Cabozantinib (XL184) in metastatic castration-resistant prostate cancer (mCRPC): Results from a phase II randomized discontinuation trial.

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Cabozantinib (XL184) in metastatic
castration-resistant prostate cancer (mCRPC)
Results from a phase II randomized
discontinuation trial.

• Authors Hussain M. et al, ASCO 2011
• Abstract 4516
• Reviewed by Dr. Lori Wood
• Date posted June 2011

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STUDY RATIONALE

• New agents for metastatic CRPCa are needed
• Cabozantinib (XL184)
• An oral TKI of MET and VEGFR
• MET drives tumor cell invasion and metastases
• MET and VEGFR synergize to promote angiogenesis
• In prostate cancer
• Pre-clinically ADT ? MET expression
• MET ? with progression and metastases

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STUDY DESIGN
Phase III Randomized Discontinuation Trial

• Metastatic CRPCa patients
• - 0-1 prior chemotherapy
• - all received Cabozantinib
• 100 mg p.o. qd x 12 weeks
• Primary objectives
• - lead-in stage RECIST RR
• - randomized stage - PFS
• Planned n200 accrual
• discontinued after n171 due
• to better than expected
• results

PR/CR
Continue
Continue (n14)
R
SD
Placebo (n17)
PD
Stop
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RESULTS
At 12 Weeks
PR/CR Open Label Extension n79 (46)
SD Randomized n31 (18)
Off Study n61 (36) PD 16 AE 15 Death
1 Other 4
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RESULTS

• Lead-in stage
• 68 overall objective disease control at week 12
• 74 measurable soft tissue disease regression
• 76 complete or partial bone scan resolution
• 67 improvement in pain
• PSA changes did not correlate with radiological
  response
• Randomization stage
• PFS 21 weeks vs. 6 weeks

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RESULTS
Best Overall Effect on Bone Scan (n 108)

• CR 19
• PR 56
• SD 21
• PD 3

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TOXICITY

• Grade ? 3 adverse events in lead-in stage
• Fatigue 16
• Thrombosis 7
• Hypertension 6
• Hand/Foot 6
• Anorexia 5
• GI Perforation 2
• 51 of patients had ? dose reduction
• 1 death potentially 2? treatment (unexplained
  death)

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STUDY COMMENTARY

• Cabozantinib is a first in class TKI to act on
  both MET and VEGFR.
• This phase II randomized discontinuation study
  with Cabozantinib showed very impressive results,
  especially bone scan and pain improvement.
• Will the endpoints looked at (bone scan and pain
  improvement) translate into an improvement in
  overall survival?
• This drug is in many other clinical trials right
  now with prostate cancer patients and no doubt we
  will hear a lot more about it.

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BOTTOM-LINE FOR CANADIAN MEDICAL ONCOLOGISTS

• Very exciting drug
• Would be great to participate in clinical trials
  with this drug