Long-term data from a phase 2 trial suggest that the experimental agent tasquinimod (Active Biotech) extends progression-free survival in men with metastatic castration-resistant prostate cancer (mCRPC), but its effect on overall survival is unclear.
In an intention-to-treat (ITT) population, median overall survival was 33.4 months with tasquinimod and 30.4 months with placebo, but the difference was not significant, report Andrew J. Armstrong, MD, ScM, associate professor of medicine at Duke Cancer Institute in Durham, North Carolina, and colleagues.
However, on multivariate analysis that controlled for tumor and patient factors, tasquinimod offered significantly better overall and progression-free survival than placebo, especially in a subset of men with cancer metastatic to bone, the researchers write.
The study was published online November 19 in Clinical Cancer Research.
Immune, Antiangiogenic Properties
Tasquinimod is an oral quinoline-3-carboxamide derivative with immunomodulatory properties and, investigators believe, both direct and indirect antiangiogenic activity.
"One clear target of the drug appears to be the myeloid suppressor cell," Dr. Armstrong told Medscape Medical News.
Myeloid suppressor cells are increased in patients with various cancers, and can infiltrate the tumor, suppress local antitumor immunity, and foster growth of tumor neovasculature, he explained.
"This drug does seem to block the function of these cells, and it does so through binding to one of their receptors, the S100 receptor," he said.
Another potential target of tasquinimod is thrombospondin, a protein that has been shown to be involved in platelet aggregation, angiogenesis, and tumor genesis.
"We clearly saw an increase in thrombospondin in our patients, and low levels of thrombospondin seem to be predictive of the survival benefit from this drug," Dr. Armstrong said.
Significant Progression-Free Survival Benefit
In the phase 2 trial on which this study was based, median progression-free survival was better with tasquinimod than with placebo (7.6 vs 3.3 months; P = 0.0042).
Dr. Armstrong's team conducted their trial of asymptomatic or minimally symptomatic mCRPC at 40 centers in Canada, Sweden, and the United States from December 2007 to June 2009. Of the 201 patients, 134 were randomized to oral tasquinimod, up to 1 mg once daily, and 67 were randomized to placebo.
After a mean duration of approximately 5 months, 41 patients in the placebo group crossed over to tasquinimod. Six months after the start of the therapy, 34 patients in the tasquinimod group continued on the drug in an open-label phase.
In addition to better overall progression-free survival with tasquinimod than with placebo, median progression-free survival was significantly better in the subgroup of men with bone metastases (8.8 vs 3.4 months; P = .019).
As of April 2012, 111 of 190 patients at 38 centers had died during a median follow-up of 37 months — 71 in the tasquinimod group and 40 in the placebo group.
For patients with bone metastases, median time to death was 34.2 months in the 92 men in the tasquinimod group and 27.1 months in 44 men in the placebo group, a difference that was not significant in the ITT analysis.
However, on multivariate analysis that controlled for prostate-specific antigen (PSA), lactate dehydrogenase, PSA doubling time, and hemoglobin, the adjusted hazard ratio (HR) favored tasquinimod in the ITT population for progression-free survival (0.52; 95% confidence interval [CI], 0.35 - 0.78; P = 0.001) and for overall survival (0.64; 95% CI, 0.42 - 0.97; P = .034).
For patients with bone metastases, the respective HRs were 0.51 (95% CI, 0.31 - 0.85; P = .009) and 0.61 (95% CI, 0.38 - 1.01; P = 0.053).
The majority of adverse events in the study were mild to moderate, primarily grade 1 or 2. However, 22% of patients discontinued therapy because of adverse effects.
Combination Therapy?
Dr. Armstrong acknowledged that the crossover and open-label portions of the phase 2 trial make it difficult to draw conclusions about the potential survival benefits of tasquinimod. Additionally, the study was relatively small and was not powered to detect a survival benefit. The drug is currently being evaluated in a phase 3 trial that will be adequately powered to detect a survival benefit, he noted.
If tasquinimod is approved by the US Food and Drug Administration, it will most likely be used in combination with other drugs, such as antiandrogens and chemotherapeutic agents. Dr. Armstrong and colleagues are currently evaluating the agent in combination with cabazitaxel ( Jevtana, Sanofi Oncology) and prednisone in men with chemorefractory mCRPC ( NCT01513733).
"I think the future will likely be through combination approaches. If tasquinimod by itself improves survival, it will largely get used before chemotherapy," he said.
The researchers will also explore whether the drug can be safely combined with other immunotherapies such as sipuleucel-t ( Provenge, Dendreon) and androgen-biosynthesis inhibitors such as abiraterone acetate ( Zytiga, Janssen).
Novel Mechanism of Action
Philip J. Saylor, MD, a genitourinary cancer specialist at Massachusetts General Hospital in Boston, who was not involved in the study, told Medscape Medical News that tasquinimod is particularly interesting because of its novel mechanism of action.
"In a landscape with so many agents that target the androgen receptor in one way or another, it stands out as different. To see early promise with monotherapy using a mechanistically distinct agent certainly brings to mind the possibility of combination therapy. I'm not sure we understand its mechanism of action well enough to, at this moment, predict the best agent to combine it with. Further studies will be needed," Dr. Saylor said.
The study was supported by Active Biotech. Dr. Armstrong reports receiving commercial research funding from Active Biotech, Dendreon, Medivation, Janssen, and sanofi-aventis; and holding a consultant/advisory board position with Active Biotech, Dendreon, Medivation, Janssen, and Bayer. Some of his coauthors report financial relationships with Active Biotech and other companies, as detailed in the paper. Dr. Saylor has disclosed no relevant financial relationships.
Clin Cancer Res. Published online November 19, 2013. Abstract
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