Rachel Justus, PharmD, BCPS

 The information discussed here represents the views of the authors and does not necessarily reflect the views of the Defense Health Agency, the Department of Defense, or the Departments of the Army, Navy, and Air Force.

POLY (ADENOSINE DIPHOSPHATE [ADP]-ribose) polymerase (PARP) inhibitors have vastly changed the approach to the treatment of ovarian cancer since the first agent was approved by the FDA in 2014. PARP inhibitors bind to the PARP enzyme that repairs single-strand DNA breaks during cell replication. Single-strand DNA breaks generally lead to double-strand DNA breaks. One of the pathways to repair double-strand breaks is the homologous recombination pathway. Multiple proteins and enzymes play a role in this pathway, including BRCA, ataxia-telangiectasia mutated (ATM), and RAD51. Patients with BRCA mutations have a deficiency of BRCA protein expression, which leads to less effective repair of double-strand DNA breaks and to cell demise.

Additionally, decreased activity or expression of other repair proteins within the homologous recombination repair pathway is a factor. This is referred to as homologous recombination or repair deficiency (HRD). Understanding a patient’s BRCA mutation status, either wild type (WT) or mutated, and HRD status, is important.

Key considerations in the use of PARP inhibitors and their role in ovarian cancer are line-of-therapy and BRCA mutation status, which dictate which PARP inhibitor is an option in the line of therapy and when to use it. Currently, there are 3 FDA-approved PARP inhibitors: olaparib, rucaparib, and niraparib.

 This review will describe which FDA-approved agent can be used in which line of therapy, with a brief summary of the supporting evidence, dosing, class-related adverse effects (AEs), and drug-specific toxicities (Table).

The first opportunity patients have to receive a PARP inhibitor is after completion of platinum-based chemotherapy with partial or complete response or in those with the BRCA mutation, which is generally referred to as maintenance therapy. The agent approved in this setting is olaparib, which is supported by results from the SOLO1 trial (NCT01844986).

 Recently, results from the PRIMA trial, published in September 2019, showed positive findings for niraparib in patients with HRD and response to platinum-based chemotherapy.

 Both of these studies were in newly diagnosed advanced ovarian cancer in patients with a response to platinum-based chemotherapy.

Subjects in the SOLO1 study were required to have the BRCA mutation, whereas this was not required in the PRIMA trial (NCT02655016).

 SOLO1 showed a 70% lower risk of disease progression compared with 35% with placebo. Progression-free survival (PFS) was 60% for olaparib versus 27% with placebo (hazard ratio [HR], 0.3; P <.001) at 36 months.

 The PRIMA trial evaluated niraparib as first-line therapy in patients with newly diagnosed ovarian cancer with or without BRCA mutations. Patients treated with niraparib demonstrated a 5.6 month-longer PFS compared with patients treated with placebo (HR, 0.62; P <.001), regardless of HRD status. A subgroup analysis of patients with HRD in the PRIMA study demonstrated 11.5 months longer PFS compared with placebo (HR, 0.43; P <.001).

All 3 PARP inhibitors may be used when patients with ovarian cancer have received at least 2 lines of platinum-based chemotherapy with response regardless of BRCA mutation—meaning that patients with or without BRCA mutations can benefit from PARP inhibitor therapy (also referred to as maintenance therapy) with increased PFS. Olaparib was evaluated in 2 studies (SOLO-2 and Study 19 [NCT00753545]), in patients with and without the BRCA mutation.

 Rucaparib was studied in the ARIEL3 trial (NCT01968213) and niraparib in the NOVA trial (NCT01847274); however, neither of these studies required a BRCA mutation for enrollment.

 All of these studies were similar in design: randomized, multicenter, phase 3 studies in platinum-sensitive patients with ovarian cancer who had received at least 2 lines of platinum-based chemotherapy with response. Patients were randomized (2:1) to treatment with a PARP inhibitor or placebo. PFS was 4 to 5 months in patients treated with a PARP inhibitor, regardless of BRCA mutation status. Those patients who had BRCA mutations had an improvement of11 to 15 months in PFS.

The last opportunity patients have to receive a PARP inhibitor is if those patients have advanced ovarian cancer, with BRCA mutation and/or HRD, and have received at least 2 lines of chemotherapy. All 3 agents (rucaparib, olaparib, and niraparib) have approval in this setting and there are specific patient characteristics that dictate which agent to use. In patients with a BRCA mutation who have received 3 or more lines of previous chemotherapy, olaparib was approved by the FDA with supporting data from Study 42 (NCT01078662).

 In this study, 34% of patients had an overall response with a median PFS of 7 months. Rucaparib is FDA approved in patients with a BRCA mutation and who have received 2 or more lines of previous chemotherapy.

The supporting study is ARIEL 2 (NCT01891344, open-label), which showed longer PFS in patients with BRCA mutation at 12.8 months versus 5.7 and 5.2 months in the 2 BRCA WT groups (HR, 0.27;P <.001.) Niraparib received an indication in October 2019 for patients with HRD who have received at least 3 lines of previous chemotherapy. Niraparib’s approval was based on the open-label QUADRA trial (NCT02354586), which showed a 28% overall response in patients with HRD versus 10% in the non-HRD group.

These agents are not without AEs and risks, the most common of which include nausea, fatigue, and decreased blood counts. All PARP inhibitors carry the risk (0.5% to 1%) of myelodysplastic syndrome and acute myeloid leukemia, depending on the trial and agent.

 Drug-specific toxicities include pneumonitis with olaparib, elevated liver enzymes and cholesterol with rucaparib, and hypertension and palpitations with niraparib.

Pharmacists play a vital role in managing patients receiving PARP inhibitor therapy. Pharmacists can aid in the direct selection of agents based on their knowledge of disease stage, BRCA mutation or HRD status, and line of treatment. Once a treatment course has been selected, the pharmacist can select appro-priate dosing based on end organ function, concomi-tant medication use, weight, or platelet function, as needed. During the entire course of treatment, pharmacists can monitor and improve adherence, ensure appropriate lab monitoring and dose adjustments if needed, monitor for or manage any potential drug-drug interactions, and ameliorate AEs or toxicities. Additionally, a key pharmacist intervention is ensuring pre-medication with oral anti-emetics (eg, ondansetron 30 minutes prior to each PARP inhibitor dose) to prevent or lessen nausea. Pharmacists also provide patient education, an understanding ofthe importance of adherence, and strategies to improve adherence.

Ideally, PARP inhibitors will delay ovarian cancer recurrence or progression in the maintenance setting. The majority of patients with ovarian cancer will have disease recurrence. Regarding monotherapy, PARP inhibitors offer another treatment option and a dosage form that can be self-administered in the outpatient setting rather than through intravenous therapy every few weeks. The efficacy of PARP inhibitors earlier in the course of the disease, as well as combination therapy with agents with different mechanisms, is ongoing. Pharmacist understanding of PARP inhibitors and help in managing their use is of paramount importance.

The authors would like to acknowledge Josh Evans and Matt Brignola in the preparation of this manuscript. 

Lynparza [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2019.

Rubraca [package insert]. Boulder, CO: Clovis Oncology, Inc; 2017.

Zejula [package insert]. Waltham, MA: TESARO, Inc.; October 2019.

Moore K, Colombo N, Scambia G, et al. Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. 

González-Martín A, Pothuri B, Vergote I, et al. Niraparib in Patients with Newly Diagnosed Advanced Ovarian Cancer. 

Pujade-Lauraine E, Ledermann JA, Selle F, et al. Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial. 

Ledermann J, Harter P, Gourley C, et al. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. 

Coleman RL, Oza AM, Lorusso D, et al. Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial. 

Lord R, Mirza M, Woelber L, et al. Safety and dose modification for patients with low body weight receiving niraparib in the ENGOT-OV16/NOVA phase III trial. 

Kaufman B, Shapira-Frommer R, Schmutzler RK, et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. 

Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 

Moore KN, Secord AA, Geller MA, et al. Niraparib monotherapy for late-line treatment of ovarian cancer (QUADRA): a multicentre, open-label, single-arm, phase 2 trial. 

Mirza MR, Monk BJ, Herrstedt J, et al. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. 

Swisher EM, Lin KK, Oza AM, et al. Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial. 

Articles

Rucaparib is FDA approved in patients with a BRCA mutation and who have received 2 more prior lines of previous chemotherapy.