Pazopanib fails to show OS benefit for ovarian cancer

The oral multikinase VEGFR*1, 2, and 3 inhibitor pazopanib failed to improve overall survival (OS) in advanced ovarian cancer patients who have not progressed following first-line chemotherapy, according to the results of the AGO-OVAR16** study.

“[Our] study met the primary endpoint [of progression-free survival (PFS)] with a significant improvement of 5.6 months in the median PFS with pazopanib vs placebo … [However, despite the] prolonged PFS, [our current findings] were not associated with improvement in median OS,” said the researchers.

At the final OS analysis, there was no difference observed between pazopanib and placebo (median, 59.1 vs 64.0 months; hazard ratio, 0.96, 95 percent confidence interval, 0.80–1.14; p=0.64). [Gynecol Oncol 2019;doi:10.1016/j.ygyno.2019.08.024]

“[The] lack of a statistically significant OS benefit … may be attributed to the long post-progression survival in this setting,” said the researchers. Moreover, the OS benefit could have been masked by confounders such as multiple antineoplastic treatments available, use of active drugs delivered as salvage therapy following tumour progression, crossover therapy, and relatively long survival durations, previous research has shown. [Ann Oncol 2016;27;373-378; Ann Oncol 2004;15:545-549]

Following the PFS benefit in the primary analysis, researchers sought to evaluate the OS benefit of once-daily pazopanib 800 mg against placebo in 940 individuals with histologically confirmed advanced ovarian cancer for up to 24 months or until disease progression. At the time of the final analysis, 498 patients had died.

The high relapse rate in this patient subgroup, the lack of effective maintenance treatment alternatives following first-line standard of care, and the preliminary antitumour activity of pazopanib shown in a previous study warranted the evaluation of pazopanib in this setting, said the researchers. [Gynecol Oncol 2010;119:32-37]

Recent evidence on other advanced solid tumours showed a significant PFS benefit but inconsistent effects on OS even after patient selection based on the expression of molecular targets for these agents. Nonetheless, these are considered major advances in the treatment of advanced solid tumours. [Lancet Oncol 2014;15:323-332; N Engl J Med 2013;368:2385-2394] “[One study noted that] the lack of statistical significance in OS does not imply lack of improvement in OS for clinical trials with a PFS benefit, especially for diseases with long median post-progression survival,” the researchers pointed out. [J Natl Cancer Inst 2009;101:1642-1649]

While OS represents the most practical endpoint for evaluating superiority of an experimental therapy over standard treatment in first-line ovarian cancer, PFS is an acceptable endpoint in this setting, hence the global approval of bevacizumab which exhibited a PFS benefit, noted the researchers. [Gynecol Oncol 2017;147:3-10; Ann Oncol 2017;28:711-717]

Given the failure of pazopanib to display OS benefit in this trial, bevacizumab remains the only approved anti-angiogenic agent in this setting despite the lack of OS improvement. “Ongoing trials are focused on the use of PARPi*** and immune checkpoint inhibitors as maintenance therapy following or in combination with first-line chemotherapy for ovarian cancer,” said the researchers.