Cabozantinib in patients with advanced prostate cancer: results of a phase II randomized discontinuation trial

Abstract

Purpose: Cabozantinib (XL184) is an orally bioavailable tyrosine kinase inhibitor with activity against MET and vascular endothelial growth factor receptor 2. We evaluated the activity of cabozantinib in patients with castration-resistant prostate cancer (CRPC) in a phase II randomized discontinuation trial with an expansion cohort.

Patients and methods: Patients received 100 mg of cabozantinib daily. Those with stable disease per RECIST at 12 weeks were randomly assigned to cabozantinib or placebo. Primary end points were objective response rate at 12 weeks and progression-free survival (PFS) after random assignment.

Results: One hundred seventy-one men with CRPC were enrolled. Random assignment was halted early based on the observed activity of cabozantinib. Seventy-two percent of patients had regression in soft tissue lesions, whereas 68% of evaluable patients had improvement on bone scan, including complete resolution in 12%. The objective response rate at 12 weeks was 5%, with stable disease in 75% of patients. Thirty-one patients with stable disease at week 12 were randomly assigned. Median PFS was 23.9 weeks (95% CI, 10.7 to 62.4 weeks) with cabozantinib and 5.9 weeks (95% CI, 5.4 to 6.6 weeks) with placebo (hazard ratio, 0.12; P < .001). Serum total alkaline phosphatase and plasma cross-linked C-terminal telopeptide of type I collagen were reduced by ≥ 50% in 57% of evaluable patients. On retrospective review, bone pain improved in 67% of evaluable patients, with a decrease in narcotic use in 56%. The most common grade 3 adverse events were fatigue (16%), hypertension (12%), and hand-foot syndrome (8%).

Conclusion: Cabozantinib has clinical activity in men with CRPC, including reduction of soft tissue lesions, improvement in PFS, resolution of bone scans, and reductions in bone turnover markers, pain, and narcotic use.

Trial registration: ClinicalTrials.gov NCT00940225.

Fig 1.

CONSORT diagram, including enrollment, random assignment, and open-label treatment of study patients. (*) Included one patient who did not meet eligibility criteria (no measurable disease). (†) Seven patients who were randomly assigned to placebo and crossed over to open-label cabozantinib treatment after unblinding were still active at the time of data cutoff. AE, adverse event; PD, progressive disease.

Fig 2.

Best changes from baseline in investigator-assessed measurements of tumor lesions in soft tissue using RECIST (version 1.0) in patients with castration-resistant prostate cancer who had measurable disease at baseline and at least one postbaseline radiographic assessment (n = 154). A reduction in the sum of measurable tumor lesions was observed in 72% of patients.

Fig 3.

Kaplan-Meier estimates of progression-free survival (PFS) in (A) randomly assigned patients with castration-resistant prostate cancer (CRPC) and (B) patients with CRPC by docetaxel pretreatment status. Panel A shows the probability of PFS from week 12 random assignment for patients with CRPC randomly assigned to continued treatment with cabozantinib (n = 14) or placebo (n = 17). Panel B shows the probability of PFS for all patients with CRPC (n = 171) by docetaxel pretreatment status from first dose of cabozantinib. HR, hazard ratio.

Fig 4.

Bone scan effects of cabozantinib treatment on study patients. Sequential whole-body technetium methylene diphosphonate bone scintigraphy is shown of four patients with advanced metastatic prostate cancer. Baseline scans show multiple areas of increased radiotracer uptake indicative of extensive bone metastases. Treatment with cabozantinib resulted in complete or partial resolution of bone scans at week 12. Bone scan resolution correlated with partial response of tumor lesions in soft tissue and pain relief in each patient.

Fig A1.

Schematic of randomized discontinuation trial design. Eligible patients with castration-resistant prostate cancer received cabozantinib treatment during a 12-week, open-label, lead-in stage. At week 12, patients with objective tumor response by RECIST (version 1.0) continued open-label treatment with cabozantinib. Patients with progressive disease (PD) were discontinued. Patients with stable disease were randomly assigned to either continued treatment with cabozantinib or matched placebo (random assignment stage). Randomly assigned patients with PD were offered to resume cabozantinib treatment if they were receiving placebo and were observed until their subsequent progression.

Fig A2.

Effects on markers of osteoblast (total alkaline phosphatase [tALP]) and osteoclast (cross-linked C-terminal telopeptide of type I collagen [CTx]) activity. (A) Best change from baseline (%) in 30 patients with castration-resistant prostate cancer with bone metastases who reached week 12 and had baseline serum tALP levels ≥ 2× the upper limit of normal. (B) Best change from baseline (%) in plasma CTx in 126 patients with bone metastases who had at least one follow-up assessment.

Fig A3.

Effects of cabozantinib on prostate-specific antigen (PSA) and tumor lesion size. Changes from baseline (%) in PSA and soft tissue tumor lesions in 139 patients with castration-resistant prostate cancer at week 6 after initiation of cabozantinib treatment.

Fig A4.

Association of bone scan changes (complete and partial resolution v stable disease and progression) with regression of tumor lesions in soft tissue, 6-month progression-free survival (PFS) rate, reduction in pain and narcotic use, and decrease in osteoclast activity (cross-linked C-terminal telopeptide of type I collagen [CTx]) from baseline in patients with castration-resistant prostate cancer treated with cabozantinib.