Lisa Barroilhet, MD, associate professor, Department of Obstetrics and Gynecology, University of Wisconsin (UW) School of Medicine and Public Health; gynecologic oncologist, UW Health, discusses the role of PARP inhibitors in patients with ovarian cancer.

All patients with ovarian cancer displaying somatic or germline 

 mutations should receive upfront PARP inhibitor maintenance therapy after completing an initial 6 cycles of chemotherapy with paclitaxel and carboplatin, Barroilhet says. Patients can receive PARP maintenance as neoadjuvant therapy or as adjuvant therapy following debulking surgery, Barroilhet notes.

Findings from the phase 3 SOLO1 trial (NCT01844986) support the use of maintenance olaparib (Lynparza) in patients with 

-mutated ovarian cancer, Barroilhet explains. In this trial, patients with newly diagnosed advanced ovarian cancer harboring a 

 mutation and experiencing a clinical response to platinum-based chemotherapy were randomly assigned to receive either maintenance olaparib or placebo for a maximum of 2 years. At a median follow-up of 7 years, the overall survival rates were 67.0% in the olaparib arm vs 46.5% in the placebo arm (HR, 0.55; 95% CI, 0.40-0.76; 

Patients with ovarian cancer with homologous recombination deficiency (HRD) may also benefit from PARP maintenance therapy, according to Barroilhet. If a patient’s germline test comes back normal, their biopsy should be sent for HRD testing to inform further treatment decisions, Barroilhet says.

In the phase 3 PRIMA trial (NCT02655016), patients with newly diagnosed advanced ovarian cancer were randomly assigned to receive either niraparib (Zejula) or placebo after response to platinum-based chemotherapy. Of the enrolled patients, 50.9% had HRD tumors. In the HRD population, the median progression-free survival (PFS) was 21.9 months with niraparib vs 10.4 months with placebo (HR, 0.43; 95% CI, 0.31-0.59; 

 < .001). In the overall population, the median PFS was 13.8 months with niraparib vs 8.2 months with placebo (HR, 0.62; 95% CI, 0.50-0.76; 

 < .001). Based on these data, and with shared decision making, niraparib maintenance therapy can be considered for patients with HRD disease, Barroilhet explains.

Patients treated with bevacizumab (Avastin) plus upfront or neoadjuvant chemotherapy can continue to receive a dual maintenance approach with bevacizumab plus olaparib, Barroilhet notes. This combination may be effective in patients with HRD ovarian cancer, Barroilhet concludes.

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Lisa Barroilhet, MD, discusses the role of PARP inhibitors in patients with ovarian cancer.

Dr Barroilhet on the Role of PARP Inhibitors in BRCA+ and HRD Ovarian Cancer

Dolores A. Buchler, MD Faculty Fellow in Gynecologic Oncology

University of Wisconsin School of Medicine and Public Health

Targeted therapy in ovarian cancer is a relatively new field, and one that is rapidly expanding. PARP inhibitors are the most commonly used targeted therapy for patients with recurrent ovarian cancer, and the indications for the use of these drugs have broadened in recent months. Their popularity has increased as newly reported study findings support their efficacy and because of their oral bioavailability and convenient dosing schedule.

PARP inhibitors block the enzyme poly (ADP-ribose) polymerase, causing multiple doublestrand DNA breaks to form in patients who have homologous recombination deficiency (HRD). The best-known HRD pathway proteins are BRCA1 and BRCA2, which are encoded by t u mor - suppr e ssion genes that can harbor germline mutations. 

-related ovarian cancers make up about 15% of all ovarian cancers diagnosed in the United States, and the genes are most commonly altered in patients with familial breast and ovarian cancer syndromes. Patients with 

mutations have up to a 60% lifetime risk of developing ovarian cancer.

mutations are particularly susceptible to double-strand DNA breaks. In the presence of a PARP inhibitor, repair of DNA damage, which is an expected part of any cell cycle, cannot be performed efficiently and tumor cells die (Figure). Normal cells that do not replicate their DNA as frequently as cancer cells do and that lack 

 abnormalities survive PARP inhibition. This means that some of the most frustrating adverse effects of traditional chemotherapy, such as hair loss, are avoided.

There are 3 PARP inhibitors on the market that are approved for the treatment of patients with ovarian cancer: olaparib (Lynparza), rucaparib (Rubraca), and niraparib (Zejula).

The FDA approved olaparib in December 2014 for use in patients with suspected or confirmed

-mutated advanced ovarian cancer who have been treated with 3 or more prior lines of chemotherapy. A phase III clinical trial accruing at UW Carbone Cancer Center and centers throughout the United States is examining olaparib with and without cediranib, a potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, compared with standard platinum-doublet chemotherapy (NCT02446600). This is the largest multiarm prospective trial examining the efficacy of olaparib paired with other targeted therapy.

Rucaparib was approved in December 2016 for patients with confirmed somatic or germline 

 mutations who have been treated with 2 or more prior lines of chemotherapy. Testing of tumor tissue in the recurrent setting in order to identify a potential somatic 

mutation is now becoming commonplace, while it was rarely performed prior to rucaparib’s approval.

In March 2017, following a report in the 

niraparib was approved for maintenance treatment of patients with recurrent ovarian cancer who meet the common definition of platinum sensitivity. This is the first FDA-approved maintenance therapy for ovarian cancer and has the potential to change standard practice.

In general, PARP inhibitors are well tolerated. Common toxicities include anemia, nausea, and fatigue. Myelodysplastic syndromes are seen in up to 2% of patients treated with these medications, and patients should be appropriately counseled regarding this adverse effect.

PARP inhibition may be beneficial outside of

positive patients. The study findings that led to niraparib’s FDA approval for all platinum-sensitive patients show improved survival in patients with and without known BRCA mutations (Table).1 This raises questions about larger implications for other mutations in genes associated with HRD, including 

. Potentially, abnormalities in these genes could be markers for platinum sensitivity.

Table. Efficacy Findings in Pivotal Niraparib Trial

As we enter this new landscape of precision medicine in ovarian cancer, we must be prepared to offer these therapies to our patients at various points during their treatment course, which often extends over years. We know little about using a different PARP inhibitor after the first has failed. The optimal timing of screening for somatic 

 mutations has not been defined. One could argue that biopsy at the time of recurrence would be the most accurate; however, many patients do not have disease amenable to core biopsy. Until more is known, many providers rely on tissue from the original cancer debulking surgery.

Further, although the Society of Gynecologic Oncology recommends genetic counseling and genetic testing for all patients with ovarian cancer, only about half of eligible patients have BRCA testing results available at the time of cancer recurrence. There are many opportunities here to enrich the care of patients battling recurrent ovarian cancer. PARP inhibitors have opened the door to the potential of targeted therapy in treating this challenging disease.

Mirza MR, Monk BJ, Herrstedt AM, et al; ENGOT-OV16/NOVA Investigators. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. 

2016;375(22):2154-2164. doi: 10.1056/NEJMoa1611310.

Articles

PARP inhibitors are the most commonly used targeted therapy for patients with recurrent ovarian cancer, and the indications for the use of these drugs have broadened in recent months.

Lisa M. Barroilhet, MD

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