In a study of men with metastatic castration-resistant prostate cancer, the novel investigational agent OGX-011 showed a trend for overall survival while only modestly affecting PSA levels.
On the heels of this presentation, the FDA granted OGX-011 a second fast track designation for progressive metastatic prostate cancer in combination with first-line docetaxel (Taxotere) treatment. The designation means the FDA will take actions as appropriate to expedite the development and review of OGX-011 for approval. OncoGenex Pharmaceuticals Inc. had previously received a fast track designation for second-line treatment in combination with docetaxel for progressive metastatic prostate cancer following docetaxel alone.
OGX-011 is a 2´-methoxyethyl antisense compound that potentiates chemotherapy in xenografts and inhibits the expression of clusterin, a cytoprotective chaperone protein associated with high Gleason score and progression of castration-resistant prostate cancer. Overexpression of clusterin in preclinical models confers resistance to hormone therapy, radiation, and chemotherapy, explained Kim N. Chi, MD, the study's first author, who is an associate professor of medicine at the University of British Columbia, Vancouver.
The primary endpoint was PSA response (≥50% decline), while progression-free and overall survival were secondary endpoints. At the time of the 32-month median follow-up, 58 patients had died.
Survival results warrant further study
"The PSA response rate in the OGX-011 arm met the criterion for further study; however, the response rate in the control arm appeared similar," said Dr. Chi.
PSA response (confirmed) was observed in 58% of the experimental arm and 54% of the control arm. Decline of ≥30% was seen in 80% and 76% of patients in each arm, respectively. At 12 weeks, a PSA decline of ≥30% was observed in 65% and 59% of patients, respectively, Dr. Chi reported.
PSA progression as best response did not occur in any patient receiving OGX-011 plus docetaxel, but was seen in 7% of the control arm. By Response Evaluation Criteria in Solid Tumors (RECIST), partial responses were seen in 19% and 25% of patients, respectively, and stable disease in 77% and 50%.
The median progression-free survival for the OGX-011/docetaxel combination was 7.3 months versus 6.1 months with standard therapy. Three-month progression-free survival rates were 82% and 73%, respectively.
Interestingly, although progression-free survival was not significantly improved, the combination was independently associated with improved overall survival in a prespecified multivariate analysis, Dr. Chi reported.
Median survival was 23.8 months with the combination versus 16.9 months with docetaxel, for a hazard ratio of 0.61 (p=.06) favoring OGX-011 in the unadjusted analysis. In the multivariate analysis, OGX-011 was associated with a statistically significant 51% reduction in risk of mortality (p=.012).
Good performance status and bone/nodal metastases also significantly predicted better survival.
"There was also evidence of a biological effect, as treatment with OGX was associated with a reduction in serum clusterin level," Dr. Chi added.
The mean change from baseline by day 1 of cycle 2 was –18% with OGX-011 and +8% with standard therapy (p=.0005).
Adverse events associated with OGX-011 included fatigue, fever and chills (primarily after the first infusion), and elevated creatinine. Lymphopenia was observed in approximately half the patients comprising the experimental arm, more than double the risk observed with docetaxel alone, but was not associated with an increased infection rate. Altogether, Dr. Chi said he considered the novel agent to be well tolerated.
Commenting on recent trials of novel agents that have failed to meet their primary endpoints (ie, PSA "response" or progression-free survival) while showing overall survival gains, Dr. Chi said, "At this point we need to find biomarkers, such as perhaps circulating tumor cells, that can serve as better intermediate endpoints than our current definitions, which are clearly not surrogates for overall survival."
A phase III study of OGX-011 is scheduled to begin in 2010.