New York, NY—Men with castration-resistant prostate cancer (CRPC) now have several different treatments that improve their survival—docetaxel (Taxo-tere), cabazitaxel (Jevanta), abiraterone (Zytiga), and sipuleucel-T (Provenge). The newest potential therapy to improve survival in this group of patients is the radiopharmaceutical radium-223 (Alpharadin), which is currently under US Food and Drug Administration review.
In the pivotal phase 3 ALSYMPCA (Alpharadin in Symptomatic Prostate Cancer) trial, radium-223 improved survival in metastatic CRPC and had “remarkable” effects on bone scans, with a safety profile that was as good as that of placebo. Data are less mature for a second drug, cabozantinib (XL-184), which also may be another “transformative” drug for CRPC, according to experts who spoke at the 2011 Chemotherapy Foundation Symposium in November.
“Radium-223 promises to become a new standard of treatment for men with CRPC who have bone metastasis,” said A. Oliver Sartor, MD, Professor of Cancer Research at Tulane University and Medical Director of the Tulane Cancer Center, New Orleans. “We now have a variety of agents that prolong survival. In the future, we will need to learn how to combine them and sequence them. But the question is, can we afford this?”
ALSYMPCA enrolled 922 patients with CRPC and at least 2 bone metastases but without visceral metastasis who were randomized to receive radium-223 or placebo. A definite survival benefit for radium-223 was shown at a preplanned interim analysis, after which the study was stopped and men in the placebo group were allowed to cross over to the radiopharmaceutical arm.
The median overall survival was 14.0 months with radium-223 versus 11.2 months with placebo. The risk for time to a first skeletal-related event was reduced by 39% in patients who received radium-223. Radium-223 was of benefit in all prespecified subgroups, including those who had received docetaxel previously. The adverse effect rate associated with radium-223 was less than that with placebo, and more patients in the placebo group discontinued treatment.
Cabozantinib, the second drug for CRPC discussed at the meeting, showed promising results in a phase 2 trial. Cabozantinib is a dual inhibitor of MET and vascular endothelial growth factor receptor 2, explained David C. Smith, MD, Professor of Medicine, University of Michigan, Ann Arbor, who discussed studies of the drug at the meeting.
The phase 2 randomized discontinuation trial compared cabozantinib versus placebo in 171 men (median age, 68 years) with metastatic CRPC that was progressing. Among this group, 54% had bone pain, 42% were taking narcotics for their pain, and approximately 40% had received docetaxel previously.
Randomization was discontinued after 12 weeks, because cabozantinib led to controlled disease (ie, complete response, partial response, or stable disease) in 68% of patients. Bone scans showed some evidence of activity of cabozantinib in almost all of the patients, Dr Smith commented.
The major toxicities were fatigue (63%), thrombocytopenia (8%), and gastrointestinal perforation (1%); 50% of patients required dose reductions. No significant effect was observed in patients who received docetaxel previously.
The moderator of the session, William K. Oh, MD, Mount Sinai School of Medicine, New York, NY, said that both radium-223 and cabozantinib target the microenvironment. “Radium-223 will be transformative, because of its efficacy and favorable toxicity. Cabozantinib should also be transformative. It had a remarkable effect on bone scans, but we need to see more studies,” he stated.
