An Expanding Role For PARP Inhibitors Shows Promise In Treating Ovarian Cancer

After Anna Valencia Hall received a diagnosis of stage 3C ovarian cancer in May 2014, she underwent surgery followed by six treatments with platinum-based chemotherapy, which put her in remission for a year and a half. After a recurrence, another six rounds of chemotherapy got her healthy again.

Valencia Hall’s oncologist wanted to give her the best possible chance of staying in remission, so in June 2017, she prescribed Zejula (niraparib), a once-daily oral treatment that’s part of an emerging class of medicines known as poly (ADP-ribose) polymerase (PARP) inhibitors. Just a few months before Valencia Hall’s disease returned, Zejula had become the first PARP inhibitor approved by the Food and Drug Administration (FDA) to treat women with recurrent ovarian cancer who do not have a genetic abnormality but previously responded well to platinum-based chemotherapy. Valencia Hall was a perfect candidate for the drug, which is referred to as a maintenance treatment because it’s prescribed with the goal of preventing ovarian cancer from returning.

She has been free of the disease since starting Zejula and has experienced no side effects, aside from a temporary drop in platelet counts that her oncologist corrected by dialing down Valencia Hall’s daily dose. “Zejula has allowed me to live my life as I see fit,” says Valencia Hall, 51, a freelance graphic artist in Phoenix. “It’s an oral medication, so I don’t have to go in for infusions. The opportunity to have this as a maintenance therapy is exciting — it’s hope.”

Zejula is one of three PARP inhibitors that are taking an increasingly prominent role in ovarian cancer treatment and improving patients’ prognosis. With dozens of clinical trials underway, including some that seek to combine PARP inhibitors with other cancer treatments, that role could expand even more.

Drugs in this class work by inhibiting the PARP enzyme, which normally helps damaged DNA repair itself. Preventing this repair causes cancer cells to die, especially those that already have DNA repair defects due to a mutated BRCA 1 or 2 gene or other abnormalities. So far, clinical trials have shown that these drugs can lengthen the time until the disease progresses; their impact on the length of life is still being investigated. For women using a PARP inhibitor for maintenance, the drugs can help increase the time between courses of chemotherapy for recurrent disease.

“In the past, we would take patients who had a high risk of recurrence and just watch them until cancer came back because we didn’t have maintenance therapies that were effective, tolerable or convenient,” says Dr. Bradley Monk, a professor and director of the division of gynecologic oncology at Creighton University School of Medicine at St. Joseph’s Hospital and Medical Center in Phoenix, Arizona, and also medical director of gynecologic oncology research for the U.S. Oncology Research Network. PARP inhibitors have been “significant because they’re expanding the treatment opportunity for many patients,” he adds.

Each year, more than 22,000 women in the U.S., about half of whom are over age 63, receive a diagnosis of ovarian cancer, according to the American Cancer Society. A small proportion of women have inherited mutations in BRCA1, BRCA2 or other cancer-related genes that raise their risk of ovarian cancer and can take steps to fend off the disease, including surgery to remove their ovaries. But most cases occur out of the blue, and because the symptoms can be vague and easily overlooked, like bloating or stomach pain, many women do not receive a diagnosis until the disease has advanced to the point where it can be hard to treat. The disease will recur in about 85% of women who initially respond to chemotherapy.

For women with ovarian cancer, PARP inhibitors have been an option since 2014, when the FDA approved Lynparza (olaparib) as a maintenance therapy for patients with BRCA mutations who had received three or more chemotherapy treatments. Rubraca (rucaparib) followed in 2016 and Zejula in 2017.

PARP INHIBITORS REACH MORE PATIENTS

Over the past two years, the FDA approved more uses of PARP inhibitors so that many more patients can benefit from these medicines and access the drugs earlier in treatment. In April 2018, Rubraca was approved as a maintenance therapy to treat recurrent ovarian cancer in women who responded at least partially to platinum-based chemotherapy, whether or not they had a genetic mutation. That December, Lynparza was approved as a first-line maintenance treatment for BRCA-mutated ovarian cancer, meaning patients can be given the drug after successfully completing just one round of platinum-based chemotherapy.

That was based on a clinical trial showing the drug reduced the rate of disease progression or death by 70%.

Most recently, in October 2019, the FDA approved Zejula for use in patients with advanced ovarian cancer associated with a cellular abnormality called homologous recombination deficiency. BRCA1 and BRCA2 are two of these types, but in ovarian cancer, about 17 other such genetic abnormalities can drive the disease. Between 41% and 50% of ovarian tumors are thought to have homologous recombination deficiency, which can be detected with a tumor test, Myriad myChoice CDx, that the FDA also approved last October.

In a clinical trial leading to the approval, 24% of participants with homologous recombination deficiency-positive ovarian cancer responded well to Zejula, experiencing some tumor shrinkage. That may not sound like a high response rate, but it surpasses the overall response rate to PARP inhibitors among all patients with ovarian cancer either with or without mutations, says lead clinical trial investigator Dr. Kathleen Moore, associate professor of gynecologic oncology at Stephenson Cancer Center at the University of Oklahoma.

“These are heavily pretreated patients in which the response rate has typically been 12%, so this was double what we normally see,” Moore says. “The clinical benefit here was quite high.” She adds that patients with BRCA mutations did particularly well: Nearly 40% of those who previously responded well to platinum-based chemotherapy responded to Zejula. The most common side effects include gastric upset, mouth sores, rash, headache and dizziness. The drug can also cause anemia and abnormal blood counts, which, in rare cases, can lead to myelodysplastic syndrome, a bone marrow problem, or the blood cancer acute myeloid leukemia.

As PARP inhibitors continue to help a widening population of patients with ovarian cancer, a push is underway to use them earlier in the treatment process. Several trials presented at the 2019 European Society for Medical Oncology conference demonstrated the potential value of that strategy.

One study found an 84% survival rate among patients who took Zejula for two years following chemotherapy, regardless of their homologous recombination deficiency status, compared with 77% who got a placebo. The median progression-free survival period (time from treatment to disease progression) for patients taking the drug was 14 months compared with eight months for those on placebo.

Another study evaluated an investigational PARP inhibitor, veliparib, combined with chemotherapy as a first-line treatment followed by veliparib alone for maintenance. Median progression-free survival among patients on that regimen was 23.5 months versus 17.3 months for those taking a placebo.

The third trial presented at the conference involved Avastin (bevacizumab), a drug that cuts off the blood supply to tumors. The FDA approved Avastin in 2018 to treat advanced ovarian cancer in conjunction with chemotherapy.

During the more recent trial, patients with newly diagnosed advanced ovarian cancer took Avastin plus chemotherapy, followed by Avastin with Lynparza for maintenance. Those who took Lynparza along with Avastin had a median progression-free survival of 22 months compared with 17 months for those who received Avastin and a placebo.

In all three studies, progression-free survival rates were the highest among homologous recombination deficiency-positive patients, but the fact that PARP inhibitors extended survival even among those without those mutations was encouraging to oncologists who treat ovarian cancer.

“These were all positive studies that undoubtedly show that PARP inhibitor maintenance following chemotherapy will extend beyond BRCA-associated ovarian cancer,” Moore says. “It’s highly likely that a much larger proportion of women with ovarian cancer who are diagnosed in 2020 will receive a PARP inhibitor (than in previous years). Women will be able to live longer with their cancer because we’re developing effective therapies that push out progression-free survival.”

COMBINATIONS GAIN STEAM

A clinical trial investigating a novel PARP combination proved a lifesaver for Diane Sarver, who first received a diagnosis of ovarian cancer in 2010. Chemotherapy put her cancer in remission three times, but when she relapsed again in 2015, she decided to search for a novel treatment strategy and traveled from her home in Lake Oswego, Oregon, to The University of Texas MD Anderson Cancer Center in Houston.

Sarver was entered into an early-phase trial combining Lynparza with the investigational drug AZD2014, which interferes with a cellular pathway (called phosphatidylino-sitol-3 [PI3] kinase) that drives resistance to PARP inhibitors. Within seven weeks of starting the combination therapy — which consists of two oral drugs taken twice a day —, Sarver’s ovarian cancer came under control. As part of the ongoing trial, she continues to take the two drugs, which, she says, have caused no side effects — and she’s still disease-free.

What’s notable about Sarver’s case is that she didn’t inherit any genetic mutations that would predict such a long-lasting response to PARP inhibitors. Although her tumor tested positive for a rare BRCA mutation, it was considered nonactionable — scientists did not yet know whether or not the mutation produced an aberrant protein that would make it likely to respond to the drug combination being studied. The theory behind the trial is that blocking PI3 kinase may transform tumors that would not normally respond to PARP inhibition into responders.

“I’m amazed that I’ve had such a good outcome,” says Sarver, 69, a retired clinical technologist and mother of two grown children. Her only limitation is that she has to fast two hours before and after taking the drugs, she says, but the lack of side effects has given her the freedom to travel, speak to medical students about her experiences and spend time with her family.

“I’ve seen both children through their college graduations,” Sarver says. “I feel completely functional and am grateful to have never experienced any fatigue or other physical restriction.”

MD Anderson is now planning several midstage clinical trials combining PARP and PI3 kinase inhibition, including one that pairs Lynparza with Piqray (alpelisib), a drug currently used to treat some patients with breast cancer. In an early trial of the combination that was reported in April 2019, 36% of patients had a partial response of some tumor shrinkage and half achieved stable disease, meaning their cancer didn’t get worse. “That was impressive, considering the bulk of the patients had become resistant to platinum chemotherapy,” says Dr. Shannon Westin, a clinical investigator in the department of gynecologic oncology and reproductive medicine at MD Anderson. “And there was a similar response rate regardless of mutation status, which was very exciting.”

RESEARCHERS PURSUE MORE USES

Pairing PARP inhibitors with drugs that boost the immune system’s ability to fight cancer is another idea being investigated in the treatment of ovarian cancer, because tumors with unstable DNA repair abilities might also be easier for the immune system to recognize. For example, Keytruda (pembrolizumab) inhibits programmed cell death protein 1 (PD-1), an immune “checkpoint” responsible for keeping the immune system under control.

The drug essentially takes the brakes off the immune system so it can better recognize and attack cancer. In an early trial combining Keytruda with Zejula, 65% of patients with ovarian cancer saw their disease come under control, either with total or partial tumor shrinkage or with stable disease.

Several other ongoing studies are combining PARP inhibition with immunotherapy, including a trial of Zejula with Tecentriq (atezolizumab), an inhibitor of a protein called programmed death-ligand 1 (PD-L1), and Cotellic (cobimetinib), which inhibits the cancer-associated mitogen-activated (MEK) protein. Another study combines Zejula with TSR-042, an investigational PD-1 blocker.

Could PARP inhibitors be useful for some women even earlier in the treatment process? MD Anderson recently started a small trial designed to investigate the potential of using the agents in place of chemotherapy in women with newly diagnosed cancer who have BRCA mutations. During the trial, patients will receive Lynparza for up to three months before moving on to surgery and chemotherapy. A similar trial is ongoing using the PARP inhibitor Talzenna (talazoparib) for BRCA-mutated breast cancer.

There could be many advantages of starting treatment with a PARP inhibitor rather than chemotherapy, Westin says. Patients can take the drugs at home instead of going to a facility for chemotherapy infusions. And PARP inhibitors don’t cause many of the uncomfortable side effects common with chemotherapy, like neuropathy (numbness and tingling in the extremities) and hair loss. “Some patients could potentially avoid that toxicity,” Westin says.

“The question is: Do we even need chemotherapy?” Westin adds. “Can we utilize a more targeted therapy to get better results? This is the next step.”