According to preliminary results from a 12-week open-label lead-in stage of an adaptive design phase II study reported at the ASCO Genitourinary (GU) Cancers Symposium, cabozantinib (XL184)—a novel wide-spectrum tyrosine kinase inhibitor (TKI)— achieved dramatic results in patients with castration-resistant prostate cancer (CRPC). The study was supported by Exelixis, the manufacturer of cabozantinib.
Treatment with cabozantinib achieved an overall disease control rate of 74% at week 12. Complete or partial resolution of bone metastases was seen in 53 of 62 patients (85%), and disease stabilization was observed in 8 of 62 patients (13%). Among 43 patients with bone metastases and bone pain at baseline, 26 (60%) reported improvement at week 6 or 12. Among 33 patients who were taking narcotic medication for bone pain at baseline, 21 patients (64%) reported improvement at week 6 or 12, and 13 patients (46%) discontinued narcotics at week 12.
Cabozantinib is a small-molecule TKI directed against VEGFR2, MET, KIT RET, AXL, Tie2, and FLT3. David C. Smith, MD, of the University of Michigan Health System in Ann Arbor and lead author of the study, explained that the drug has shown broad antitumor activity across multiple tumor types, and has demonstrated antitumor activity in bone and soft tissue in patients with prostate cancer. Cabozantinib targets 3 key cell types in metastatic bone lesions: osteoblasts, tumor cells, and osteoclasts. All 3 express-activated VEGFR and MET.
“The drug has a profound effect on bone metastases and achieves regression of soft-tissue disease in preclinical studies,” said Smith.
Patients enrolled in the phase II study received cabozantinib 100 mg 4 times a day for 12 weeks. Treatment after that point was based on treatment response. Patients with partial response were treated with open-label cabozantinib; those with stable disease were randomized to cabozantinib versus placebo; patients with progressive disease were discontinued. Patients included in the trial had to have pathologically and radiologically confirmed CRPC and could have been treated with up to 1 prior line of chemotherapy.
One hundred patients were enrolled in the trial with a median age of 68 years. Forty-seven percent had prior docetaxel-containing chemotherapy. Seventy-four patients completed the 12-week lead-in stage of the trial. At the ASCO GU symposium, data were presented on 100 patients who completed 12 weeks of treatment and 62 patients with known bone metastasis and at least 1 bone scan during the 12 weeks of treatment.
Smith said that tolerability with cabozantinib was similar to that of other TKIs. The most frequently reported adverse events of all grades (more than 30% of patients) were fatigue (71%), decreased appetite (52%), diarrhea (46%), nausea (40%), constipation (34%), and dyspnea (33%). Phase III regulatory studies are planned in patients with painful bone metastases, metastatic CRPC patients with bone metastases, and those with premetastatic CRPC.
Two independent experts not associated with the study were impressed by Smith’s data. Oliver Sartor, MD, of Tulane University in New Orleans, Louisiana, said that the scans of patients in the lead-in phase of the study were “remarkable” and that the drug appears to have a “whole new mechanism of action.” Celestia Higano, MD, of the University of Washington in Seattle, said, “I have never seen these kinds of [bone] changes with any agent.”