Nationwide Ovarian Cancer Clinical Trial Shows Promise
When IBM IT architect Laura Elzie, 60, was first diagnosed with ovarian cancer three years ago by her long-time primary care physician she was momentarily stunned when she heard, “Some of us never know how we are going to leave this world, but at least you know.” For months she’d been told her pain, a symptom caused by constipation, was treatable. It wasn’t until she complained and asked for a sonogram that the truth came to light.
Elzie’s doctor referred her to oncologists at Duke Cancer Institute and UNC Lineberger Cancer Center. She even got a third opinion from the University of Texas MD Anderson Cancer Center in Houston. Upon choosing Duke gynecologic oncologist Angeles Secord, MD, Elzie was scheduled for surgery, followed by chemotherapy.
Cleared after six months, this mother-of-four and grandmother-of-nine went back to work—commuting weekly between North Carolina and Texas. She remained in remission for eight months before her cancer recurred.
Then, following additional surgery and chemotherapy, Elzie had the opportunity to enter the NOVA clinical trial at Duke: a Phase 3, randomized, double-blind, placebo-controlled study of the investigational drug Niraparib. Niraparib is a poly ADP-ribose polymerase (PARP) inhibitor, a type of drug that works by preventing base excision repair of DNA in cancer cells. PARP inhibitors, developed for synthetic lethality, enhance the accumulation of DNA strand breaks and promote genomic instability and programmed cell death.
The nationwide trial was designed to evaluate the efficacy of *Niraparib as maintenance therapy in patients who had received at least two previous regimens of platinum-containing chemotherapy, a type of regimen used to treat most ovarian cancer patients. These same patients must have also responded to their most recent therapy as assessed by the prolongation of what researchers refer to as “progression-free survival,” the length of time after treatment in which a patient lives with a disease that does not worsen. Progression-free survival is one way to see the level of success of a new treatment.
Sponsored by Niraparib drug maker Tesaro, Inc., the June 2013 to June 2016 trial enrolled 597 patients across 108 study locations, including nine patients from Duke.
“Across the board they found a significantly improved progression-free survival in the study,” said Secord, associate director of clinical research for gynecologic oncology at Duke. “It was quite impressive.”
Secord had several patients participating in the trial, including Elzie.
The study found that women with germline BRCA 1 or 2 mutations who were treated with Niraparib had a progression-free survival of 21 months compared to 5.5 months for the control group.
Put another way, as Secord explained, “Niraparib decreased a patient’s risk of disease progression by 73 percent.”
The reason why chemotherapy and PARP inhibitors in combination work especially well to fight ovarian cancer in women with the germline BRCA 1 and 2 mutations, Secord explained, is that “BRCA 1 and 2 genes encode proteins that repair DNA, and when those genes are mutated, patients are at a higher risk for cancer, but they are also more likely to do better and respond to chemotherapy better because their cancer cells can’t repair their own DNA when they’re damaged by chemotherapy agents.”
Then, when a PARP inhibitor is used, she said, “it’s an additional hit.”
While the most dramatic improvement was found in the BRCA 1 or 2 mutation carriers, improvement was also seen in patients with HRD (homologous recombination defect) positive tumors, and overall in the non-germline BRCA mutation group.
Women with HRD positive tumors who were treated with Niraparib showed a median progression-free survival of 12.9 months compared to 3.8 months on the placebo.
Meanwhile, the median progression free survival for all non-germline BRCA mutation patients was 9.3 months on the drug compared to 3.2 months for the placebo, representing more than a 50 percent improvement.
Elzie, part of the latter group, was cancer-free for 10 months during the trial, slightly exceeding the median.
“The drug definitely prevented the cancer from recurring and prolonged that period of time she was in a cancer-free period,” said Secord.
While doctor and patient can never know for sure who was given the study drug, Secord said that she’s “pretty sure” that Elzie was on it because she experienced its most common side-effect—thrombocytopenia—a deficiency of blood platelets. Platelet transfusions and lowering the dose of the study drug resolved the issue.
Elzie’s cancer did recur after the trial, requiring more surgery plus a third round of chemotherapy.
“She’s on chemotherapy now and doing well and doesn’t show signs of progressive disease at this point,” said Secord.
Secord explained that once ovarian cancer recurs, for the most part, it’s not a curable disease, though there are always exceptions.
That said, she pointed out that “ovarian cancer patients receive adjuvant therapy and continuing therapy because we can treat even in recurrence.”
Secord stressed that advances in precision medicine— “getting the right drug to the right patient, and hopefully at the right time”— makes for an exciting time in ovarian cancer research.
“Whereas in the past we were picking out what to treat people with based on just our clinical experience, now we’re in a situation where we can test for gene mutations, and we can test their tumor for HRD, and we can make rational decisions about when to use a drug and which drug to use based on the patient’s personal characteristics and their tumor characteristics,” she explained.
There is currently another Tesaro, Inc.-sponsored Niraparib trial open to Duke patients and others called Quadra (NCT02354586), which is a study for women who have active recurrence and allows for three to four priors. For more information on Quadra, visit https://clinicaltrials.gov/ct2/show/NCT02354586?term=Quadra&rank=2.
UPDATE : On March 27, 2017, the U.S. Food and Drug Administration approved niraparib (ZEJULA, Tesaro, Inc.), a poly ADP-ribose polymerase (PARP) inhibitor, for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy.