Deciding When to Use PARP Inhibitors, and Which One

New therapeutic options—with more on the horizon—offer challenges and opportunities in the treatment of ovarian cancer. Understanding the set of decisions that surround poly (ADP-ribose) polymerase (PARP) inhibitors was the theme of a continuing education session presented Saturday during the annual meeting of the Society of Gynecologic Oncology’s 2018 Annual Meeting on Women’s Cancer, taking place in New Orleans, Louisiana.

“Times are tricky,” said Bradley Monk, MD, FACS, FACOG, professor of gynecologic oncology at the University of Arizona and Creighton University and Arizona Oncology. “Targeted therapies are here” and choices are not as straightforward as they once were.

“You have to make 2 decisions: are PARP inhibitors appropriate? Yes or no? And if it’s yes, then you have to decide which one," Monk explained.

Monk was among 3 faculty to present “Show Me the Data: Levering Evidence to Optimize Applications of PARP Inhibitor Strategies in Ovarian Cancer,” chaired by 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.

Also presenting were Michael J. Birrer, MD, PhD, director of the University of Alabama Birmingham Comprehensive Cancer Center and professor of Medicine, Division of Hematology & Oncology; and Ursula A. Matulonis, MD, director of Gynecologic Oncology and professor of Medicine at Harvard Medical School.

The interactive format used case scenarios to test participants’ existing knowledge from key clinical trials involving the PARP inhibitors olaparib (Lynparza, AstraZeneca), rucaparib (Rubraca, Clovis Oncology), and niraparib (Zejula, Tesaro), before Monk, Birrer, and Matulonis each offered perspectives on critical questions:

• When are PARP inhibitors best used in the treatment paradigm?
• Which molecular markers can guide treatment decisions with PARP inhibitors?
• Who should get a PARP inhibitor?
• Which PARP inhibitor characteristics inform treatment choices?

Deciding to Use a PARP Inhibitor

“This is all about DNA repair,” Monk said, in offering background on how PARP inhibitors came to be. Over time, DNA is constantly breaking down, and homologous recombination (HR) DNA repair seeks to repair double strand breaks to avoid the genetic turmoil that leads to cancer. However, the presence of BRCA mutations interferes with this process, and can instead cause errors in DNA repair that give rise to cancer. In 2005, scientists discovered an alternate method of repair of single broken strands of DNA, by blocking the protein PARP, can cause double strand breaks to form, killing dangerous cells but leaving healthy ones alone. PARP inhibitors have many potential uses, but ovarian cancer offers the most immediate application.

As Monk noted, in 40% to 50% of epithelial ovarian cancers, genetic alterations are responsible for the HR repair pathway. Thus, identifying the germline and somatic mutations involved in HR DNA repair helps guide decision making on when to use a PARP inhibitor. The 3 approved PARP inhibitors are not the same, he said, and each 1 must be assessed based on its indication and data.

“It’s all about the sequencing,” Monk said. Increasingly, interpreting a biomarker will depend on whether the therapy will be used in front-line or second-line treatment. He showed slides featuring trials may soon give oncologists more choices in management of ovarian cancer, pending upcoming FDA decisions:

• Bevacizumab. FDA accepted a supplemental biologics license for the angiogenesis inhibitor to be used as frontline therapy for women who already have advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer. A decision is expected June 25, 2018.
• Rucaparib. Approved for treatment in active disease when patients with germline/somatic BRCA mutations who have received at least 2 lines of chemotherapy, the PARP inhibitor has an application under FDA’s priority review status to expand is approval to include recurrent ovarian cancer maintenance treatment. A decision is due by April 6, 2018, based on results of the ARIEL 3 trial.
• Olaparib is currently approved for treatment and maintenance of recurrent ovarian cancer, while niraparib is approved for maintenance of recurrent ovarian cancer.

Monk said key considerations include whether the benefit of PARP inhibitors will be greater if bevacizumab is used earlier, and whether toxicity changes. He is also looking ahead to PARP inhibitor combinations: trials are under way studying the class with bevacizumab, as well as various PARP inhibitors with immunotherapy, and even triplet therapy with PARP inhibitors, immunotherapy, and bevacizumab.

HRD Testing in Ovarian Cancer

“We’re still trying to find the perfect biomarker,” Birrer said, but short of that, there’s a lot that can be done to connect patients with therapies for maximum efficacy.

He discussed the complexities of homologous recombination deficiency (HRD) testing. Getting patients the right therapy starts with understanding starting that while BRCA1 and BRCA2 are still the most common mutation, they are far from the end of the story: Many more have been identified, and within BRCA1/2 there are distinctions between germline and somatic mutations.

Birrer discussed how the ARIEL 2 trial used a next-generation sequencing assay to examine how BRCA1 and BRCA2 mutations genomic loss of heterozygosity (LOH) might also indicate HR deficiency, and affect response to rucaparib. Data show that those in the BRCA mutant group had the best response (12-month progression-free survival), compared with BRCA wild-type with LOH high (5.7 months) and BRCA wild-type LOH low carcinomas (5.2 months).

In the NOVA trial, patients with BRCA mutations had the best results with niraparib, but non-BRCA mutation patients still had good results.

Birrer said while some patients still do not receive testing, “All patients with ovarian cancer should undergo genetic testing,” and HRD assays are now available.

Which PARP Inhibitor to Select

Matulonis said there are multiple factors that can affect which PARP inhibitor is selected, from clinical trial results to other drugs the patient is taking, to dosing schedules, to insurance coverage. She presented tables summarizing clinical trial results, FDA approvals and dosing, HRD results (where applicable), drug—drug interactions, and which enzymes the various PARP inhibitors use to metabolize the drugs, as this can have a corresponding effect on certain cell transporters.

The challenge for physicians, she said, is that PARP inhibitors are so new that drug—drug interactions may not be flagged in some health system electronic health records. This is especially true, “If a patient is on a complicated regimen,” she said. Liver function tests are important to catch effects on cell transporters.

Hypertension and fatigue are legitimate concerns, but often patients work through early side effects, and often dose modification is all that is needed. She presented physicians with patient cases and a series of decision-making scenarios that, through a series of decision making scenarios that, like Monk, spoke to the challenge of sequencing, both in treatment and in maintenance, noting the ARIEL 3 data “are very convincing in the maintenance setting.”

The continuing education session was presented by Physicians Education Resource, which is owned by the same company that owns The American Journal of Managed Care^®, and the session was funded through educational grants from AstraZeneca, Clovis Oncology, Myriad Genetics, and Tesaro.