News
CHICAGO – The PARP inhibitor olaparib plus the antiangiogenic cediranib nearly doubled progression-free survival in women with recurrent, platinum-sensitive ovarian cancer in a phase II study.
Median progression-free survival (PFS) was 17.7 months with the combination, compared with 9 months for olaparib alone (hazard ratio, 0.42; P = .005).
Dr. Joyce F. Liu
Olaparib plus cediranib also significantly increased the overall response rate from 48% to 80% (P = .002), Dr. Joyce F. Liu reported at the annual meeting of the American Society of Clinical Oncology.
This included 5 complete responses and 30 partial responses in the 44 women assigned combination therapy, versus 2 complete and 20 partial responses in the 46 treated with olaparib alone.
"One very exciting possibility about this combination is that it can offer an alternative to standard chemotherapy for women in this setting," she said in an interview. "It offers us more options."
Typically, these patients will receive platinum-based doublets containing carboplatin plus paclitaxel or pegylated liposomal doxorubicin, or gemcitabine, resulting in a median PFS of 8-13 months in phase III studies, said Dr. Liu of Dana-Farber Cancer Institute, Boston, during a press briefing.
Women with platinum-sensitive ovarian cancer are also the patients most likely to be considered for surgical debulking, commented Dr. Don Dizon, director of the Oncology Sexual Health Clinic at Massachusetts General Hospital Cancer Center, Boston. For these women, targeted agents like olaparib and cediranib may provide an alternative if the drugs are able to reset the disease.
Preclinical data have suggested a synergy between PARP (poly-ADP-ribose polymerase) inhibitors and antiangiogenics, and Dr. Liu previously reported phase I data showing an overall response rate of 44% with olaparib plus cediranib in recurrent ovarian cancer (Eur. J. Cancer 2013;49;2972-8).
Study details
The open-label, phase II study randomly assigned 90 women (median age, 58 years) with recurrent, platinum-sensitive ovarian, fallopian tube, or primary peritoneal cancer to olaparib 400 mg twice daily or cediranib 30 mg daily plus olaparib 200 mg twice daily, all until disease progression by RECIST criteria.
All patients had high-grade serous or endometrioid histology or other high-grade histological subtypes, if a germ-line BRCA mutation was documented.
There was a slight trend for patients treated with olaparib alone to have higher baseline CA125 levels than patients treated with the combination (115.3 vs. 68 U/mL) and to have received more prior lines of therapy (two lines: 39% vs. 22.7%; 3 or more lines: 24% vs. 18.2%), Dr. Liu observed.
Randomization was stratified by BRCA status, with 52% of participants being BRCA carriers.
Several PARP inhibitors, including the highly potent BMN 673, have shown promising activity in the treatment of breast and ovarian cancers that have BRCA1 or BRCA2 mutations.
The influence of BRCA
A post hoc analysis revealed a trend toward prolonged PFS with olaparib plus cediranib in BRCA mutation carriers (19.4 vs. 16.5 months; HR, 0.55; P = .16).
Surprisingly, the difference was more marked and statistically significant, however, in women without a BRCA mutation or unknown mutation status (16.5 vs. 5.7 months; HR, 0.32; P = .008), Dr. Liu reported.
The finding was "unexpected," but it should be kept in mind that this was a post hoc analysis of a phase II trial and that the finding needs to be confirmed, she told reporters.
When asked whether olaparib plus cediranib is superior to cediranib alone, Dr. Liu said the current findings of a 17.7-month PFS would at least suggest that the combination is more active than cediranib monotherapy, which has demonstrated a 5.2-month PFS in recurrent platinum-sensitive or platinum-resistant disease.
Adverse events
Treatment with olaparib plus cediranib increased the rate of adverse events, but overall the toxicity profile was acceptable, she said. The most common grade 3/4 toxicities with combination therapy versus olaparib alone were hypertension (17 grade 3 and 1 grade 4 events vs. 0), diarrhea (10 grade 3 events vs. 0), and fatigue (12 vs. 5 grade 3 events).
Toxicities were generally manageable with aggressive symptom management and dose holds or reductions, the latter required in 77% of olaparib/cediranib patients versus 24% olaparib-alone patients.
Four patients, all in the combination arm, went off treatment for toxicity: 1 myelodysplastic syndrome, 1 weight loss, 1 avascular necrosis in the setting of preexisting avascular necrosis, and 1 vaginal fistula formation.
"The degree of activity observed with this combination supports additional clinical evaluation of cediranib and olaparib together in ovarian cancer," Dr. Liu concluded.
The study was supported by the National Cancer Institute. Dr. Liu and her coauthors reported no relevant financial disclosures.