Impressive Results with New Drugs for Advanced Prostate Cancer
Chicago, IL—The potential of 2 novel agents still in clinical trials, and 1 drug that was recently approved, offer new hope to patients with metastatic castrate- resistant prostate cancer (mCRPC), a disease with a dire prognosis and few good current treatment options.
One of the investigational agents, alpharadin (radium-223 chloride [R- 223]), may have just earned a chance for an expedited approval by the US Food and Drug Administration (FDA) because of its positive results.
R-223 is a first-in-class alpha-emitter radioisotope pharmaceutical, which targets bone metastases with its highenergy alpha radiation, thereby affecting prostate metastatic cells. However, because of its short-range effects, it spares the patient’s bone marrow.
In 2 phase 2 clinical trials reported at the 2011 ASCO Annual Meeting, R-223 was tested in mCRPC patients with bone metastasis (N = 101). The combined aim of the trials was to determine if normalization of levels of alkaline phosphatase (ALP), a marker of bone metabolism, could be taken as a surrogate for R-223 efficacy.
In both trials—one a randomized, placebo-controlled study (N = 64) and the other a dose escalation trial (N = 117)—ALP normalization was strongly correlated with overall survival (OS).
In both trials, the median survival was 102 weeks in patients with ALP normalization versus <58 weeks for those without ALP. In the dose-escalation study, treatment response increased with the increasing dose.
Of note, approximately 50% of patients treated with R-223 did not achieve ALP normalization, indicating ALP as a potentially good marker to gauge patient response.
Phase 3 Trial Terminated Early
Within hours of these findings being reported at the meeting, R-223 manufacturer announced off-site that an interim analysis of their R-223 phase 3 trial in mCRPC (N = 922) produced such impressive results that the trial was immediately halted in accordance with the recommendation of the Independent Data Monitoring Committee.
In patients with mCRPC and bone metastases, R-223 treatment resulted in an OS of 14.0 months versus 11.2 months for placebo.
Lead investigator Chris Parker, MD, of the Royal Marsden Hospital, said, “Approximately 90% of men with advanced prostate cancer have bone metastases, which are the main cause of disability and death in this disease.” Based on the observed survival benefits of these 3 trials, R-223 is expected to become an important treatment option for this patient population.
Surprising Results with Cabozantinib
A second surprise was reported for the novel agent cabozantinib, an inhibitor of tumor growth and metastasis signaling pathways involving MET and vascular endothelial growth factor receptor 2. In a phase 2 clinical trial, patients with mCRPC and progressive measurable disease received 100 mg of cabozantinib daily; response was assessed at 6 and 12 weeks.
Although the trial was slated to recruit up to 200 patients, accrual was halted at 168 patients, because of early observed rates of robust clinical activity. Interim analysis for cabozantinibtreated patients showed bone metastases shrinking in 76% of subjects.
Of the 108 patients evaluable for bone scan, 21 demonstrated complete resolution of bone lesions and 61 had partial shrinkage—these lesions can lead to bone fractures, severe pain, and eventual death.
Study investigators reported that, “Cabozantinib showed clinical activity regardless of prior treatment with docetaxel,” indicating that patients were still responsive to agents like cabozantinib.
Progress with Abiraterone
After an expedited 6-month review, the novel agent abiraterone acetate (Zytiga) was approved by the FDA in April 2011. Since then, physicians have been using the drug in patients who have been previously treated with the standard treatment ketoconazole (Nizoral), a molecule with a similar mechanism of action to abiraterone.
As the transition from the old standard treatment to the one showing superior efficacy goes forward, the question is, would patients receiving ketoconazole before treatment be resistant to abiraterone? (Patients taking ketoconazole were excluded from the abiraterone registration trial.)
An interim analysis for the first 14 ketoconazole-experienced patients with mCRPC was reported at the meeting. Median follow-up was 13.1 weeks. Treatment response was defined as percent decline in prostate-specific antigen (PSA) from baseline.
Results showed that abiraterone therapy induced a ≥50% decline in PSA at 12 weeks in 3 of 14 patients, and a ≥30% decline in 6 of 14 patients.
Of the patients without a ≥30% PSA decline, 1 had developed Response Evaluation Criteria In Solid Tumors– defined disease progression at 12 weeks and the remainder had stable disease.
Although accrual for this trial is ongoing, results thus far are promising. Trial investigators did comment, however, that the lower responses observed in this study compared with ketoconazole-naïve patients with mCRPC suggests the potential for overlapping mechanisms of resistance.