In a report on the trial in the online edition of The 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 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 to receive olaparib alone. 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 when researchers compared two subsets of the 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.
Severe side effects to treatment, though relatively rare, were more common in the cediranib-and-olaparib group, with fatigue, diarrhea, and hypertension the most frequent problems.
“Ovarian cancer is the leading cause of death from gynecologic malignancy in the United States,” noted the study’s senior author, Ursula Matulonis, MD, medical director of Gynecologic Oncology at the Susan F. Smith Center for Women’s Cancers at Dana-Farber. “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 continued. “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, and both will be supported by the National Cancer Institute and run through the NRG Oncology cooperative group. One, led by Matulonis and Dana-Farber colleague Joyce Liu, MD, MPH, the lead author of the current study, will compare cediranib and olaparib to chemotherapy in women with platinum-sensitive ovarian cancer. The other will compare olaparib alone, olaparib and cediranib, and chemotherapy in patients with platinum-resistant ovarian cancer.
Cediranib and olaparib attack two markedly different vulnerabilities in cancer cells. Cediranib is an angiogenesis inhibitor that prevents tumors from forming new blood vessels that help them grow and spread. 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 clinical trial.
The study authors said it is not entirely surprising that the drug duo performed better in women whose tumors do not carry BRCA mutations than in women whose tumors do. 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 did not provide much further benefit in the current study.
In ovarian tumors without BRCA mutations, by contrast, a separate dynamic appears to be at work. Denying tumors sufficient 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, the authors wrote, and hence the combination of drugs is better than olaparib alone, the authors wrote.
Co-authors of the study are William Barry, PhD, Weixiu Luo, MS, Philippa Quy, Christin Whalen, RN, Lisa Obermayer, and Eric Winer, MD, of Dana-Farber; Michael Birrer, MD, and Hang Lee, PhD, of Massachusetts General Hospital; Jung-Min Lee, MD, Elise Kohn, MD, and S. Percy Ivy, MD, of the National Cancer Institute; Ronald Buckanovich, MD, of the University of Michigan; Gini Fleming, MD, of the University of Chicago; BJ Rimel, MD, of Cedars-Sinai Medical Center, Los Angeles; Mary Buss, MD, of Beth Israel Deaconess Medical Center; Sreenivasa Nattam, MD, of Fort Wayne Medical Oncology and Hematology; and Jean Hurteau, MD, of North Shore University HealthSystem, Evanston, Ill.
This study was funded in part by the Cancer Therapy Evolution Program of the National Cancer Institute and supported by an American Recovery and Reinvestment Act (ARRA) grant through the US National Institutes of Health (3 U01 CA062490-16S2).