Overview of PARP Inhibitors in the Treatment of Ovarian Cancer

In the United States, ovarian cancer is the fifth-leading cause of cancer deaths among women and the leading cause of gynecological cancer deaths.^1,2 Additionally, 10% to 15% of ovarian cancer cases nationwide are a result of germline or somatic BRCA mutations.³ With cognizance of tumor genetics, practice has shifted to include targeted agents in ovarian cancer treatment.

PARP enzymes are responsible for detecting and repairing single-stranded and double-stranded DNA breaks during cell replication. BRCA1/2 mutations hinder the homologous recombination repair pathway, and tumor cells utilize PARP enzymes to repair DNA.⁴ For this reason, these tumors are particularly sensitive to the mechanism of PARP inhibitors.

There are 3 PARP inhibitors that are FDA approved in multiple settings of ovarian cancer: olaparib (Lynparza; AstraZeneca), rucaparib (Rubraca; Clovis Oncology), and niraparib (Zejula; GlaxoSmithKline).^5-7 However, there are points of note for each regarding pivotal trial results, safety profiles, and significant differences (Table^5-7).

Olaparib

Olaparib was the first PARP inhibitor approved in 2014 for patients with ovarian cancer with a germline BRCA mutation.^5,8 Based on results of the phase 3 SOLO-2 trial (NCT01874353), it received approval in the maintenance setting following platinum-based therapy in recurrent ovarian cancer with an underlying BRCA mutation.⁹

In the SOLO-2 trial, the median progression-free survival (PFS) in the olaparib arm was significantly longer than placebo at 19.1 vs 5.5 months (HR, 0.3; 95% CI, 0.22-0.41; P < .0001). Additionally, during a different phase 2 trial (NCT04858334), investigators evaluated olaparib regardless of BRCA mutation as a maintenance therapy in patients with partial response

or complete response following platinum therapy, with the results showing that PFS remained longer in the olaparib arm (8.4 vs 4.8 months) vs the placebo arm (HR, 0.35; 95% CI, 0.25-0.49; P < .0001).¹⁰ Long-term follow-up also demonstrated an overall survival benefit regardless of BRCA mutation; FDA approval for this indication followed in 2019.⁵

In the PAOLA-1 trial (NCT02477644), investigators combined olaparib and bevacizumab, a vascular endothelial growth factor receptor inhibitor also utilized in maintenance therapy. Patients received bevacizumab up front with platinum-based therapy and were randomized to bevacizumab with either olaparib or placebo.¹¹

During the PAOLA-1 trial, the greatest benefit was seen in patients with homologous recombination deficiency (HRD) including BRCA mutations, with a median PFS of 37.2 vs 17.7 months with placebo (HR, 0.43; 95% CI, 0.28-0.66). Subsequently, the combination obtained FDA approval as up-front maintenance in this corresponding setting.⁵

The safety profile of olaparib is consistent across all trials.^5,8-11 Among the common toxicities is myelosuppression, especially anemia, which occurs in 23% to 44% of patients. Fatigue develops in approximately 67% of patients; gastrointestinal toxicities, particularly nausea, are experienced in 45% to 77% of patients. One unique concern is pneumonitis, with an incidence in less than 1% of patients during trials.

Rucaparib

A second PARP inhibitor, rucaparib, was approved in 2016 with similar indications in ovarian cancer to olaparib.⁶ The ARIEL2 trial (NCT01891344) found a significant PFS benefit in patients with either a BRCA mutation or high loss of heterozygosity at a median PFS of 12.8 months vs 5.7 months, respectively, compared with 5.2 months in patients with low loss of heterozygosity (HR, 0.27; 95% CI 9.0-14.7; P < .0001).¹²

After the submission of further positive results from the ARIEL3 trial (NCT01968213), rucaparib was approved for maintenance therapy following response to platinum-based therapy, with median PFS doubled compared with placebo at 10.8 months vs 5.4 months (HR, 0.36; 95% CI, 0.3-0.45; P < .0001).¹³

During clinical trials, rucaparib was found to have a similar adverse effect (AE) profile to olaparib.^6,12-13 Anemia, fatigue, and nausea occurred at rates of 39%, 73%, and 76%, respectively. Additionally, dyspepsia and dysgeusia were more common with rucaparib than with olaparib.^14-16 Drug-specific concerns for rucaparib included elevated liver enzymes (60%-70%) and increased cholesterol (40%-84%).

Niraparib

In 2017, the FDA approved niraparib for maintenance treatment of patients with recurrent epithelial ovarian cancer based on the results of the NOVA trial (NCT01847274).^7,14 The study included patients with platinum-sensitive recurrent ovarian cancer with and without BRCA mutations, and niraparib was given to patients after their penultimate platinum regimen.

During the NOVA trial, all cohorts benefited from niraparib therapy, with a PFS of 21 months in the BRCA-mutated group in contrast with 5.5 months with placebo (HR, 0.26; 95% CI, 0.17-0.41; P < .0001).¹⁴ Both patients with HRD and non–BRCA-carrying patients also benefited from maintenance niraparib.

In the PRIMA trial (NCT02655016), investigators assessed niraparib in the first-line maintenance setting for patients responding to platinum-based therapy regardless of biomarker status.17 PFS in the HRD population was 21.9 vs 10.4 months (HR, 0.43; 95% CI, 0.31-0.59, P < .0001) and 13.8 vs 8.2 months in the overall population (HR, 0.62; 95% CI, 0.50-0.76; P < .0001).

To evaluate efficacy following relapse, investigators conducted a single-arm QUADRA trial (NCT02354586), which included heavily pretreated patients. The reported overall response rate was 28% in patients with HRD disease or a BRCA mutation (95% CI, 15.6-42.6; P = .00053).¹⁵

Niraparib has a similar toxicity profile to other PARP inhibitors^7,14-17; however, it is associated with the highest rates of anemia (50%-64%), neutropenia (30%-42%), and thrombocytopenia (61%-66%).⁷ Additionally, body weight and baseline platelet count predict increased risk of thrombocytopenia in the first month of treatment.7 Nausea occurs in 57% to 74% of patients; fatigue is seen in 57% of patients. Drug-specific concerns include hypertension (20%) and palpitations (10%).

Summary

PARP inhibitors have expanded treatment options in ovarian cancer. Drugs in this class are well tolerated, and discontinuations due to AEs are rare. All PARP inhibitors may rarely cause secondary hematologic malignancies, with incidence varying between trial and agent.¹⁷ Activity against BRCA mutations make this class valuable against breast cancer tumors harboring similar mutations.

Interest in olaparib and rucaparib in prostate and pancreatic cancer has increased due to the sensitivity of HRD pathways against proposed mechanisms in these cancers.^6,7 There is another PARP inhibitor, veliparib, under investigation in ovarian cancer.¹⁸

Verona Abdelmeseh, PharmD, is a PGY-2 oncology pharmacy resident at Lifespan who obtained her PharmD from St. John’s University in New York.

Britny Rogala, PharmD, BCOP, is a clinical pharmacist specialist in oncology at Women & Infants Hospital in Rhode Island and a clinical assistant professor at the University of Rhode Island.

Justin Liauw, PharmD, BCOP, is a clinical pharmacist specialist in hematology/ oncology at Lifespan who obtained his PharmD from the University of Rhode Island.

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