An unprecedented complete or partial resolution of bone metastases was observed with the investigational tyrosine kinase inhibitor cabozantinib in a trial of men with metastatic castration- resistant pr ostate cancer.
Interim results from the phase 2 discontinuation trial were reported by Maha Hussain, MD, Associate Director for Clinical Research, Uni versity of Michigan Comprehensive Cancer Center, Ann Arbor.
Cabozantinib is a dual inhibitor of the tyrosine kinases MET and vascular endothelial growth factor receptor (VEGFR) 2. MET is upregulated in many tumor types and promotes tumor cell invasion and metastasis. Both MET and the VEGFR2 signaling pathways appear to direct crosstalk between tumor cells, osteoblasts, and osteoclasts, said Dr Hussain.
In the study, 171 patients with metastatic castration-resistant pr ostate cancer with progressive measurable soft-tissue disease received cabozantinib during a 12-week lead-in phase, after which further treatment was based on response. The patients with a complete or partial response received open-label cabozantinib, those with stable disease were randomized to cabozantinib or to placebo, and those with disease progression or adverse events discontinued cabozantinib.
Of the 171 patients, 74 had received previous treatments for metastatic castration-resistant pr ostate cancer, in cluding docetaxel (Taxotere)-based chemo therapy and abiraterone acetate (Zytiga).
Bone metastasis was evident in 87% of the patients, and 91% had metastasis at ≥2 sites. Bone pain was reported by 54% of the patients, and 42% were using narcotics for bone pain.
Randomization was suspended after 122 patients, based on the high rate of clinical activity of cabozantinib; 79 men had at least a partial response and entered the open-label extension phase and 31 with stable disease entered the randomized portion of the trial. The disease control rate (no progression) at week 12 was 68%.
The safety and tolerability of cabozantinib were consistent with previous experience with the drug. In the lead-in phase, the most common grade 3 adverse event was fatigue (in 16% of patients). Adverse events necessitated cabozantinib dose reduction in 51% of the patients.
In 151 patients with at least 1 postbaseline assessment, 74% showed meaningful evidence of tumor regression, said Dr Hussain. The tumor regression occurred irrespective of previous treatments, she said.
In the randomized discontinuation phase, median progression-free survival (PFS) was 21 weeks in the cabozantinib group and 6 weeks in the placebo group (P = .007), an 87% reduction in the risk of progression for patients assigned to cabozantinib versus placebo.
Excluding the patients randomized to placebo, the median PFS was 29 weeks for the overall population. The median PFS was 24 weeks in the subset of doce - taxel-naïve patients and 29 weeks in patients who previously received doce - taxel, which suggests that cabozantinib treatment results in durable disease control in both docetaxel-naïve and previously treated populations.
Bone Scan Findings and Clinical Progress
The bone scan–assessable population included 108 patients with evidence of bone metastasis, a baseline bone scan, and at least 1 postbaseline bone scan assessment. Of these, 61 had partial resolution and 21 had complete resolution of bone metastases; 21 had stable disease on bone scan, and only 3 had progressive disease.
Of the 83 patients with bone metastases and bone pain at baseline, 68% had improvement of pain at either week 6 or 12. Of the 67 patients who required narcotic analgesics at baseline to control bone pain, 70% were able to decrease or discontinue narcotic medication for bone pain.
In addition, 55 patients had bone pain at baseline, 10 had complete resolution, 32 had partial resolution, and 13 had stabilization of disease with cabozantinib by bone scan evaluation. Of these patients, 80% with complete resolution, 84% with partial resolution, and 38% with disease stabilization reported improvements in bone pain. These findings are the first to show an association between changes in lesions on bone scans and improvement in clinical symptoms of disease.
Of 67 patients assessable for postbaseline review of narcotic consumption, 47 (70%) were able to decrease or discontinue narcotic medication for bone pain.