A trio of randomized, controlled trials of different molecularly targeted therapies showed variable results in ovarian cancer, as reported at the 2012 ASCO Annual Meeting in Chicago. The phase III AURELIA trial demonstrated that the addition of the vascular endothelial growth factor (VEGF) inhibitor bevacizumab (Avastin) to chemotherapy achieved a doubling of progression-free survival in patients with difficult-to-treat platinum-resistant ovarian cancer. This is the first randomized trial to show a progression-free survival benefit in platinum-resistant patients.
A second trial, investigating the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib plus paclitaxel and carboplatin chemotherapy followed by olaparib maintenance therapy, showed a significant 2.6-month improvement in progression-free survival vs chemotherapy alone in platinum-sensitive ovarian cancer. A third trial, studying the endothelial growth factor receptor (EGFR) inhibitor erlotinib (Tarceva), showed no benefit in progression-free survival in the first-line setting when given as maintenance therapy immediately following six to nine courses of platinum-containing chemotherapy in high-risk patients.
Shifting Focus Advocated
The presenters of the AURELIA and olaparib trials were enthusiastic about improved progression-free survival in their respective studies of platinum-resistant and platinum-sensitive disease. However, the formal discussant of these trials, Michael Seiden, MD, of Fox Chase Cancer Center, Philadelphia, suggested that the strategy of pursuing molecularly targeted therapy for ovarian cancer may be misguided and is likely not to improve overall survival. To move the field forward, Dr. Seiden suggested that research efforts should focus on genomic instability in ovarian cancer and therapies that target oncogenes (see sidebar).
The randomized, phase III AURELIA trial found that treatment with standard chemotherapy plus bevacizumab doubled progression-free survival over standard chemotherapy alone in patients with platinum-resistant ovarian cancer from a median of 3.4 months to 6.7 months (P < .001). This is the best progression-free survival observed in this group of patients thus far, and the benefit was seen in all subgroups .
“These are exciting results,” said Eric Pujade-Lauraine, MD, PhD, of Groupe D’Investigateurs Nationaux Pour l’Etude des Cancer Ovariens (GINECO) and the Université Paris Descartes, France. “Next year, we will report survival results. My personal opinion is that … bevacizumab plus chemotherapy should be considered a new standard of care for these patients.”
Platinum-resistant ovarian cancer represents an unmet need. About 25% of patients will not respond to first-line therapy, and almost all patients with recurrent ovarian cancer will ultimately develop resistance. Previous combinations have failed to improve survival, and prior to this study, median overall survival was less than 1 year.
Patients enrolled in the trial could have up to to two prior lines of treatment. Chemotherapy was selected by the investigator and included weekly paclitaxel, topotecan, or pegylated doxorubicin. Patients were randomized to chemotherapy plus bevacizumab (n = 179) vs chemotherapy alone (n = 182). Those whose disease progressed on chemotherapy alone could cross over to the bevacizumab-containing arm. Median follow-up was 13 months in the bevacizumab arm and 13.9 months in the chemotherapy arm.
Bevacizumab was tolerable, with no unexpected side effects, and did not appear to potentiate the toxicity of chemotherapy, Dr. Pujade-Lauraine said.
In the bevacizumab arm, a trend was observed toward a decrease in disease-related adverse events, but the incidence of grade 3 or higher peripheral neuropathy was greater. Dr. Pujade-Lauraine attributed this to higher exposure to chemotherapy in that arm, because more patients were responding and thus continued to be treated, whereas more progression occurred in the chemotherapy-alone arm, and those patients were taken off treatment.
An international, randomized phase II trial found that olaparib maintenance therapy after four to six cycles of olaparib plus concurrent paclitaxel and carboplatin chemotherapy significantly increased progression-free survival by a median of 2.6 months vs no further therapy in patients with recurrent platinum-sensitive serous ovarian cancer (P = .0012). All subgroups appeared to benefit from olaparib maintenance therapy.
“The study is still being followed for survival data, and we have an active biomarker program,” said lead author Amit Oza, MD, of Princess Margaret Hospital, Toronto.
The study enrolled 152 women who had received up to 3 previous platinum-containing regimens. At baseline, groups were well balanced for demographic and disease characteristics. Progression-free survival curves began to diverge at 6 months. No separation of curves was seen during the concurrent portion of treatment.
The concurrent-plus-maintenance olaparib regimen was well tolerated and deliverable, Dr. Oza said. In the maintenance phase, grade 3 or higher adverse events were reported in 28.8% of the olaparib group vs 16.4% of those with no further therapy.
The next steps will be to determine the optimal patient population for olaparib maintenance therapy and to define an acceptable tablet dose and schedule for long-term treatment to enable the next generation of clinical studies.
The erlotinib trial recruited 835 patients with high-risk stage I or stage II–IV ovarian cancer who began treatment with erlotinib or observation after first-line platinum-containing therapy. Median follow-up was 51 months. At baseline, the two groups had similar demographic and disease characteristics. Median progression-free survival was 12.7 months in the erlotinib group vs 12.4 months in the observation arm. Overall survival was a median of 51 vs 59 months, respectively. No difference in outcome was observed for stage and response to first-line therapy. Quality-of-life data will be analyzed, as will potential biomarkers using fluorescence in situ hybridization and immunohistochemistry.
Toxicity associated with erlotinib was expected, mainly grade 1 or 2 diarrhea and grade 1–3 rash. About 25% of patients stopped erlotinib due to rash. No relationship between the emergence of rash and progression-free survival was observed.
“Maintenance erlotinib did not increase progression-free or overall survival,” stated presenting author Ignace B. Vergote, MD, of University Hospital Leuven and KU Leuven, Belgium. “At this moment, we cannot identify a subgroup of patients that might benefit from maintenance erlotinib.” ■
Disclosure: Dr. Pujade-Lauraine disclosed advisory board and symposia honoraria from Roche. Drs. Oza and Vergote reported no potential conflicts of interest.
1. Pujade-Lauraine E, Hilpert F, Weber B, et al: AURELIA: A randomized phase III trial evaluating bevacizumab plus chemotherapy for platinum-resistant recurrent ovarian cancer. 2012 ASCO Annual Meeting. Abstract LBA5002. Presented June 2, 2012.
2. Oza AM, Cibula D, Oaknin A, et al: Olaparib plus paclitaxel plus carboplatin followed by olaparib maintenance treatment in patients with platinum-sensitive recurrent serious ovarian cancer. 2012 ASCO Annual Meeting. Abstract 5001. Presented June 2, 2012.
3. Vergote IB, Joly F, Katsaros D, et al: Randomized phase III study of erlotinib versus observation in patients with no evidence of disease progression after first-line platin-based therapy for ovarian carcinoma. 2012 ASCO Annual Meeting. Abstract LBA5000. Presented June 2, 2012.
“We are approaching the 15th year of exploring molecularly targeted therapies in ovarian cancer,” said Michael Seiden, MD, of Fox Chase Cancer Center, Philadelphia, and formal discussant of the papers presented during an oral abstract session on gynecologic cancer at the 2012 ASCO Annual Meeting.