Maintenance Pazopanib in Ovarian Cancer: No Survival Benefit, High AEs

Mucinous carcinoma of the ovary; source: KGH, Wikimedia Commons

Maintenance therapy with the oral agent pazopanib improved progression free survival (PFS) by a median of 5.6 months in patients with advanced ovarian cancer but did not impact overall survival, according to the results of a phase III randomized trial reported in the Journal of Clinical Oncology.

The international Arbeitsgemeinschaft Gynaekologische Onkologie Studiengruppe Ovarialkarzinom trial 16 (AGO-OVAR 16) trial was sponsored by UK-based GlaxoSmithKline (GSK) which manufactures pazopanib. A total of 940 patients with ovarian, fallopian tube, or peritoneum cancers were randomized 1:1 to receive either 800 mg of pazopanib once daily or placebo for up to 24 months. Patients had stage II through IV disease and had to have not progressed after first-line platinum-based chemotherapy.

Pazopanib is an oral multikinase inhibitor of the vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), and c-Kit.

After a median of 24.3 months of follow-up, the median PFS was 17.9 months in the pazopanib arm and 12.3 months in the placebo arm (hazard ratio [HR] = 0.77; P = .0021). However, an interim survival analysis did not shown any significant difference between the two study arms after events in 36.5% of the study population.

Treatment discontinuation occurred more frequently in the pazopanib arm-33% of patients discontinued treatment compared with 5.6% of patients in the placebo arm. The incidences of grade 3 or 4 adverse events were also higher in the pazopanib arm and included hypertension in 30.8% of the patients, neutropenia (9.9%), liver-related toxicity (9.4%), diarrhea (8.2%), fatigue (2.7%), thrombocytopenia (2.5%), and palmar-plantar erythrodysesthesia (1.9%).

Three patients in the pazopanib arm had a fatal adverse event-a myocardial infarction, pneumonia, and posterior reversible encephalopathy syndrome. One patient in the placebo arm had fatal acute leukemia.

In an exploratory analysis, pazopanib appeared to have superior benefit in the 78% of patients who were not of East Asian descent (HR = 0.69; median PFS benefit, 5.9 months). In contrast, the 22% of patients of East Asian descent had an HR of 1.16.

Lead author Andreas du Bois, MD, PhD, a clinician and researcher in the department of Gynecology and Gynecologic Oncology, Essen, Germany, and colleagues concluded that additional analyses are needed to identify subgroups of patients for whom the improved efficacy balances out the increased toxicity of the maintenance therapy.

The current standard of care for advanced ovarian cancer is debulking surgery followed by platinum-based chemotherapy. Many patients respond to treatment but most relapse within a median of about 16 months, and the majority die of their advanced disease. Prior studies, including two testing the efficacy of bevacizumab plus chemotherapy as a maintenance therapy, showed angiogenesis plays a key role in spurring further ovarian cancer growth. Smaller studies with pazopanib have shown single=agent activity in the setting of recurrent ovarian cancer.

However, in an editorial accompanying the study, Kate E. Oliver, MD, of Walter Reed National Military Medical Center in Bethesda, Maryland, and William P. McGuire, MD, of Inova Fairfax Hospital, Annandale in Virginia, highlighted the relatively high discontinuation rate of patients in the pazopanib arm and its unfavorable benefit-to-risk profile. Noting that owing to previous study results, GSK had withdrawn its application in the European Union for approval of pazopanib as a maintenance therapy for ovarian cancer, they wrote, “Despite the positive PFS results reported by this [trial] and other phase III trials in [ovarian cancer], development of pazopanib in the maintenance setting will undoubtedly falter.”

In their editorial, they warned that the increased toxicity observed with pazopanib and other anti-angiogenic agents as well as the possibility that these treatments may not benefit a subset of patients “should raise caution regarding the [indiscriminate] use of surrogate end points such as PFS for drug approval.” They further commented that “[p]erhaps the putative gold standard of OS, especially when combined with QOL metrics, should be embraced once again.”