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Paclitaxel With and Without Pazopanib for Persistent or Recurrent Ovarian Cancer: A Randomized Clinical Trial
Debra L Richardson1, Michael W Sill2, Robert L Coleman3
1Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas.
Importance:
Ovarian cancer is the leading cause of gynecologic cancer deaths in the United States. Pazopanib is an oral, multitarget kinase inhibitor of vascular endothelial growth factor receptors 1, 2, and 3; platelet-derived growth factor receptors α and β; and proto-oncogene receptor tyrosine kinase (c-KIT).
Objective:
To estimate the progression-free survival (PFS) hazard ratio (HR) of weekly paclitaxel and pazopanib compared with weekly paclitaxel and placebo in women with recurrent ovarian cancer. Secondary objectives included frequency and severity of adverse events, proportion responding, and overall survival (OS) in each arm. Translational research objectives included exploring the association between possible biomarkers and single-nucleotide polymorphisms in vascular endothelial growth factor A, interleukin 8, and hypoxia-inducible factor 1α; and PFS, OS, and proportion responding.
Design, Setting, And Participants:
A randomized, placebo-controlled, double-blind phase 2 study was conducted at 26 participating institutions. Patients were enrolled between December 12, 2011, and April 22, 2013. Data were frozen on August 11, 2014. Participants were patients with persistent or recurrent epithelial ovarian, fallopian tube, or primary peritoneal carcinoma with 1 to 3 prior regimens and performance status of 0 to 2. One hundred six patients enrolled; 100 were evaluable for toxic effects.
Interventions:
All patients received paclitaxel 80 mg/m2 intravenously on days 1, 8, and 15 every 28 days and were randomized 1:1 to pazopanib 800 mg orally daily or placebo.
Main Outcomes And Measures:
The primary end point was PFS. The study was designed to detect a 37.5% reduction in the hazard with 80% power (α = 10%).
Results:
A total of 106 women (median age [range], 61 [35-87] years; 88 [83%] white) were enrolled. Study arms were well balanced for age, performance status, measurable disease, and prior bevacizumab. Proportion responding was 14 of 44 (31.8%) vs 10 of 44 (22.7%) for pazopanib plus paclitaxel vs paclitaxel alone. Median PFS was 7.5 vs 6.2 months for pazopanib plus paclitaxel vs paclitaxel alone, respectively (HR, 0.84; 90% CI, 0.57-1.22; P = .20). Median OS was 20.7 vs 23.3 months for pazopanib plus paclitaxel vs paclitaxel alone (HR, 1.04; 90% CI, 0.60-1.79; P = .90). Severe hypertension was more common on the pazopanib plus paclitaxel arm (relative risk, 12.0; 95% CI, 1.62-88.84). More patients discontinued treatment on the paclitaxel arm for disease progression (34 of 52 [65.4%] vs 17 of 54 [31.5%]), and more on the pazopanib plus paclitaxel arm for adverse events (20 of 54 [37%] vs 5 of 52 [9.6%]). No association was found between single-nucleotide polymorphisms (interleukin 8 and hypoxia-inducible factor 1α) and OS and proportion responding. Patients with VEGFA CC genotype may be more resistant to weekly paclitaxel than those with the AC or AA genotype, with 1 of 14 (7%), 3 of 15 (20%), and 4 of 8 (50%) responding, respectively.
Conclusions And Relevance:
The combination of pazopanib plus paclitaxel is not superior to paclitaxel in women with recurrent ovarian cancer.
Trial Registration:
clinicaltrials.gov Identifier: NCT01468909.
Insights
Pazopanib combined with paclitaxel did not improve progression-free survival in recurrent ovarian cancer patients. This combination therapy showed no significant benefit over paclitaxel alone, despite increased adverse events.
Area of Science:
- Gynecologic Oncology
- Medical Oncology
- Pharmacology
Background:
- Ovarian cancer is a leading cause of gynecologic cancer mortality in the U.S.
- Pazopanib is an oral multitarget kinase inhibitor targeting VEGFR, PDGFR, and c-KIT.
- Recurrent ovarian cancer presents a significant clinical challenge.
Purpose of the Study:
- To evaluate the efficacy of pazopanib plus paclitaxel versus paclitaxel alone in patients with recurrent ovarian cancer.
- To compare progression-free survival (PFS) as the primary endpoint.
- To assess secondary endpoints including adverse events, response rate, and overall survival (OS).
Main Methods:
- A randomized, placebo-controlled, double-blind, phase 2 study.
- 106 patients with persistent or recurrent epithelial ovarian, fallopian tube, or primary peritoneal carcinoma were enrolled.
- Patients received weekly paclitaxel with either pazopanib or placebo.
Main Results:
- Median PFS was 7.5 months for pazopanib plus paclitaxel vs. 6.2 months for paclitaxel alone (HR, 0.84; P=.20).
- Median OS was 20.7 months vs. 23.3 months, respectively (HR, 1.04; P=.90).
- Severe hypertension was more frequent with pazopanib; more patients discontinued pazopanib due to adverse events.
Conclusions:
- The combination of pazopanib and paclitaxel is not superior to paclitaxel alone for recurrent ovarian cancer.
- The observed toxicity profile warrants careful consideration of this combination therapy.
- Further research into predictive biomarkers, such as VEGFA genotypes, may inform treatment strategies.
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