ** P< ** ** ** 0 ** ** ** Weeks Post Injection Tumour Volume (mm )

24 GX-0 (ncogenex Technologies Inc) -mer complementary to the translation initiation site ME-gapmer Improved scheduling Longer tissue t/ Longer suppression of target Less non-specific toxicity H (Na + )S - P R Base Base (Na + )S - P R R = -CH CH CH Difficulties in the Clinical Assessment of Targeted Therapies What is the right dose? Biologically Effective Dose vs Maximally Tolerated Dose Assessment of biological effectiveness Surrogate tissue vs tumour tissue Antisense skepticism Single molecular target unlikely to be effectual in most solid tumour malignancies Selection of the most appropriate patient population important A combined approach will likely be required 4

25 GX-0: Clinical Trials for 00 NCIC.CTG. IND.5: Phase I trial of GX-0 + NHT prior to Radical Prostatectomy NSAA LHRH Agonist SURGERY GX-0 Week 4 5 NCIC.CTG.IND54: Phase I trial of GX-0 + Docetaxel Docetaxel (q w) Docetaxel (weekly) GX-0 Week IND.5: Phase I Trial of GX-0 + NHT Prior to Radical Prostatectomy Human Neoadjuvant Model for Clinical Proof of Principal Primary bjective To determine the toxicity and define a recommended phase II dose based on toxicity and biological effectiveness Secondary bjectives. Plasma pharmacokinetic profile.. Target tissue GX-0 concentration.. Effect on clusterin expression in post-radical prostatectomy specimens (IHC, ISH, Western, rtpcr). 4. Effect on clusterin expression in patient peripheral blood mononuclear cells (surrogate tissue). 5. Effect on patient clusterin serum levels (surrogate tissue). 6. Correlations between plasma and prostate PK with toxicity and biological effectiveness 5

26 IND.5: Current Accrual Activated December 00 Dose Level GX-0 (Days,,5,8,5,,9) 40 mg Planned # Patients Patients Accrued 80 mg 60 mg 4 0 mg mg mg mg -6 - Patient Characteristics N= Median Age (Range) 64 (45-7) Gleason Score Baseline PSA Clinical Stage <0 0-0 >0 c a b a

27 Hem Toxicity 40/80 mg (N=4) WBC Grade 4 Granulocytes Hemoglobin Platelets 60 mg (N=) WBC Granulocytes Hemoglobin Platelets 0 mg (N=6) WBC 4 Granulocytes Hemoglobin 4 Platelets 480 mg (N=6) WBC Granulocytes Hemoglobin 5 Platelets 640 mg (N=) WBC Granulocytes Hemoglobin Platelets Non-Hem Toxicity 40/80 mg (N=4) Hot flashes Grade 4 Arthralgias 60 (N=) Fatigue Hot Flashes Rigors/Chills Rhinitis Headache 0 mg (N=6) Fatigue 5 Rigors/Chills 4 Fever Nausea Arthralgias Myalgias 480 mg (N=6) Fatigue Rigors/Chills 6 Fevers 4 Arthralgias 640 mg (N=) Fatigue Rigors/Chills Fever 7

28 Bch Toxicity 40/80 mg (N=4) Grade 4 Cr AST ALT 60 (N=) Cr AST ALT 0 mg (N=6) Cr AST ALT 480 mg (N=6) Cr AST ALT 640 mg (N=) Cr AST ALT Prostate Tissue GX-0 Concentrations (ug/g) TISPK DSE 8

29 rtpcr Clusterin Expression in Prostatectomy Specimens 40 0 Relative Quantity of Clusterin mrna (%) Control 40 mg 80 mg 60 mg 0 mg 480 mg Treatment Groups Clusterin Expression in Prostatectomy Specimens Immunohistochemistry: Visual Score N TR <M-NHT GX mg GX-0-60mg GX-0-0mg GX-0-480mg 9

30 Conclusions: GX-0 Well tolerated and dose escalation continues Single agent and in combination with docetaxel A phase II dose of GX-0 based on toxicity and optimal biological effectiveness will be determined First proof of principal demonstration of dose dependent target inhibition for an antisense molecule Phase II trials in neoadjuvant setting for prostate cancer, HRPC, breast and lung cancer planned for 004 Summary: Management of HRPC No treatment for HRPC has (as yet) been shown in RCT to improve survival Consider observation Palliation of symptoms Radiotherapy Adequate analgesia Second line hormonal therapies Benefit is not well defined but standard practice Best suited for asymptomatic patients, chemo ineligible Bisphosphonates nly Zoledronic Acid has been shown to be of benefit SRE decreased Patient benefit and cost-effectiveness debatable More to come: osteoporosis, delay of progression 0

31 Summary: Management of HRPC Chemotherapy is active in HRPC Mitoxantrone an accepted standard Palliation of pain, delay in progression Docetaxel +/- Estramustine and other combinations Single agent Docetaxel a standard in Vancouver Improved response rates Landmark RCTs will report soon Toxicity an issue verall benefit will likely be modest in HRPC Active regimens as basis for further development Combination with novel therapies Earlier disease» Adjuvant» Neoadjuvant» Androgen dependent recurrence Clinical trials of novel therapies Acknowledgments VGH Prostate Center Martin Gleave Larry Goldenberg Eliana Beraldi Antonio Hurtado Ladan Fazli Ted Jones BC Cancer Agency Nevin Murray NCIC.CTG Elizabeth Eisenhauer

Recent Progress in Management of Advanced Prostate Cancer

Recent Progress in Management of Advanced Prostate Cancer Review Article [1] April 15, 2005 By Philip W. Kantoff, MD [2] Androgen-deprivation therapy, usually with combined androgen blockade, is standard initial treatment for advanced prostate cancer. With failure