For many women with ovarian cancer that has returned after initial treatment, a two-drug combination can significantly extend the time that the disease is kept in check, according to a phase 2 clinical trial led by investigators at the Susan F. Smith Center for Women’s Cancers at Dana-Farber.
As reported in Lancet Oncology, researchers compared the drugs cediranib and olaparib, versus olaparib alone, in their ability to stall the advance of ovarian cancer in women with a recurrent form of the disease that responds to platinum-based chemotherapy agents. The investigators found that the median period before the disease began to worsen – known as progression-free survival (or PFS) – was nearly 18 months for women receiving the combined therapy, versus nine months for those receiving olaparib alone.
The results were even more striking in two subsets of study participants. In women whose ovarian tumors lacked mutations in the genes BRCA1 or BRCA2, the median PFS for those treated with the combination therapy was 16.5 months, vs. 5.7 months for those treated with olaparib only. In women whose tumors did carry BRCA mutations, the median PFS for the combined-therapy group was 19.4 months, vs. 16.5 for the olaparib-alone group.
The study enrolled 90 patients with platinum-sensitive, recurrent ovarian cancer. Half were randomly assigned to receive cediranib and olaparib (both in pill form), and half received olaparib alone.
Severe side effects to treatment, though relatively rare, were more common in the cediranib-and-olaparib group, with fatigue, diarrhea, and hypertension being the most frequent problems.
Cediranib and olaparib attack two markedly different vulnerabilities in cancer cells. Cediranib is an angiogenesis inhibitor that prevents tumors from forming new blood vessels. Olaparib is a poly(ADP-ribose) polymerase – or PARP – inhibitor that hampers cancer cells’ ability to repair damaged DNA, potentially sending them into a death spiral. Both drugs, used as single agents, had been shown to be active in women with recurrent ovarian cancers, and, as a pair, were found to be active and tolerable to patients in a phase 1 trial.
The study authors say it isn’t entirely surprising that the drug duo performed better in women whose tumors don’t carry BRCA mutations. The BRCA genes are involved in repairing DNA damage. When BRCA is hamstrung because of a mutation, a cancer cell is particularly vulnerable; when a second repair pathway is shut down with olaparib, that vulnerability can become fatal to the cell. This explains why olaparib has had promising results in patients with tumors with BRCA mutations – and why the addition of cediranib didn’t provide much further benefit.
In ovarian tumors without BRCA mutations, by contrast, a separate dynamic appears to be at work. Denying tumors sufficent blood with an angiogenesis inhibitor like cediranib reduces the amount of oxygen available to the cells, creating a condition known as hypoxia. With less oxygen, they may be more susceptible to the DNA-repair blocker olaparib. Hence, the combination of drugs is better than olaparib alone, the authors write.
“Ovarian cancer is the leading cause of death from gynecologic malignancy in the United States,” notes Ursula Matulonis, MD, medical director of Gynecologic Oncology at the Susan F. Smith Center for Women’s Cancers, who led the study with Joyce Liu, MD. “Although many patients benefit from initial treatment, most eventually will relapse. That has spurred a search for therapies that can be effective after resistance to initial therapies develops.
“In this study, we saw a remarkable improvement in progression-free survival with combination cediranib and olaparib in this group of patients,” she continues. “This approach merits further study as an alternative to conventional chemotherapy for this disease.”
Two, large-scale phase 3 clinical trials comparing the combination therapy to other drug regimens are slated to begin enrolling patients early next year, both supported by the National Cancer Institute.