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Tasquinimod prolongs radiographic PFS, not OS, in metastatic prostate cancer
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Tasquinimod significantly improved radiographic PFS in men with chemotherapy-naive, metastatic castration-resistant prostate cancer, according to the results of a randomized controlled trial.
However, the agent did not confer an OS benefit, results showed.
Despite treatment advances, metastatic castration-resistant prostate cancer remains uncurable. Newly introduced agents frequently confer minor survival improvements and resistance commonly occurs.
The novel oral therapy tasquinimod (ABR-215050; Active Biotech, Ipsen) significantly extended PFS in a phase 2 randomized controlled trial of men with metastatic castration-resistant prostate cancer. Results of a multivariate analysis from this trial showed PFS improvement may be associated with improved OS, especially in patients with bone metastases.
Michael Carducci, MD, FACP, professor of oncology and urology at Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Medicine, and colleagues conducted a double blind, placebo-controlled phase 3 study to confirm the benefit of tasquinimod in this patient population.
The study included data from 1,245 chemotherapy-naive men (median age, 71 years; range, 43-92) from 37 countries.
The researchers randomly assigned men to daily oral tasquinimod (n = 832) or placebo (n = 413) until disease progression or unacceptable toxicity.
Initial dosing began at 0.25 mg per day for at least 2 weeks. After establishing tolerability, patients could escalate their dose to 0.5 mg per day for 2 weeks, then to a maximum daily dose of 1 mg per day.
Patients unsuitable for dose escalation continued treatment at their maximum tolerated dose.
Baseline levels of tumor pain were higher among patients in the tasquinimod arm (Visual Analog Scale > 4: 18.6% vs. 14.5%). These patients also had a shorter time from diagnosis (median, 45.7 months vs. 57.7 months).
Radiographic PFS — defined as the interval from random assignment to radiologic progression or death — served as the primary endpoint. OS was a key secondary endpoint.
Median follow-up at the time of data cutoff was 30 months in the tasquinimod arm and 30.7 months in the placebo arm.
Treatment with tasquinimod conferred a 36% risk reduction for radiologic progression or death. The tasquinimod arm has a median radiographic PFS of 7 months, compared with 4.4 months in the placebo arm (HR = 0.64; 95% CI, 0.54-0.75).
No significant OS benefit was observed at either of the two interim analyses. Because no safety concerns were raised, the study continued. A total of 492 deaths occurred in the tasquinimod arm (59.1%), compared with 238 deaths in the placebo arm (57.6%).
Tasquinimod did not improve OS in the final analysis (median, 21.3 months vs. 24 months; HR = 1.1; 95% CI, 0.94-1.28).
Patients assigned tasquinimod achieved a longer median time to salvage therapy (11.4 months vs. 8.1 months; P = .001) and to further cytotoxic therapy (25.8 months vs. 16 months; P = .021).
A greater proportion of patients assigned tasquinimod required a dose reduction of 1 mg/ day (17.5% vs. 5.6%) or 0.5 mg/day (1.4% vs. 0%). Further, more patients in this arm discontinued due to adverse events (17.7% vs. 10.2%).
The most common adverse events included gastrointestinal disorders (tasquinimod vs. placebo, 60.2% vs. 47.9%), general disorders and administration site conditions (55.1% vs. 39.9%), and musculoskeletal and connective tissue disorders (48.2% vs. 36.7%).
Serious adverse events occurred in 229 patients assigned tasquinimod (27.6%) and 97 patients assigned placebo (23.6%). Common serious adverse events included renal and urinary disorders (7.3% in both arms), infections and infestations (5.1% vs. 4.1%), and blood and lymphatic system disorders (4.3% vs. 4.1%).
Both arms had similar rate of death due to adverse events (tasquinimod, n = 27; placebo, n = 15).
“On the basis of the lack of OS benefit observed in this study, further clinical development of tasquinimod in this patient population was not pursued,” Carducci and colleagues wrote. – by Cameron Kelsall
Disclosure: Carducci reports consultant roles with Astellas, AstraZeneca, Clovis Oncology, Medivation and Merck. Please see the full study for a list of all other researchers’ relevant financial disclosures.
Perspective
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Donald L. Trump
Cora Sternberg, MD, FACP, and colleagues reported the results of a large trial involving 1,245 patients, which asked the question: “Is tasquinimod active in castration-resistant prostate cancer?” Perhaps the first question the reader may ask is: What is tasquinimod? Tasquinimod is one of a series of quinolone-3–carboxamide compounds being developed by Active Biotech. The mechanism of action of tasquinimod is not entirely certain, but the agent is believed to act on the tumor microenvironment — perhaps by modulating the activity of one or more classes of innate immune cells, such as the regulatory myeloid-derived suppressor cells (MDSC).
In an earlier randomized, placebo-controlled phase 2 trial, tasquinimod had substantial impact on PFS (7.6 months vs. 3.3 months; HR 0.57). In follow-up studies, activity seemed particularly evident in men with bone metastases.
The current study was designed to delineate the impact of tasquinimod on OS. This was a well-designed and carefully conducted multi-national study. Although the previously noted delay in PFS was confirmed (7 months vs. 4.4 months, HR 0.63), the researchers observed no improvement in OS.
Although a number of confounding factors — post-study treatment and imbalance in risk factors — may contribute to the lack of a survival, in this large study, tasquinimod did not improve survival. This is unfortunate since it fails to validate a promising new target in prostate cancer, and it took a very large study to find the answer was “no.”
There is more to come with respect to agents targeting the tumor microenvironment, however. A number of agents have been shown to block MDSC activity — COX-2 inhibitors, amino-bisphosphonates, phosphodiesterase-5 inhibitor (sildenafil and tadalafil), KIT–specific antibodies, nitroaspirin, triterpenoid, all-trans retinoic acid, 25-hydroxyvitamin D3, gemcitabine, VEGF–trap, bevacizumab (Avastin, Genentech), doxorubicin, cyclophosphamide, antagonists of CXCR2 and CXCR4, sunitinib and PROK2-specific antibody — and MDSCs are only one component of the tumor microenvironment which may be amenable to disruption to good therapeutic advantage. However, based on this large trial it does not appear that one such agent, tasquinimod, will prove to be useful in castration-resistant prostate cancer.
Reference:
Gabrilovich DI, et al. Nat Rev Immunol. 2012;doi:10.1038/nri3175.
Disclosure: Trump reports no relevant financial disclosures.
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