Genitourinary Tumors Poster Discussion

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 CRPCSummary

• 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

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Abiraterone Phase II Trial in CRPCSummary

• 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

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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,

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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?

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Adrenal Steroid Synthesis Pathway
C17a-hydroxylase
C17/20 lyase
9
CYP450c17 Deficiency
10
Abiraterone Structure
Attard et al. Urol Oncol 2005
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Phase I Trials Limited dosing
Attard et al. Urol Oncol 2005
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Abiraterone Phase I Trial
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Abiraterone Phase I Trial
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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
Attard et al. ASCO 2007
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Abiraterone Phase I Trial
Attard et al. ASCO 2007
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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)

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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

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Abiraterone Acetate Phase I Trial
Ryan et al. ASCO 2007
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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
Attard et al. ASCO 2007
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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 RCCSummary

• 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

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Sorafenib in RCC
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Verzoni et al Sorafenib in RCCAuthors
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.

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Sorafenib in RCC US EAP
Fligin et al., ASCO 2007
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Sorafenib in RCC US EAP
Fligin et al., ASCO 2007
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First LIne RCC Sorafenib vs IFN
Szczylik et al., ASCO 2007
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First LIne RCC Sorafenib vs IFN
Szczylik et al., ASCO 2007
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Verzoni et al Sorafenib in RCCAuthors
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.

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Sorafenib in RCC US EAP
Fligin et al., ASCO 2007
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Verzoni et al Sorafenib in RCCAuthors
Conclussions

• 4
• Response to therapy correlates with the presence
  of risk factors according to Motzers prognostic
  model.

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Verzoni et al Sorafenib in RCCAuthors
Conclussions

• 4
• Response to therapy correlates with the presence
  of risk factors according to Motzers prognostic
  model.
• But
• data not shown in the poster

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Sorafenib in RCC TARGET trial
Bukowski et al., ASCO 2007
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Verzoni et al Sorafenib in RCCAuthors
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.

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Verzoni et al Sorafenib in RCCSafety
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Sorafenib in RCC US EAP
Fligin et al., ASCO 2007