Clinical Challenges: PARP Inhibitors in Ovarian Cancer

The use of poly (ADP-ribose) polymerase (PARP) inhibitors as maintenance therapy in advanced epithelial ovarian cancer (EOC) has been shown to improve progression-free survival (PFS), particularly in disease associated with a germline mutation in BRCA1, BRCA2, or both.

In the United States and Europe, where EOC remains one of the leading causes of cancer death in women, PARP inhibitors have undergone testing as single agents and in combination with chemotherapy, antiangiogenic agents, and ionizing radiation, and in both the recurrent and newly diagnosed advanced disease settings. Although most tumors eventually become resistant to these targeted agents, there is evidence to suggest that a small group of women with the disease may continue without progression for many years.

Three PARP inhibitors — olaparib (Lynparza), niraparib (Zejula), and rucaparib (Rubraca) — were approved as maintenance therapy for platinum-sensitive EOC by the FDA and the European Medicines Agency, irrespective of BRCA mutation or homologous recombination deficiency (HRD) status. As intensive evaluation of these PARP inhibitors continues, experts note that the indications for their use are broadening significantly, with patient selection and setting influenced by genetic profiles, dosing schedules, tolerability, and affordability.

“Data have consistently shown that women with tumor-related or genomic changes also benefit, particularly those with tumors that exhibit HRD and tumor-associated mutations in BRCA,” said Don S. Dizon, MD, of the Lifespan Cancer Institute, the Rhode Island Hospital, and the Warren Alpert Medical School of Brown University in Providence, and an American Society of Clinical Oncology (ASCO) expert in patient care.

“Data also suggest that PARP inhibitors may be active even in the absence of any mutations, and the approval of niraparib speaks to this,” Dizon told MedPage Today.

Guidelines from ASCO, as well as the National Comprehensive Cancer Network and the Society of Gynecologic Oncology, recommend that all women with a diagnosis of EOC receive genetic counseling and undergo germline and somatic tumor testing, even in the absence of a family history of the disease.

However, it is estimated that only 30% of patients do so, Dizon noted. “These guidelines state unequivocally that all women with ovarian cancer should be tested for a germline genetic mutation.”

“Given the availability of both olaparib and niraparib as a single agent, and olaparib and [the antiangiogenic agent] bevacizumab [Avastin] as combination therapy, it is particularly important to test for mutations to help guide appropriate treatments and inform individual patients of the benefits,” he emphasized. “For example, a patient with a mutation in BRCA stands to benefit significantly from olaparib maintenance after first-line chemotherapy.”

In the phase III SOLO-1 trial, women with newly diagnosed advanced ovarian cancer with a germline or somatic mutation in BRCA1 and/or BRCA2 who had a complete or partial clinical response after platinum-based chemotherapy had a 70% lower risk of disease progression or death with olaparib than with placebo. The estimated difference in median PFS between the two groups was approximately 3 years.

Ongoing follow-up of patients in the trial will determine whether a subgroup experiences enduring long-term benefit with curative potential when treated with olaparib, the investigators noted.

In the phase III PRIMA trial, a similar survival benefit was seen when niraparib was compared with placebo (21.9 vs 10.4 months, respectively; HR 0.43, 95% CI 0.31-0.59). However, in women without HRD or a BRCA mutation, Dizon noted, the improvement in PFS with niraparib compared with placebo was more modest (8.1 months vs 5.4 months, HR 0.68, 95% CI 0.49-0.94).

Shannon N. Westin MD, MPH, of the University of Texas MD Anderson Cancer Center in Houston, called the different clinical indications for PARP inhibitors in high-grade EOC “great news.”

“In upfront ovarian cancer, after response to initial therapy, PARP inhibitors can be used as maintenance regardless of genetic testing,” she told MedPage Today. “[Although] we know that the biggest impact is for women with a BRCA mutation, there is [also] activity in women whose tumors are positive for HRD.”

In the phase III PAOLA-1 trial, a significant PFS benefit was seen when maintenance olaparib was added to first-line standard therapy for advanced ovarian cancer that included bevacizumab. The investigators reported that the PFS benefit was “substantial” in women with HRD-positive tumors, even in the absence of a BRCA mutation.

Women with no evidence of HRD or a BRCA mutation may also receive some benefit from PARP inhibitors in the maintenance setting, Westin noted.

In the phase II QUADRA trial, for instance, clinically relevant activity was observed with niraparib in women with heavily pretreated ovarian cancer, especially those with HRD-positive platinum-sensitive disease, which includes not only those with a BRCA mutation but also BRCA wild-type disease. “These findings support expanding the treatment indication for PARP inhibitors to include patients with HRD-positive ovarian cancer beyond those with BRCA mutations,” the researchers said.

As the role for targeted therapy in ovarian cancer has expanded, so too has the use of genomic testing for clinicians, Westin said, noting the approval of next-generation sequencing for ovarian cancer.

“This makes it easier to order and ensures the patient is not going to get a big bill,” she said. “The fact that PARP inhibitors can be used in patients with a somatic BRCA mutation has also supported the use of genomic testing and made it essential to get during the upfront treatment setting.”

All three approved PARP inhibitors appear equally effective, but “there are differences,” noted Kathleen Moore, MD, MS, of the Stephenson Cancer Center at the University of Oklahoma Health Sciences Center in Oklahoma City, and the lead investigator for both the SOLO-1 and QUADRA trials.

Moore recommended that in the upfront scenario, BRCA status and response to platinum-based chemotherapy — whether partial or complete — be considered. In patients in whom bevacizumab has already been initiated and the strategy is to layer on olaparib, Moore advised a review of HRD status. In the platinum-sensitive recurrent setting, the use of PARP inhibitors would depend on the response to re-induction platinum-based chemotherapy, cell type, and various patient factors, she said.

“I believe most providers [should] pick the one or two [PARP inhibitors] they are most comfortable managing and stick with those,” Moore told MedPage Today. All have class effects of common but low-grade nausea, fatigue, and, sometimes, diarrhea/constipation, she pointed out. In addition, 21% to 25% of patients may develop grade 3 anemia requiring transfusion.

Since niraparib is given once daily, it may be more convenient when taken at night, said Moore, who noted that 15% to 20% of patients may develop hypertension and palpitations. On the other hand, she stated, rucaparib and olaparib are not associated with hypertension or palpitations but must be taken twice daily.

Last Updated June 15, 2020