SOGUG meeting New drugs after docetaxel chemotherapy in patient with mcrpc

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1 SOGUG meeting New drugs after docetaxel chemotherapy in patient with mcrpc Stéphane OUDARD, MD, PhD Head of the Oncology department Georges Pompidou Hospital, Paris France University Rene Descartes, Paris 5 Advanced prostate cancer management Metastatic hormone-sensitive prostate cancer Metastatic castration-resistant 1st line LHRH analogues Antiandrogens DOCETAXEL TAXOTERE LHRH antagonist Survival benefit vs Mitoxantrone

Metastatic CRPC - First line therapy Docetaxel 75 mg/m 2 every 3 weeks is the standard of care in first-line metastatic CRPC 1 Heidenreich A, et al. (2010 update) www.uroweb.

2 Metastatic CRPC - First line therapy Docetaxel 75 mg/m 2 every 3 weeks is the standard of care in first-line metastatic CRPC 1 Heidenreich A, et al. (2010 update) 2 Mohler J, et al. (2009 update) 3 Basch EM, et al. J Clin Oncol 2007;25:1 6 4 Horwich A, et al. Ann Oncol 2009;20(Suppl 4):76 8 Cancer progression during or after Docetaxel What are the options? 2

3 Currently available secondary hormonal manipulations in CRPC: marginal benefit Rationale: elevated intratumor androgen levels despite castrate serum levels Includes androgen withdrawal, adrenal testosterone inhibitors, low doses DES, corticosteroids, somatostatin analogues Marginal benefit: PSA response in 10-60% of cases Short duration (< 4-6 months) Currently available secondary hormonal manipulations in CRPC: marginal benefit Total Drug Patients (n) >50% PSA response (%) Duration (months) Kelly Hydrocortisone Storile l Dexamethasone NR Tannock Prednisone Dawson Hydrocortisone + AAW Sartor Aminoglutethamide + AAW + hydrocortisone Small Ketoconazole + hydrocortisone Small Ketoconazole + hydrocortisone + AAW Dawson Megestrol acetate NR Osborn Megestrol acetate NR Scher High-dose bicalutamide Joyce High-dose bicalutamide NR 3

4 Advanced prostate cancer management Metastatic hormone-sensitive prostate cancer Metastatic castration-resistant 1st line Metastatic Castration-resistant 2nd line LHRH analogues Antiandrogens LHRH antagonist DOCETAXEL TAXOTERE Survival benefit vs Mitoxantrone 2004 UNMET MEDICAL NEED Progression after Docetaxel: No agent currently approved in patients progressing after Docetaxel Currently available options provide palliation only Retreatment with Docetaxel: Small retrospective studies 1-5 In selected patients: good initial responders (PSA decrease 50%) Effect on PSA seems to decrease with rechallenge 5 1 Eymard JC, Oudard S et al. BJU Int 2010, 2 Ansari et al. Oncol reports 2008; 20: Beer TM et al. Cancer. 2008, 112: ; 4 Garmey EG et al, Clin Adv Hematol Oncol. 2008; 6(2): ; 5 Gernone et al. EAU 2010 (abstract 896) 4

Cabazitaxel (Jevtana ): a next generation taxane X Y Y X Docetaxel -OH O -OCCH 3 Cabazitaxel -OCH 3 -OCH 3 Both extracted from needles of the European Yew tree Taxus baccata 99th AACR annual meeting,

5 Cabazitaxel (Jevtana ): a next generation taxane X Y Y X Docetaxel -OH O -OCCH 3 Cabazitaxel -OCH 3 -OCH 3 Both extracted from needles of the European Yew tree Taxus baccata 99th AACR annual meeting, San Diego, April 2008 (abstract #3227) Cabazitaxel (Jevtana ): selected to overcome taxane resistance Some patients do not answer to Docetaxel (acquired or constitutional resistance). This may be due to various mechanisms: affinity for multidrug resistant (MDR) membrane-associated P-glycoprotein (PgP) efflux pump, alterations of tubulin, overexpression Bcl-2, Aurora-A Cabazitaxel: Poor affinity for the PgP efflux pump greater penetration of the blood brain barrier compared with docetaxel and paclitaxel Active in vitro and in vivo on tumors resistant to Docetaxel R Taxane Docetaxel and paclitaxel have a strong affinity for the PgP pump If the PgP pump is overexpressed, it drives drug out of tumor cell H Mita AC et al, Clin Cancer Res. 2009, 15,

6 Cabazitaxel: A next-generation taxane Preclinical data Activity against tumor cells and tumor models that are resistant to, or not sensitive to currently available taxanes¹, ² As potent as docetaxel against sensitive cell lines and tumor models¹, ² Phase I studies Dose-limiting toxicity was neutropenia Antitumor activity in mcrpc including docetaxelresistant disease 3 ¹Attard G, Greystoke A, Kaye S, De Bono J. Pathol Biol (Paris). 2006;54(2): ²Pivot X, Koralewski P, Hidalgo JL, et al. Ann Oncol. 2008;19(9): Mita AC, Denis LJ, Rowinsky EK, de bono JS et al. Clin Can Res. 2009; Jan 15;15(2): De Bono J et al. Lancet, 2010, 376:

7 TROPIC: Phase III registration study 146 Sites in 26 Countries mcrpc patients who progressed during and after treatment with a docetaxel-based regimen (N=755) Stratification factors ECOG PS (0, 1 vs. 2) Measurable vs. non-measurable disease cabazitaxel 25 mg/m² q 3 wk + prednisone* for 10 cycles (n=378) *Oral prednisone/prednisolone: 10 mg daily. Primary endpoint: Overall Survival Secondary endpoints: Progression-free survival (PFS), response rate, and safety mitoxantrone 12 mg/m² q 3 wk + prednisone* for 10 cycles (n=377) Inclusion: Patients with measurable disease must have progressed by RECIST; otherwise must have had new lesions or PSA progression De Bono J et al. Lancet, 2010, 376: Patient characteristics MP (n=377) ECOG PS: ECOG performance status; PSA: Prostate-specific antigen. CBZP (n=378) Age Median (years) (%) ECOG PS (%) 0, PSA (ng/ml) Median Measurability of disease (%) Measurable disease Disease Site (%) Bone Lymph node Visceral Population with a very advanced disease De Bono J et al. Lancet, 2010, 376:

8 TROPIC trial: Pre-protocol treatments MP (n=377) CBZP (n=378) Total prior docetaxel dose (mg/m²) Median Months from last docetaxel dose to progression Median Number of patients progressed (%) During last docetaxel treatment <3 months since last docetaxel dose months since last docetaxel dose Chemotherapy (%) 1 regimen regimens regimens A heavily pretreated population who progressed rapidly after first line docetaxel De Bono J et al. Lancet, 2010, 376: TROPIC Trial: overall survival (Primary endpoint) Proportion of OS (%) MP CBZP Median OS (months) Hazard ratio % CI P-value <.0001 Censored MP CBZP Combined median follow-up: 13.7 months Time (months) Number at Risk MP CBZP % reduction in the risk of death De Bono J et al. Lancet, 2010, 376:

9 TROPIC Trial: Progression-free survival Proportion of PFS (%) MP Time (months) CBZP Median PFS (months) Hazard ratio % CI P-value PFS composite endpoint: PSA progression, pain progression, tumor progression, symptom deterioration, or death. Censored MP CBZP Combined median follow-up: 13.7 months Number at Risk MP CBZP % reduction in risk of progression De Bono J et al. Lancet, 2010, 376: TROPIC Trial: Response rate and time to progression MP (n=377) CBZP (n=378) Hazard ratio (95% CI) P-value Tumor assessment Response rate* (%) Median TTP (months) ( ) < PSA assessment Response rate* (%) Median TTP (months) Pain response rate (N patients) Response rate (%) 3.1 (168) 7.7 TTP: time to progression ; *50% decrease or more in PSA 6.4 (174) ( ) 0.91 ( ) De Bono J et al. Lancet, 2010, 376:

10 Treatment exposure on study drug Number of cycles Median (Range) Treatment delays 9 days >9 days MP (n=371) 4.0 (2-7) 6% 2% CBZP (n=371) 6.0 (3-10) 7% 2% Dose reduction* 5% 10% Relative dose intensity (%) Median *as percentage of total number of treatment cycles An excellent dose intensity with few dose reductions or treatment delays De Bono J et al. Lancet, 2010, 376: Most Frequent Treatment-Emergent Adverse Events* MP (n=371) CBZP (n=371) Grade 3/4 Grade 3/4 All grades (%) (%) All grades (%) (%) Any adverse event Febrile neutropenia Neutropenia* Diarrhea 11 < Fatigue Back pain Nausea 23 < Vomiting Hematuria Abdominal pain *Sorted by 2% incidence rate for grade 3 events in the cabazitaxel arm. Low rate of grade 3-4 peripheral neuropathy (1% in each group) De Bono J et al. Lancet, 2010, 376:

11 Comparison of Cabazitaxel and docetaxel and mitoxantrone hematotoxicity according to the line of treatment Hematological Toxicity (gr 3-4) % Doc Cab Mito Mito Tax327 Tropic Tax327 Tropic Anemia Neutropenia Febrile neutropenia Thrombocytopenia Tax327 study: docetaxel and mitoxantrone given in first-line setting Tropic study: cabazitaxel and mitoxantrone given in second-line setting TROPIC Trial: Fatal Events MP (n=371) CBZP (n=371) Total deaths during study 275 (81.9%) 270 (72.8%) Due to progression 264 (71.2%) 218 (58.8%) Due to AE 7 (1.9%) 18 (4.9%) Due to other reasons 15 (4.0%) 12 (3.2%) Cause unknown (> 3 mo following last dose) 11 (3.0%) 20 (5.4%) 22 11

12 Conclusion on Cabazitaxel study Cabazitaxel demonstrated a statistically and clinically significant survival improvement compared with mitoxantrone in study population 15.1 months vs 12.7 months 28% reduced risk of death (HR=0.72, P <.0001) Survival benefit consistent across subgroups Secondary endpoints of PFS, RR, and TTP also significantly improved Safety profile was manageable Proactive management of side effects recommended (neutropenia/diarrhea) Cabazitaxel is the first treatment to show a survival benefit in patients with mcrpc after failure of docetaxel-based therapy 23 Cabazitaxel: Further development Which dose of cabazitaxel to use 25 or 20 mg/m 2? Is cabazitaxel as effective as docetaxel in first-line setting? Is cabazitaxel more or less hematotoxic than docetaxel? Will cabazitaxel be evaluated in early stages? 24 12

Castration-resistant prostate cancer New agents in development Pre-Docetaxel Docetaxel Post-Docetaxel Cabazitaxel Abiraterone MDV3100 TAK-700 Sunitinib Ipilimumab Abiraterone: oral & irreversible

13 Castration-resistant prostate cancer New agents in development Pre-Docetaxel Docetaxel Post-Docetaxel Cabazitaxel Abiraterone MDV3100 TAK-700 Sunitinib Ipilimumab Abiraterone: oral & irreversible inhibition of CYP17 Cholesterol Desmolase Low-dose steroid replacement decreases ACTH and minimizes mineralocorticoid-related toxicity Pregnenolone Progesterone Deoxycorticosterone Corticosterone Aldosterone CYP17 17αhydroxilase 17α-OH- Pregnenolone DHEA CYP17 C17, 20-lyase 17-Deoxycorticol 17α-OH- Progesterone Cortisol 5α-reductase Androstenedione Testosterone DHT ACTH x6 reduced by low-dose steroids Estradiol CYP19: aromatase Inhibits testosterone production in testis, adrenal glands and prostate Attard et al. J. Clin. Oncol. 2008, 26:

Abiraterone in second-line metastatic CRPC COU-AA-301 study Patients Progressive mcrpc Failed 1 or 2 chemo regimen, including 1 with docetaxel Stratification factors: ECOG PS [0-1 versus 2] Worst

14 Abiraterone in second-line metastatic CRPC COU-AA-301 study Patients Progressive mcrpc Failed 1 or 2 chemo regimen, including 1 with docetaxel Stratification factors: ECOG PS [0-1 versus 2] Worst pain over previous 24 hours (BPI short form; 0-3 [absent] vs 4-10 [present] Prior chemotherapy[1 vs 2] Type of progression [PSA only vs radiographic progression] R A N D O M I Z E 2:1 Abiraterone: 1000 mg daily Prednisone 5 mg BIG n=797 Placebo daily Prednisone 5 mg BIG n= sites in 13 countries (US, Europe, Australia, Canada) Primary endpoint: Overall Survival Secondary end points: TTPP, rpfs, PSA response De Bono J et al. ESMO

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17 Comparison of Cabazitaxel and Abiraterone phase III studies in mcrpc Pts characteristics & Outcome Cabazitaxel (/MP) Abiraterone (/P) Age (years) 68 (62-73) 69 (42-95) ECOG PS 2 7% 10.7% Pain at baseline 46% 44.3% Median PSA (υg/l) Visceral mets 25% 24.3% Measurable disease 53% 69% Number of line of CT > 2 31% 28.2% PSA response rate 39.2% ( ) 29.1% Pain response rate 9.2% ( ) NR Tumour response rate 14.4% ( ) NR PFS (months) cpfs ( mths) rpfs ( mths) Overall Survival (months) MDV3100: an improved AR antagonist? Higher affinity for the androgen receptor than bicalutamide Prevents nuclear translocation and co-activator recruitment of the ligand-receptor complex Induces tumour cell apoptosis No AR agonist activity in castrate-resistant setting Induces tumour responses in CRPC patients who have failed other hormone therapies AR: Antiandrogen Receptor Tran C, et al. Science 2009;324:

18 MDV 3100 Phase I-II study PSA response Chemotherapy-Naïve (n=65) Post-Chemotherapy (n=75) PSA Change from Baseline 62% (40/65) >50% Decline 51% (38/75) >50% Decline Scher HI, et al. Lancet [published on-line april 2010] MDV3100 (AFFIRM) - phase III study post-docetaxel mcrpc after up to 2 lines chemo, 1 with docetaxel R A N D O M I Z E 2:1 N=1170 Primary end point: overall survival MDV mg QD (n=780) Placebo QD (n=390) *ClinicalTrials.gov identifier: NCT

19 Other antiandrogens in development TAK-700 (Orteronel) (phase III post-docetaxel) TOK-001, CYP17 inhibitor (phase I/II) SARDS ARN-509 (phase II) HDAC Inhibitors Steroid sulfatase inhibitors Co-factor antagonists Conclusion Management of CRPC is rapidly evolving Clinical trial data with abiraterone and MDV-3100 confirm continued AR addiction in patients with mcrpc o Highlights continued importance of the AR axis, even in advanced disease Docetaxel is the standard in first-line mcrpc Progression after Docetaxel is no more an unmet need: Cabazitaxel shows a significant survival advantage compared to the active agent mitoxantrone/prednisone Abiraterone also provides survival advantage versus placebo The most appropriate sequencing of Abiraterone and Cabazitaxel remains to be determined 19

Androgens and prostate cancer: insights from abiraterone acetate and other novel agents

Androgens and prostate cancer: insights from abiraterone acetate and other novel agents Ian Davis Ludwig Institute for Cancer Research Austin Health, Melbourne, Australia Supported in part by an Australian