Targeted Therapy Combination Improves PFS in Ovarian Cancer

Joyce F. Liu, MD, MPH

Combining the oral targeted agents olaparib and cediranib resulted in a near-doubling of median progression-free survival (PFS) among women with recurrent ovarian cancer in a phase II study highlighted Saturday during the 2014 American Society of Clinical Oncology (ASCO) Annual Meeting.

The median PFS, the primary endpoint of the trial, was 17.7 months among patients treated with the combination, compared with 9 months for olaparib alone.

“The significant activity that we saw with the combination suggests that this could potentially be an effective alternative to standard chemotherapy,” lead investigator Joyce F. Liu, MD, MPH, an instructor in Medical Oncology at the Dana-Farber Cancer Institute in Boston, Massachusetts, said in a statement.

During a press briefing, Liu said researchers are exploring designs for a phase III trial involving the two agents, which are both investigational.

The two drugs have different mechanisms of action and the phase II study was the first to explore agents with these targets in combination in ovarian cancer, Liu said.

Olaparib is a small-molecule inhibitor of poly(ADP-ribose) polymerase (PARP) enzymes, which are active in repairing DNA damage, and has shown particular promise in tumors that harbor mutations in BRCA genes, whose proteins also play a role in DNA repair. Cediranib targets angiogenesis by inhibiting vascular endothelial growth factor receptor signaling.

Key Results Detailed

Liu, who received a Conquer Cancer Foundation of ASCO Young Investigator Award in 2008, said the combination regimen was pursued after preclinical studies “suggested that PARP inhibitors and antiangiogenic agents may work synergistically in ovarian cancer.”The study accrued 90 women with platinum-sensitive relapsed ovarian, fallopian tube, or primary peritoneal cancer whose disease had recurred at least 6 months after the last platinum chemotherapy treatment. The criteria specified high-grade serous or endometrioid histological subtype, although other high-grade subtypes were permitted if there was a known germline BRCA mutation.

The participants were randomized 1:1 to receive either olaparib (200 mg twice daily) plus cediranib (30 mg daily), or olaparib alone (400 mg twice daily).

Liu said the PFS advantage for the combination regimen was “highly statistically significant,” with a hazard ratio of 0.42 (95% CI, 0.23-0.76) and a P value of .005.

The combination appears to have “slightly more activity” among patients who carry a BRCA mutation, said Liu. In all, 48 patients were known BRCA mutation carriers, including 23 people in the combination arm and 25 patients in the olaparib-alone group, according to the abstract.

For those with the mutation, the median PFS was 19.4 months in the combination arm versus 16.5 months in the olaparib-alone arm (HR = 0.55, P = 0.16). For those without a mutation or whose BRCA status was unknown, the median PFS was 16.5 months with the combination therapy versus 5.7 months with olaparib alone (HR = 0.32, P = .008).

Liu said the activity among patients without a known mutation “was a little bit unexpected, but that needs to be confirmed with further analysis.”

In terms of toxicities, the combination of the two agents resulted in a dramatic increase in adverse events (AEs) of grade 3/4 severity, with an overall rate of 70% in the dual therapy arm compared with 7% for olaparib alone, according to the abstract. AEs that occurred at different rates in the combination-therapy versus olaparib-alone arms, respectively, included fatigue (27% vs 7%), diarrhea (23% vs 0%), and hypertension (39% vs 0%).

Comparing Regimens

Liu characterized the regimen as tolerable “with aggressive symptom management” and dose adjustments.In summary, Liu said the clinical activity with the novel combination “compares favorably to standard-of-care chemotherapy.” Patients with platinum-sensitive ovarian cancer are typically treated with platinum-based chemotherapy doublets that have demonstrated median PFS rates of between approximately 8 months and 13 months in phase III studies, said Liu.

Patients in this setting most likely would be candidates for surgical debulking or surgical retreatment if disease recurs, noted Don S. Dizon, MD, the director of the Oncology Sexual Health Clinic at Massachusetts General Hospital in Boston, who participated in the briefing as an ASCO expert. He said it is important to realize that “none of these options are off the table with this nonchemotherapy-based treatment should it prove to be an effective line of therapy.”

In response to a question about the cost-effectiveness of dual targeted therapy, Liu said she could not comment on that aspect of two agents that the FDA has not yet approved. She noted, however, that several facets of that equation would have to be weighed as developments unfold.

“As we go forward in studying this combination, it makes it very important to look at what the costs are in terms of tolerability for patients, how it compares against chemotherapy, patient preference, and, of course, the monetary cost and what it’s cost effectiveness is,” said Liu.

Liu J, Barry WT, Birrer MJ, et al. A randomized phase 2 trial comparing efficacy of the combination of the PARP inhibitor olaparib and the antiangiogenic cediranib against olaparib alone in recurrent platinum-sensitive ovarian cancer. J Clin Oncol. 2014;32: 5s. (suppl; abstr LBA5500).

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