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Genitourinary Tumors Poster Discussion

Abstracts. 50 PD: Inhibition of androgen synthesis results in a high response rate in castration refractory cancer (CRPC)Alison Reid et al. (RMH, UK)51 PD: Abiraterone, an oral, irreversible, CYP450c17 enzyme inhibitor appears to have activity in post-docetaxel castration refractory prostate cance

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Genitourinary Tumors Poster Discussion

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    1. Genitourinary Tumors Poster Discussion Luis Paz-Ares Hospital Universitario Doce de Octubre Madrid

    2. Abstracts 50 PD: Inhibition of androgen synthesis results in a high response rate in castration refractory cancer (CRPC) Alison Reid et al. (RMH, UK) 51 PD: Abiraterone, an oral, irreversible, CYP450c17 enzyme inhibitor appears to have activity in post-docetaxel castration refractory prostate cancer (CRPC) patients (pts) Gerhardt Attard et al. (RMH, UK) 52 PD: Safety and activity of sorafenib in advanced renal cell cancer Elena Verzoni, et al. (INT, IT)

    3. Abstracts 50 PD: Inhibition of androgen synthesis results in a high response rate in castration refractory cancer (CRPC) Alison Reid et al. (RMH, UK) 51 PD: Abiraterone, an oral, irreversible, CYP450c17 enzyme inhibitor appears to have activity in post-docetaxel castration refractory prostate cancer (CRPC) patients (pts) Gerhardt Attard et al. (RMH, UK) 52 PD: Safety and activity of sorafenib in advanced renal cell cancer Elena Verzoni, et al. (INT, IT)

    4. Abiraterone Phase I Trial in CRPC Summary Oral drug, daily dosing Targets CYP17 Phase I trial: safety, activity, Pks, PDs 38 patients Mild toxicity profile (Mcorticoid activity) Encouraging activity: PSA response rate: 22/34 (65%) 11/20 RECIST responses Evidence of CYP17 activity inhibition

    5. Abiraterone Phase II Trial in CRPC Summary Oral drug, daily dosing Targets CYP17 Phase II trial, standard 2 stages design and elegibility 28 patients entered, 21 evaluable Favourable toxicity profile (Mcorticoid activity) Encouraging activity: PSA response rate 48% Independent of prior docetaxel exposure

    6. Do we need more drugs? Incidence & mortality due to prostate cancer Available systemic treatments Hormonal Angrogen deprivation (orchidectomy, LHRH, AD) Secondary manipulations AD withdrawal Ketokonazol Chemotherapy (Docetaxel, MTZ) New Options Satraplatin ET-743, epotilons, vinflunine,…

    7. Rationale further AR targeting Relevance of AR signallig and AR- response pathways after AD AR protein and mRNA levels in CRPC patients Low levels of androgens are sufficient to maintain CRPC growth (AR expression up-regulation) Androgen source unclear Altered synthesis/inactivation of androgens ? Endogenous androgen production by CRPC?

    8. Adrenal Steroid Synthesis Pathway

    9. CYP450c17 Deficiency

    10. Abiraterone Structure

    11. Phase I Trials: Limited dosing

    12. Abiraterone Phase I Trial

    13. Abiraterone Phase I Trial

    14. Abiraterone Phase I Trial PSA decline rate Durable = 50% PSA declines in 22/34 pts (65%) Durable = 90% PSA declines in 10/34 pts One PSA rise but PR on CT scan RECIST response data 20/30 evaluable by RECIST 11/20 had confirmed radiological partial responses 7/20 ongoing stable disease

    15. Abiraterone Phase I Trial

    16. Abiraterone Phase I Trial

    17. Abiraterone Phase IITrial 28 patients recruited to date 21 patients have reached 3 months on study 10/21 (48%) have had confirmed PSA response Rejection of null hypothesis 2/12 confirmed partial responses (RECIST) 2 of the above 10 have had PSA falls of = 90% No relationship between docetaxel progression and abiraterone response Good tolerance (hypokalaemia)

    18. Pending Questions Confirm activity (large numbers) Predictors of activity Molecular determinants (AR mutation, amplification ??) Prior treatment Hormone levels CTCs Other clinical contexts (earlier disease stages) Drug combinations Dexametaxone Ketokonazole Docetaxel other Randomized trials to be started

    19. Abiraterone Acetate Phase I Trial

    20. Pending Questions Confirm activity (large numbers) Predictors of activity Molecular determinants (AR mutation, amplification ??) Prior treatment Hormone levels CTCs Other clinical contexts (earlier disease stages) Drug combinations Dexametaxone Ketokonazole Docetaxel other Randomized trials to be started

    21. Abiraterone Phase I Trial

    22. Pending Questions Confirm activity (large numbers) Predictors of activity Molecular determinants (AR mutation, amplification ??) Prior treatment Hormone levels CTCs Other clinical contexts (earlier disease stages) Drug combinations Dexametaxone Ketokonazole Docetaxel other Randomized trials to be started

    23. Contratulations !!!! Dr. Attard, Dr Reid and all the team Keep with the nice work !!!!

    24. Abstracts 50 PD: Inhibition of androgen synthesis results in a high response rate in castration refractory cancer (CRPC) Alison Reid et al. (RMH, UK) 51 PD: Abiraterone, an oral, irreversible, CYP450c17 enzyme inhibitor appears to have activity in post-docetaxel castration refractory prostate cancer (CRPC) patients (pts) Gerhardt Attard et al. (RMH, UK) 52 PD: Safety and activity of sorafenib in advanced renal cell cancer Elena Verzoni, et al. (INT, IT)

    25. Sorafenib in RCC Summary Sorafenib 400 mg bid Expanded access program at a single Institution 136 RCC patients (1 year), all histologies Mostly clear cell and pretreated Expected toxicity profile (HFS, asthenia, anorexia, HBP) Dose reduction 35%, dose interruption 49% Risk factors: anemia, poor PS, severe liver mets Expected Activity: Response rate 7% (!!), DCR 70% (also non clear cell cancers) Median TTP 6.5 months, median RD 8 months

    26. Sorafenib in RCC

    27. Verzoni et al: Sorafenib in RCC Authors Conclussions # 1 In agreement with literature data the overall rate of disease control we achieved was very high (70%) in opposition to a number of partial responses rather moderate (7%). # 2 Also in heavily pretreated patient population is possible to achieve a response which is independent of the number and of the type of previous treatments.

    28. Sorafenib in RCC: US EAP

    29. Sorafenib in RCC: US EAP

    30. First LIne RCC: Sorafenib vs IFN

    31. First LIne RCC: Sorafenib vs IFN

    32. Verzoni et al: Sorafenib in RCC Authors Conclussions # 3 As regards the activity of sorafenib on different histological tumour types in our series, 29 cases of non clear-cell RCC have been treated: results show that two papillary tumours type 2 and 1 cromophobe responded to treatment with sorafenib. This evidence deserves to be further investigated and raises the hypothesis that probably the activity of sorafenib is not exclusively linked to the presence of von Hippel-Lindau gene mutation.

    33. Sorafenib in RCC: US EAP

    34. Verzoni et al: Sorafenib in RCC Authors Conclussions # 4 Response to therapy correlates with the presence of risk factors according to Motzer’s prognostic model.

    35. Verzoni et al: Sorafenib in RCC Authors Conclussions # 4 Response to therapy correlates with the presence of risk factors according to Motzer’s prognostic model. But… data not shown in the poster

    36. Sorafenib in RCC: TARGET trial

    37. Verzoni et al: Sorafenib in RCC Authors Conclussions # 5 Sorafenib 400 mg bid continuous dosing appeared well tolerated; however some patients, such those with performance status 2 and anemia, seem at higher risk of adverse events and this raises the question whether a dose reduction of sorafenib should be considered for this subset of patients.

    38. Verzoni et al: Sorafenib in RCC Safety

    39. Sorafenib in RCC: US EAP

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