乌鸦传媒

CHICAGO -- Progression-free survival almost doubled in women with platinum-sensitive relapsed ovarian cancer treated with two targeted drugs instead of one, a small randomized trial showed.

Patients treated with the two investigational agents olaparib and cediranib had a median PFS of 17.7 months compared with 9.0 months for patients who received only olaparib, according to Joyce Liu, MD, of Dana Farber Cancer Institute in Boston, and colleagues.

The combination outperformed monotherapy in patients with and without BRCA mutations, but the between-group difference was greater in women with BRCA wild-type tumors, for which olaparib alone was substantially less effective, they reported here at the American Society of Clinical Oncology meeting.

"We found that the combination markedly increased progression-free survival," Liu told 乌鸦传媒. "This was highly statistically significant. We feel that the degree of activity of the cediranib/olaparib combination supports additional clinical evaluation in ovarian cancer."

Olaparib is an oral , and cediranib is an oral angiogenesis inhibitor. Each drug has demonstrated single-agent activity in recurrent ovarian cancer. Preclinical studies suggested a potential for synergism with the two drug classes in ovarian cancer, said Liu.

The combined evidence provided a rationale for a randomized, phase II trial to compare olaparib alone versus olaparib plus cediranib. The target patient population had platinum-sensitive ovarian, fallopian tube, or primary peritoneal ovarian cancer that had recurred ≥6 months after the last platinum chemotherapy.

The patients were randomized to olaparib alone or to a lower dose of olaparib in combination with cediranib. Patients were stratified for BRCA mutation status, and the primary endpoint was PFS, as confirmed radiographically.

The primary endpoint was progression-free survival (PFS). Secondary endpoints included response rate, overall survival, and toxicity.

The phase II study included 90 patients. Analysis of the primary endpoint showed almost a 60% reduction in the hazard for progression in the combination arm versus olaparib alone (HR 0.42, 95% CI 0.23-0.76, P=0.005).

The stratified analysis showed that patients with and without BRCA mutations fared better with the combination. However, only the subgroup of patients with BRCA wild-type or unknown tumors derived a statistically significant improvement in PFS: 16.5 versus 5.7 months (P=0.008).

Among patients with BRCA-mutated tumors, olaparib monotherapy led to a median PFS of 16.5 months compared with 19.4 months with the combination. The difference translated into a 45% reduction in the progression hazard, but did not achieve statistical significance (95% CI 0.24-1.27, P=0.16).

No unexpected toxicities occurred, and, in general, the toxicity was acceptable with aggressive management dose reductions, said Liu. The most common treatment-related adverse events were hypertension, diarrhea, and fatigue.

Putting the results into context, Liu said a platinum-taxane doublet is the most common therapy for the types of patients included in the trial. The combinations have been associated with PFS durations of 8 to 13 months.

"This was a small, randomized, phase II study," said Liu. "We really do need to confirm these results. The other thing that is unknown is how this combination compares against standard chemotherapy. The progression-free survival in our study compares quite favorably with what we have seen with standard platinum-based chemotherapy, but we don't know in a direct comparison how this combination would hold up against standard chemotherapy."

The results are encouraging because they suggest that PFS might be improved without the use of cytotoxic chemotherapy, according to a British gynecologic oncologist who has studied both drugs.

"Although this was a small study, I think it's really something that needs to be taken forward and compared against standard chemotherapy because this questions whether chemotherapy is what we should be doing in these patients or whether we should be using molecular targeted therapies," Jonathan Ledermann, BSc MD, of University College London, told 乌鸦传媒.

The results also are noteworthy because they do not eliminate from consideration other potential therapies, said ASCO expert Don Dizon, MD, of Massachusetts General Hospital in Boston.

"Women with platinum-sensitive ovarian cancer are the patients we would most likely consider for surgical re-treatment because we believe that if we are able to resect recurrent disease that is still platinum-sensitive, that will afford an important survival advantage," Dizon said during an ASCO press briefing.

"None of the options are off the table with this nonchemotherapy, oral-based treatment should it prove to be an effective therapeutic option."

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