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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 2011Abstract: 4516Reviewed by: Dr. Lori WoodDate 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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R

PR/CR

STUDY DESIGN

- 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 n=200; accrual discontinued after n=171 due to better than expected results

Phase III Randomized Discontinuation Trial

SD

PD

Continue

Continue (n=14)

Placebo (n=17)

Stop

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RESULTS

PR/CR

Open Label Extension

n=79 (46%)

SD

Randomized

n=31 (18%)

Off Study

n=61 (36%)

PD = 16%

AE = 15%

Death = 1%

Other = 4%

At 12 Weeks

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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

• CR = 19%• PR = 56%• SD = 21%• PD = 3%

Best Overall Effect on Bone Scan (n = 108)

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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