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Putting PARP Inhibitor Perspectives Into Practice in "Beyond the Guidelines" Session

Mary Caffrey
Much about using PARP inhibitors is open to debate, starting with what kind of genetic test to give before using them. Combination therapies are the next frontier, according to an expert panel.
Achieving consensus on which poly (ADP-ribose) polymerase (PARP) inhibitor to use and when during management of ovarian cancer proved challenging Sunday for 4 oncologists who took attendees through a lively discussion of applying current standards from professional societies to everyday practices, in “Beyond the Guidelines: Investigator Perspectives on the Current and Future Role of PARP Inhibition in the Management of Ovarian Cancer,” an education session presented at the Society of Gynecologic Oncology’s (SGO) 2018 Annual Meeting on Women’s Cancer, taking place in New Orleans, Louisiana.

Moderator Neil Love, MD, of Research to Practice, guided the 4-part discussion dealing with the basic biology, current role, tolerability considerations, and investigational pipeline of this class of therapy, which panelist Mansoor R. Mirza, MD, medical director of the Nordic Society of Gynecologic Oncology, said were a leap over past treatments. Ovarian cancer was moving out of the realm of the worse diseases thanks to PARP inhibitors, Mirza said. “You’re not curing it, but you’re changing it to a chronic disease.”

From questions of testing to treatment to managing side effects, Love put out scenarios involving pateints with specific characteristics, and there was frequently variation among the panelists and the audience on the best approach. And that reflects the debate within the field, they said.

Robert L. Coleman, MD, FACOG, FACS, professor and executive director of the Cancer Network Research in the Department of Gynecologic Oncology and Reproductive Medicine at the University of Texas MD Anderson Cancer Center, first presented an overview of ovarian cancer biology, starting with testing protocols. All 3 leading groups in the space—SGO, the National Comprehensive Cancer Network, and the American Society of Clinical Oncology—call for genetic testing and counseling of women with ovarian cancer, but which kind?

The first point of divergence: Coleman explained that BRCA1 and BRCA2 testing can start in the tumor or the germline, and some platforms offer both. Germline panel tests can capture the non-BRCA genes that indicate homologous recombination (HR) deficiency, which is seen in up to 50% of epithelial ovarian cancers. But as the panelists discussed, testing raises issues, such as generating the need for genetic counseling services or reports on unknown medical conditions, which Coleman noted cannot then be ignored.

“You can’t just test and forget about it,” he said. “If you are already resource strapped, multi-panel testing can be more of a burden.”

Joyce Liu, MD, MPH, assistant professor of medicine at Harvard Medical School and director of Clinical Research in the Department of Gynecologic Oncology at Dana-Farber Cancer Center, led the discussion of how PARP inhibitors are being used currently. She listed the 3 with current FDA approvals:
  • Olaparib (Lynparza, AstraZeneca), for treatment after at least 3 other therapies in germline BRCA-mutated ovarian cancer and maintenance after response to platinum-based chemotherapy for all epithelial ovarian cancer
  • Rucaparib (Rubraca, Clovis Oncology), for treatment after at least 2 other therapies in somatic or germline BRCA-mutated ovarian cancer; she noted that this therapy awaits FDA action for maintenance (deadline for action is April 6, 2018).
  • Niraparib (Zejula, Tesaro), for maintenance following platinum-based therapy for all epithelial ovarian cancer.
Liu noted that trial results show progression-free survival benefits for all 3 therapies. The big questions today are choosing between PARP inhibitors or combinations of chemotherapy and bevacizumab in platinum-sensitive patients. Ongoing trials are using PARP inhibitors in combination with other therapies, but it’s not known yet whether this is a better approach than holding off on PARP inhibitors until they are needed.

She asked the key question: is a PARP inhibitor given for relapsed disease as effective as a PARP inhibitor given for maintenance?

Mirza said this explains why many oncologists use bevacizumab upfront. Giving the PARP inhibitor too soon, he said, means “taking the risk that this patient will have less efficacy for PARP [inhibitors] later.”

Later in the discussion, Kathleen Moore, MD, director of the Oklahoma TSET Phase I Program and associate professor for the Section of Gynecologic Oncology in the Department of Obstetrics and Gynecology at the University of Oklahoma Health Sciences Center, put it this way when discussing combination trials: “I don’t want to use up all my good drugs up front if I’m going to need them later.”

Moore then led the discussion on making considerations for tolerability, which she said included abdominal pain that could cause alarm in patients. Other drugs the patient may be taking are a key consideration, as are: (1) the effect on serum creatinine levels; (2) decreases in hemoglobin, platelets, and neutrophils; and (3) fatigue.

She noted that patients who have an infusion of chemotherapy can plan their schedules around days they know they will be tired. Fatigue every day is debilitating in a different way, and oncologists must prepare patients for this. “Sleep disruption is also a big part of fatigue,” Moore said.

The key, she said, “You want to keep patients on the active drug at a good dose for as long as possible.”

So what is next? Mirza pointed to the trials involving combinations, as well as upcoming results for veliparib, which Moore noted has a different mechanism of action than the PARP inhibitors seen thus far, which may make it more effective with chemotherapy combinations.

There is the ongoing debate of how early to introduce PARP inhibitors, and whether they should be used with checkpoint inhibitors. Four phase 3 trials that use PARP inhibitors and checkpoint inhibitors are under way.

The challenge of PARP inhibitor resistance remains, but Mirza is optimistic. “I really believe this will change the standard of care of our patients upfront,” he said, adding that medicine is still in the “learning curve” of PARP resistance.

Research to Practice presented the continuing education session, with grants from AbbVie Inc., AstraZeneca, Clovis Oncology, Myriad Genetic Laboratories, and Tesaro.

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