PARP Inhibitors for the Treatment of Ovarian Cancer

Ovarian cancer is the leading cause of death from gynecologic cancers, and the five-year survival rate is about 47.6%. Treatment course usually includes surgery, adjuvant chemotherapy, maintenance treatment, treatment for platinum-sensitive relapse, maintenance, and treatment for recurrent disease.

During a presentation at the Asembia 2020 Summit, Amy Ly Indorf, PharmD, BCOP, clinical oncology pharmacist at the University of Washington Medicine at the Seattle Cancer Care Alliance in Seattle, WA, discussed poly-ADP ribose polymerase (PARP) inhibitors, which are becoming an important part of ovarian cancer treatment.

Olaparib, rucaparib, and niraparib are PARP inhibitors that are Food and Drug Administration (FDA)-approved for ovarian cancer, and olaparib is also approved in combination with bevacizumab. In the upfront maintenance treatment setting, the phase III SOLO-1 trial assessed olaparib 300 mg versus placebo, and the median progression-free survival (PFS) was 49.9 months with olaparib versus 13.8 months with placebo (hazard ratio [HR], 0.30; P<0.001). The phase III PRIMA trial assessed niraparib 300 mg versus placebo, and the median PFS was 13.8 months versus 8.2 months, respectively, in patients who received neoadjuvant therapy (HR, 0.59). In patients who had a partial response after platinum-based chemotherapy, the median PFS was 16.4 months and 9.5 months, respectively (HR, 0.60).

In the recurrent maintenance treatment setting, the phase III SOLO-2 trial assessed olaparib 300 mg versus placebo, and the median PFS was 19.1 months versus 5.5 months, respectively (HR, 0.30). In the ARIEL3 trial, rucaparib 600 mg was compared against placebo, and the median PFS was 10.8 months versus 5.4 months, respectively (HR, 0.36). Among patients with BRCA-mutated disease, the median PFS was 16.6 months versus 5.4 months, respectively (HR, 0.23), and among patients with homologous-recombinant deficiency (HRD) disease, the median PFS was 13.6 months versus 5.4 months, respectively (HR, 0.32). The NOVA trial compared niraparib 300 mg versus placebo. Median PFS in patients with BRCA-mutated disease was 21.0 months versus 5.5 months, respectively (HR, 0.27); median PFS in patients with HRD disease without BRCA mutation was 12.9 months and 3.8 months, respectively (HR, 0.38); and median PFS among those without BRCA mutation was 9.3 months versus 3.9 months, respectively (HR, 0.45).

In the recurrent disease setting, the phase II Study 42 (SOLO-3), assessed olaparib 300 mg versus placebo and resulted in a tumor response rate of 31.1% with olaparib. In the phase I/II Study 10, rucaparib 600 mg was compared with placebo, and rucaparib resulted in an overall response rate (ORR) of 59.5%. In the phase II QUADRA study, niraparib 300 mg was compared against placebo, and the ORR with niraparib was 34% in patients with BRCA-mutated disease.

The phase III PAOLA-1 trial assessed bevacizumab 15 mg/kg plus olaparib 300 mg or placebo. The median PFS was 22.1 months in the olaparib plus bevacizumab cohort versus 16.6 months in the bevacizumab plus placebo cohort. Among patients with BRCA-mutated disease, median PFS was 37.2 months versus 17.7 months, respectively. Among patients with HRD disease, median PFS was 28.1 months versus 16.6 months, respectively. The phase II ANANOVA trial compared niraparib 300 mg with or without bevacizumab 15 mg/kg. Median PFS was 11.9 months for niraparib plus bevacizumab versus 5.5 months with niraparib alone. Among patients with BRCA-mutated disease, median PFS was 14.4 months versus 9.0 months, respectively. Among patients with HRD disease, median PFS was 11.9 months versus 6.1 months, respectively.

The VELIA trial compared chemotherapy plus veliparib 150 mg or placebo and found that median PFS was 23.5 months in the veliparib plus chemotherapy cohort versus 17.3 months in the placebo cohort. Veliparib is awaiting FDA approval. In the TOPACIO-KEYNOTE-162 trial, researchers assessed niraparib 200 mg plus pembrolizumab 200 mg. The objective response rate was 18%.

Non-hematologic adverse events (AEs) associated with PARP inhibitors include fatigue, nausea, and diarrhea. Management of these AEs within the first four to eight weeks is crucial to avoiding the need for dose reductions. Anemia, thrombocytopenia, and neutropenia are common hematologic AEs associated with this drug class. Complete blood count panels should be conducted monthly, and treatment should be discontinued if the toxicity does not recover by 28 days.

Some unique AEs associated with these drugs include pneumonitis in olaparib-treated patients; hypercholesterolemia, photosensitivity, dyspepsia, and dysgeusia in rucaparib-treated patients; and insomnia and hypertension in niraparib-treated patients.

Next, Dr. Indorf discussed quality of life associated with these therapies. “Side effects for PARP inhibitors should make us question whether or not we know or have data to support [their] use in the maintenance setting from a quality of life standpoint,” said Dr. Indorf. In a study published in 2018 in The Lancet Oncology, the PFS benefit of olaparib maintenance in recurrent, platinum-sensitive disease was achieved without impacting quality of life: The mean time without significant symptoms or toxicity was 15 months with olaparib versus 7.7 months with placebo (P<0.0001). A 2019 study published in the Journal of Clinical Oncology observed a PFS benefit of niraparib with a two- to fourfold greater mean time without significant symptoms or toxicity than patients receiving placebo among those on maintenance therapy for recurrent, platinum-sensitive disease.

An increasing number of patients are receiving oral chemotherapy at home, shifting the responsibility of treatment management from provider to patient. Assessment of adherence is critical; barriers to adherence include AEs and financial toxicity. Pharmacists should perform medication education, ensure patients have antiemetics, assess financial barriers, routinely assess symptoms, communicate dose changes and tablet sizes, and evaluate prescription refills. Recommend that patients use alarms, pill diaries, and use organizers to ensure adherence. “Patients should have written, concrete guidance for when to call, so they can self-triage at home,” said Dr. Indorf.

Treatment cost is another consideration: 30-day supplies cost approximately $17,000 for 120 olaparib tablets, $20,000 for 120 rucaparib tablets, and $26,000 for 90 niraparib capsules. “To put this into perspective,” she said, “even a 10% to 20% copay is approximately $2,100 to $4,200 for patients, which is not a realistic expectation. We should really be advocates for our patients in helping them acquire these drugs in a non-financially toxic way.” There are patient assistance programs available for all three PARP inhibitors, she noted.

Presentation: Improving Outcomes in Ovarian Cancer: Focus on PARP Inhibitors and Pharmacist Implications. Asembia 2020 Specialty Pharmacy Summit Virtual Experience, May 20, 2020.