Michael J. Birrer, MD, PhD
Despite a decrease in the diagnosis of ovarian cancer and in the number of deaths due to the malignancy in the United States over the past 25 years, the disease remains a silent killer that is responsible for approximately 14,000 deaths every year.1
The 5-year survival rate stands at about 46.2%, significantly lower than the 90% rate for breast cancer, the 80% for endometrial cancer, and the nearly 70% for cervical cancer.1,2
Yet researchers and clinicians are optimistic these days that they are closer than ever to more effective therapies for this disease. “It’s actually a very exciting time,” said Michael J. Birrer, MD, PhD, in an interview with OncologyLive. He said there was “a very discouraging period of time, from the late 1990s all the way up until 2000 to 2010, with just carbotaxol [for treatment]," referring to the chemotherapy combination of carboplatin and paclitaxel.
“There wasn’t a lot of progress, particularly as we saw progress with other tumors.” But Birrer, a professor of Medicine at Harvard Medical School and director of the Gillette Center for Gynecologic Oncology at Massachusetts General Hospital, said there are many clinical trials in progress now.
He said that the 2 most noteworthy developments in ovarian cancer treatment at this time involve poly(ADP-ribose) polymerases (PARP) inhibitors and antiangiogenesis therapies. Another promising approach is the development of drugs that target the folate receptor.
Both PARP inhibitors and antiangiogenic drugs could form some potent combinations in the future, said Mansoor Raza Mirza, MD, a key researcher in the PARP inhibitor field who is chief oncologist at Righospitalet in Copenhagen, Denmark.
“I hope that now we will have PARP inhibitors, some combinations of PARP inhibitors with other drugs, like antiangiogenic drugs. We’re already doing trials with that,” Mirza said. “We’re really in a very interesting era, and we’re seeing some major gains for our patients.”
PARP Inhibitors Reshaping the Field
A flurry of research findings in recent weeks shows how vital PARP inhibitors as an emerging class of agents have become to the development of new treatments for patients with ovarian cancer. The field has blossomed with 1 approved drug and at least 4 other agents undergoing clinical trials.
These drugs take advantage of cellular DNA damage caused by BRCA1
mutations, blocking PARP enzymes that cancer cells need to repair the damage.2 They can be used as monotherapy in patients with known mutations in DNA repair proteins or as combination therapy with DNA-damaging chemotherapeutic agents or radiotherapy.
) mutations are believed to be present in 10% to 20% of high-grade ovarian cancers, while somatic alterations in BRCA1/2
and DNA repair defects are evident in an estimated 50% of high-grade tumors, according to the My Cancer Genome database.
The FDA approved the PARP inhibitor olaparib (Lynparza) in 2014 as monotherapy in patients with advanced ovarian cancer with deleterious gBRCA
mutations after 3 or more prior lines of chemotherapy. The approval was based on the phase II Study 19, which demonstrated that women taking the drug experienced partial shrinkage or complete disappearance of the tumor, with 34% of participants experiencing an objective response rate on average of 7.9 months.3
A subsequent analysis of that data showed that in patients with platinum-sensitive relapsed serous ovarian cancer, olaparib increased overall survival (OS) when given as maintenance therapy, with the greatest OS advantage in women who had a BRCA
mutation (HR, 0.62).4
However, the P values were nominal and did not meet the criterion for statistical significance (P
In late October, AstraZeneca reported that single-agent olaparib significantly improved progression-free survival (PFS) compared with placebo in the maintenance setting for patients with advanced BRCA
-positive ovarian cancer in the phase III SOLO-2 trial.5 Although specific data from the trial are not yet available, Astra- Zeneca said that the median PFS with olaparib was significantly higher than the median 8.4-month PFS reported in the olaparib arm of phase II Study 19 in a similar population.5
Niraparib, another PARP inhibitor, also is showing promise as maintenance therapy, demonstrating significantly improved PFS compared with placebo among patients with platinum-sensitive recurrent ovarian cancer regardless of BRCA