PARP Inhibitors Are Changing Paradigm in Recurrent Ovarian Cancer

Christin Melton, ELS
Published: Wednesday, Mar 01, 2017
Bradley J. Monk, MD

Bradley J. Monk, MD

Platinum and taxane chemotherapies remain standard first-line treatments for epithelial ovarian cancer. The treatment of recurrent ovarian cancer has historically been based on how a patient responded to the first-line regimen. Patients whose cancer recurred 6 months or more after the last platinum infusion are categorized as platinum-sensitive, whereas patients whose cancer recurred within 6 months of the last infusion are classified as platinum-resistant. Greater understanding of ovarian cancer biology and the emergence of new targeted therapies is diminishing the importance of platinum response in determining how to treat recurrent disease.

During an OncLive Peer Exchange® titled “Expert Views on Therapy for Ovarian, Fallopian Tube, and Peritoneal Cancers,” a panel of gynecologic oncology specialists discussed novel agents for the second, third, fourth, and even fifth lines of therapy and the growing importance of molecular signature, histology, and time to recurrence in treatment decisions. As panel moderator Bradley J. Monk, MD, summarized, “We have had 3 new FDA approvals for targeted therapies in the last 2 years, and I anticipate within the next year, we’ll have 3 more. Our armamentarium is growing, and our paradigms are changing.”

The Importance of Ovarian Cancer Biology

Ovarian cancer, like cancers that affect other organs, comprises many subtypes. Approximately 90% are epithelial, 80% of which are subcategorized as serous carcinomas.1 Serous carcinomas are further divided into high grade and low grade, with high grade accounting for 90% of serous tumors.1 “High-grade serous patients tend to have the worst prognosis compared to those with low-grade serous cancers,” said Angeles Alvarez Secord, MD. She said high-grade serous tumors are further classified according to whether they harbor a homologous recombination deficiency (HRD), such as a germline or somatic BRCA mutation.

The BRCA gene helps repair DNA and suppresses tumor growth, and current guidelines recommend all women with epithelial ovarian cancer have a blood test for a germline BRCA alteration. Monk said it surprises him when he meets a new patient who has had epithelial ovarian cancer for a long time but never had a BRCA test. Thomas Herzog, MD, said some experts recommend clinicians also test the tumor for a somatic BRCA mutation, which a blood test would not detect. Kathleen N. Moore, MD, reminded everyone that HRD testing is another option. She said although an HRD test does not identify specific somatic mutations, it does indicate whether a patient has an important somatic mutation in the DNA repair pathway.

Robert L. Coleman, MD, said it is important to know whether the “machinery is messed up,” because the cancer cell may have a vulnerability able to be exploited with drugs that induce DNA damage. Secord called the process synthetic lethality. “If somebody has that BRCA mutation—whether it’s germline or somatic—or they have another defect that’s causing loss of homologous recombination, then the cells can’t repair themselves once they’re subjected to a DNA-damaging event,” Secord said. Coleman said synthetic lethality explains why patients with high-grade serous ovarian cancers who have a BRCA mutation have better outcomes than patients without a BRCA mutation. The same gene that predisposes their cells to malignant transformation makes those malignant cells vulnerable to DNA-damaging drugs.

PARP Inhibitors

The poly(ADP-ribose) polymerase (PARP) protein plays a significant role in repairing DNA damage. Monk described how the class of drugs known as PARP inhibitors are designed to block PARP’s enzymatic activity, thereby disrupting DNA repair and causing an accumulation of single-stranded breaks.“If you can’t repair single-stranded breaks, you get a double-stranded break. And if you have a BRCA or BRCA-like mutation, you can’t repair the double- stranded break [and] the cell dies,” he said.

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