Tasquinimod demonstrated promise in phase II trials but failed to improve overall survival in a phase III trial in treatment-naive metastatic castration-resistant prostate cancer; some experts believe this failure highlights the need for more intelligent clinical trial designs in prostate cancer.
Johann De Bono, MD
Although the drug tasquinimod demonstrated promise in phase II trials, it failed to improve overall survival (OS) in a phase III trial in men with treatment-naïve metastatic castration-resistant prostate cancer (mCRPC).1Based on the results, Active Biotech and Ipsen have discontinued development of this agent in prostate cancer, and some experts believe this failure highlights the need for more intelligent clinical trial designs in prostate cancer.
“In the phase III trial, although radiographic progression-free survival [rPFS] was longer with tasquinimodsimilar to the phase II results—this did not translate to an overall survival effect. In fact, survival favored placebo,” said lead investigator Michael Carducci, MD, Johns Hopkins University, Sidney Kimmel Comprehensive Cancer Center.
“We don’t know the reasons for the disconnect between the radiographic progression-free survival benefit and lack of a survival benefit,” he told attendees at the 2015 European Cancer Congress.
Tasquinimod is an oral therapy that is thought to target the tumor microenvironment. The drug is reported to elicit an immune response, antiangiogenic activity, and antimetastatic activity, but formal discussant of this abstract, Johann De Bono, MD, took issue with the purported mechanism of action “We don’t really know how this drug works, and that should cause concern,” said De Bono.
Carducci explained that in the phase II randomized, double-blind, placebo-controlled trial in a similar patient population, tasquinimod significantly extended radiographic progression-free survival (rPFS) versus placebo: median rPFS was 3.3 months with tasquinimod versus 7.6 weeks with placebo (P= .0042).2Safety was acceptable.
“The greatest benefit of tasquinimod in the phase II trial was in patients with bone-only metastasis, with a median rPFS of 12.1 months versus 5.4 months for placebo,” he said.
The randomized, double-blind, placebo-controlled, phase III study screened 1645 men and enrolled 1245 men with asymptomatic or mildly symptomatic, chemotherapy-naïve mCRPC with metastasis confined to the bone. Subjects were randomized in a 1:1 ratio to receive tasquinimod once a day titrated to a dose of 1 mg/day over 4 weeks or placebo and treated until the occurrence of disease progression or unacceptable toxicity.
The study met the primary endpoint, with a significant benefit for tasquinimod in rPFS: 7 months versus 4.4 months for placebo (P<.001). Subgroup analysis showed a benefit across the board for tasquinimod in rPFS.
However, no survival advantage was observed. Median OS was 21.3 months for tasquinimod versus 24 months for placebo, and no significant trends toward benefit for tasquinimod were observed in any subgroup.
More patients assigned to tasquinimod stopped treatment due to adverse events. There were more reports of decreased appetite, nausea, fatigue, and asthenia in the tasquinimod arm, which may have led to higher rates of discontinuation of study drug, Carducci said.
In his discussion, De Bono assured attendees that studying failed trials can lead to success by learning lessons about disease biology, drug pharmacology, and how to design better trials.
First, as mentioned above, he took issue with the mechanism of action of tasquinimod, noting that it is poorly understood.
“However, that shouldn’t stop going to phase III trials if the drug has significant antitumor activity,” commented De Bono.
After reviewing the phase I and II tasquinimod data, he found that the antitumor activity of the drug was “modest at best.”
“It would be more important to analyze the genome of those who were exceptional responders to understand why the drug worked in them,” he said.
The disconnect between phase II rPFS and OS in phase III has been seen before in prostate cancer with other drugs, so it shouldn’t have been a surprise, he continued.
His main argument was that rPFS is not a good surrogate marker for OS in mCRPC. “Results of this trial and other trials show that rPFS is truly not an intermediate endpoint in prostate cancer,” he stated. At best there is a poor correlation between rPFS and OS in mCRPC.”
“Randomized phase II results are overrated in prostate cancer. These trials are misleading us, with a high rate of false positivity. We need to raise the bar in clinical trials,” De Bono emphasized.
According to De Bono, the way forward is to understand the genome of prostate cancer patients and target actionable mutations. Also, better surrogate endpoints are needed to accelerate anticancer drug development.
“We need better understanding of mCRPC to advance our success in finding effective treatments for this disease,” he concluded.