Randomized, Double-Blind, Placebo-Controlled Phase III Study of Tasquinimod in Men With Metastatic Castration-Resistant Prostate Cancer

Abstract

Tasquinimod, a novel oral therapy targeting the tumor microenvironment, significantly improved progression-free survival (PFS) in a randomized, placebo-controlled phase II trial in men with metastatic castration-resistant prostate cancer (mCRPC). This phase III study was conducted to confirm the phase II results and to detect an overall survival (OS) benefit. Patients and MethodsMen with chemotherapy-naïve mCRPC and evidence of bone metastases were assigned (2:1) to receive tasquinimod once per day or placebo until progression or toxicity. The primary end point was radiographic PFS (rPFS; time from random assignment to radiologic progression or death) per Prostate Cancer Working Group 2 criteria and RECIST 1.1. The study had 99.9% power to detect an rPFS hazard ratio (HR) of 0.6 with a two-sided alpha error of .05 and 80% power to detect a target HR of 0.8 for OS, the key secondary end point. ResultsIn all, 1,245 patients were randomly assigned to either tasquinimod (n = 832) or placebo (n = 413) between March 2011 and December 2012 at 241 sites in 37 countries. Baseline characteristics were balanced between groups: median age, 71 years; Karnofsky performance status $ 90%, 77.3%; and visceral metastases, 21.1%. Estimated median rPFS by central review was 7.0 months (95% CI, 5.8 to 8.2 months) with tasquinimod and 4.4 months (95% CI, 3.5 to 5.5 months) with placebo (HR, 0.64; 95% CI, 0.54 to 0.75; P , .001). Median OS was 21.3 months (95% CI, 19.5 to 23.0 months) with tasquinimod and 24.0 months (95% CI, 21.4 to 26.9 months) with placebo (HR, 1.10; 95% CI, 0.94 to 1.28; P = .25). Grade $ 3 adverse events were more frequent with tasquinimod (42.8% v 33.6%), the most common being anemia, fatigue, and cancer pain. ConclusionIn chemotherapy-naïve men with mCRPC, tasquinimod significantly improved rPFS compared with placebo. However, no OS benefit was observed.

Reporting harms more transparently in trials of cancer drugs

“…The clinical trial report of ribociclib, a drug for breast cancer, mentions in its discussion that “Most patients had an acceptable adverse-event profile.”1 A report of a trial of liposomal irinotecan in pancreatic cancer states in the concluding paragraph that it “has a manageable and mostly reversible safety profile.”2 And a trial of tasquinimod in patients with prostate cancer reports “the tolerability was good overall.”3…”

Assessing angiogenic responses induced by primary human prostate stromal cells in a three-dimensional fibrin matrix assay

“…Tasquinimod is an investigational drug being evaluated in metastatic castration-resistant prostate cancer (mCRPC) and other solid tumor types. Unfortunately, tasquinimod failed to increase OS when given at 1 mg/day in a recent phase III trial of men with chemotherapy-naïve mCRPC, but did significantly improve radiographic PFS in this population [27]. It should be noted that this dose achieves a C max of ~0.5 μM, which is suboptimal based on an IC50 for this agent of ~0.5–1 μM [22].…”

Clinical development of immunotherapy for prostate cancer

“…In a randomized, placebo‐controlled phase 2 study of men with mCRPC, tasquinimod significantly improved PFS (7.6 months for tasquinimod and 3.3 months for placebo, P < 0.01) . However, an international, double‐blind, placebo‐controlled, phase 3 trial of chemotherapy‐naïve men with mCRPC showed no significant OS benefit (21.3 months for tasquinimod and 24 months for placebo, P = 0.25) . Despite these results, there remains interest in the use of tumor microenvironment disruptors in combination with other immunotherapies.…”