Final analysis of a phase II study of MRI based functional imaging of bone metastases in men with metastatic castrate-resistant prostate cancer (mCRPC) receiving cabozantinib.

Abstract

213 Background: Cabozantinib (C) is a small molecule inhibitor of receptor tyrosine kinases including VEGFR-2, c-MET. C trials have shown significant improvements in bone pain and bone scintigraphy in mCRPC patients (pts). We hypothesized that functional imaging using MRI could elucidate underlying biological processes by demonstrating an early decrease in vascular permeability (decrease in transfer consant - Ktrans) and subsequent decrease in cell density (increase in apparent diffusion coefficient - ADC) within bone metastases. Methods: mCRPC pts received C 60 mg daily. The primary endpoint was change in Ktrans at 2 weeks (wks) of treatment. Secondary endpoints included Ktrans and ADC longitudinal changes, and correlation with bone scan, PSA, RECIST, and changes in reported pain. All pts underwent MRI at baseline, day 0, day 15 and every 12 wks. Results: 17 pts were treated at two sites. Median age: 68 yrs (range:51-83), baseline PSA 94.78 ng/mL (7.4-2971), number of prior CRPC therapies 2 (1-8). Median progression free survival was 5.1 months; 5 pts discontinued therapy for adverse events, and 12 for progressive disease. The most common grades 3/4 toxicities were fatigue (24%) and palmarplantar erythrodysesthesia (12%). 14 pts were evaluable for the primary endpoint. At 2 wks, Ktrans decreased an average 35%, 0.074 to 0.048 min-1 (SD=0.016, p<0.0001). There was no change in Ktrans between wk 2 and end of study. There was an increase in median ADC of 150 at wk 12. There were no RECIST or 50% PSA responses. Conclusions: Ktrans decreased significantly after 2 wks of treatment, consistent with antiangiogenic properties of C. Compared to wk 2, K trans at disease progression is unchanged, which could signify that adaptive vascular change is not the primary mechanism of tumor resistance to the drug. Contrary to our hypothesis, ADC increased during the trial, which perhaps correlates with the short median time to progression. Still, MRI of bone metastases could benefit drug development for other agents in mCRPC or interrogation of bone metastases, notoriously challenging for disease response analysis, in other cancers. Clinical trial information: NCT01599793.