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Drug combination highly active in recurrent ovarian cancer
CHICAGO — The addition of the anti-angiogenesis drug cediranib to the PARP inhibitor olaparib significantly extended PFS in patients with platinum-sensitive, high-grade serous or BRCA-related recurrent ovarian cancer, according to results of a phase 2 study presented at the ASCO Annual Meeting.
“This study demonstrated that the combination of these two oral biologically-targeted therapies can combine to have significant activity in recurrent ovarian cancer that compares favorably with that seen with standard-of-care traditional chemotherapies,” researcher Joyce Liu, MD, MPH, an instructor in medicine at Dana-Farber Cancer Institute, told HemOnc Today. “We need to further explore this combination in phase 3 trials and if this degree of activity is validated, this could provide an alternative to chemotherapy for women in this setting.”
Liu and colleagues randomly assigned patients to one of the two study arms. Forty-four patients received 30 mg daily cediranib (AZD2171, Recentin; AstraZeneca) plus 200 mg olaparib (AZD2281, AstraZeneca) twice daily. An additional 46 patients received 400 mg olaparib alone twice daily.
Forty-seven patients, including 23 assigned the combination and 24 assigned olaparib alone, were known BRCA carriers.
Forty-seven patients had a PFS event at the time of the presented analysis.
Patients assigned to the combination regimen demonstrated significantly longer median PFS (17.7 months vs. 9 months). Researchers calculated an HR of 0.42 (95% CI, 0.23-0.76) in favor of the combination.
More patients assigned the combination demonstrated tumor shrinkage (80% vs. 48%).
Liu and colleagues also evaluated the combination’s efficacy according to BRCA mutation status.
Among BRCA mutation carriers, researchers observed a trend toward improved PFS among those who received the combination regimen (19.4 months vs. 16.5 months; HR=0.55; 95% CI, 0.24-1.27). Patients with wild-type BRCA, or whose BRCA status was unknown, demonstrated a marked improvement with the combination (16.5 months vs. 5.7 months; HR=0.32; 95% CI, 0.14-0.74).
“Prior studies have suggested that women with BRCA mutations may have increased sensitivity to PARP inhibitors,” Liu said. “In terms of the activity of the combination, it still seems slightly more active in the BRCA mutation carriers. What was unexpected to a certain degree, keeping in mind this was a post-hoc subset analysis of a phase 2 trial, was that the degree of difference between the arms was in the BRCA non-carriers/status unknown population.”
Incidence of grade 3 or grade 4 adverse events was higher in the combination arm (70% vs. 13%), as were rates of fatigue (27% vs. 11%), diarrhea (23% vs. 0%) and hypertension (41% vs. 0%).
“The significant activity that we saw with the combination suggests that this could potentially be an effective alternative to standard chemotherapy,” Liu said in a press release. “At the same time, this approach is not yet ready for clinical practice, as neither of these drugs is currently FDA approved for ovarian or any other cancer. We also need additional clinical trials to confirm the findings of this study and to assess how this combination compares to standard treatment.”
For more information:
Liu J. Abstract #LBA5500. Presented at: ASCO Annual Meeting; May 30-June 3, 2014; Chicago.
Disclosure: The study was funded by the NCI. The researchers report no relevant financial disclosures.
Perspective
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The combination of cediranib plus olaparib resulted in a significantly higher response rate, though at the expense of higher toxicity. Whether this response translates into gains in survival needs further follow-up. However, this combination represents an oral, non-chemotherapy–based combination treatment option for women with high-grade serous or BRCA-mutation–related ovarian cancers and definitely warrants further study.
Women with platinum-sensitive ovarian cancer are the patients for whom we would also most likely consider surgical debulking … There has not been a prospective randomized trial, but we believe that if we are able to resect the current disease that is considered platinum-sensitive, that will afford a survival advantage. What is import about this study is that none of these options are off the table with this this non-chemotherapy orally based treatment, should it prove to be an effective line of therapy.
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I am really impressed with this study. I was definitely very surprised at the results — not that I didn’t think it could potentially be positive, but the degree of effect was extremely impressive. Even with the lower dosing of olaparib in the combination arm, and even with 70% of patients having to undergo dose reductions, researchers still saw a survival benefit.
The biggest improvements of combination treatment over single-agent treatment were in those who were BRCA mutation negative, and they are a substantial portion of our patients. That is exciting and adds to the argument that we should not be limiting PARP inhibitors to only BRCA1- or BRCA2-positive patients.
There is a big push to move away from standard chemotherapy and identify less toxic therapies that still prolong life. Even with immunotherapy, we know some patients have a better response than others, so now the challenge is to figure out who those patients are. In the next 5 or 10 years, I really feel we’ll be able to be much more predictive of who will respond to which therapy, and we will move away from saying, "You have this diagnosis; therefore, you get this treatment." We will be able to individualize therapies to better match the prognostic characteristics unique to patients within broad disease sites. This offers a tremendous amount of hope for our patients.
Perspective
Back to TopThis new combination demonstrates how combining active targeted therapies can build on the progress we’re making in treating these difficult cancers. This study [and others] demonstrate how our cumulative understanding of cancer biology through basic science research, as well as understanding of the treatment effectiveness through clinical research, can help to link these successive steps of progress in cancer care that ASCO has helped contribute to over the last 50 years.