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PARP inhibition in ovarian cancer: Is one agent better than another?
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The introduction of poly (ADP-ribose) polymerase, or PARP, inhibitors has made a significant impact in ovarian cancer, prolonging PFS among certain patients, particularly those with BRCA mutations.
PARP inhibitors are the first FDA-approved cancer treatments designed to exploit a phenomenon known as synthetic lethality, during which two genetic aberrations that are not necessarily significant when they occur separately result in substantial cytotoxicity when they occur together.
Over time, cells are exposed to genotoxic stress that damage DNA, leading to single- or double-strand breaks. PARP enzymes have an important role in repairing single-strand breaks through the base excision repair (BER) pathway. When PARP enzymes are inhibited, single-strand breaks persist, leading to double-strand breaks.²
BRCA1 and BRCA2 tumor suppressors play a critical role in the repair of double-strand breaks through the homologous recombination (HR) repair pathway. Tumors with BRCA mutations develop deficiency in the HR repair pathway. Therefore, when PARP is inhibited in BRCA-mutated tumor cells, the limited function of two DNA repair pathways — BER and HR — leads to an accumulation of DNA damage, resulting in cell death and thus synthetic lethality among the BRCA-mutated tumor cells, but not healthy cells.
There are three PARP inhibitors approved by the FDA for ovarian cancer: Olaparib (Lynparza; AstraZeneca, Merck), rucaparib (Rubraca, Clovis Oncology) and niraparib (Zejula, Tesaro). In recent years, these agents have become standard care for heavily pretreated patients with recurrent, platinum-sensitive, BRCA-mutated ovarian cancer. To date, data suggest that all three inhibitors are equally efficacious, according to Ursula A. Matulonis, MD, director and chief of gynecologic oncology at Dana-Farber Cancer Institute.
“The phase 3 maintenance trials have comparable benefits to women in terms of PFS, which spans the degree of underlying DNA repair from BRCA-mutated cancer to HR-deficient (HRD) BRCA wildtype to HRD-negative and BRCA wildtype,” she said. “So, from an efficacy standpoint, I think of them as all being equivalent.”
Consequently, deciding which PARP inhibitor to prescribe — and when — remains a hot topic in the field.
Olaparib
Olaparib was the first PARP inhibitor to receive regulatory approval in the United States. The agent was approved by the FDA in December 2014 as monotherapy for heavily pretreated women with germline BRCA-mutated ovarian cancer who received three or more rounds of chemotherapy treatment. The tablet formulation of olaparib — which was previously available in capsules — was approved more than 2 years later with an additional indication as maintenance therapy in addition to monotherapy. The maintenance therapy indication now includes patients with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer, regardless of BRCA mutation status, whose tumors have completely or partially responded to first-line platinum-based chemotherapy. The decision was based on findings from the phase 3 SOLO-1 trial, which showed that olaparib maintenance therapy reduced the risk for progression or death by 70% (HR = 0.3; 95% CI, 0.23-0.41) among BRCA-positive patients randomly assigned to olaparib (n = 260) vs. placebo (n = 130) after chemotherapy, as well as Study 19, which was a randomized phase 2 trial of olaparib vs. placebo in women with high-grade serous ovarian cancer, regardless of BRCA status, who responded to platinum chemotherapy.
In January 2018, olaparib also became the first treatment for germline BRCA-mutated, HER-2-negative breast cancer.
Rucaparib
Rucaparib monotherapy received accelerated approval in December 2016 for women with advanced BRCA-mutated ovarian cancer who were previously treated with least two chemotherapy regimens. In April 2018, the agent was also approved as maintenance therapy for women with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy. The approval was based on data from the ARIEL3 trial, which showed rucaparib improved PFS compared with placebo in 561 patients with ovarian cancer (median PFS, 10.8 months vs. 5.4 months; HR = 0.36; 95% CI, 0.3-0.45).
Niraparib
In March 2017, niraparib was approved as maintenance therapy for patients with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancers, regardless of BRCA status, who achieved at least a partial response to platinum-based chemotherapy.
Results of the ENGOT-OV16/NOVA trial showed that niraparib significantly prolonged PFS in patients with BRCA mutations (n = 203; 21 months vs. 5.5 months; HR = 0.27; 95% CI, 0.17-0.41) and without BRCA mutations (n = 350; 9.3 months vs. 3.9 months; HR = 0.45; 95% CI, 0.34-0.61) compared with placebo.
Differences in safety
All three agents are associated with adverse events related to bone marrow suppression, including thrombocytopenia, anemia, neutropenia and fatigue, as well as gastrointestinal toxicities such as nausea, vomiting, dysgeusia, abdominal distention, anorexia, poor appetite, diarrhea and constipation, according to Matulonis.
Niraparib has the highest rate of thrombocytopenia (any grade, 61%, vs. 29% for rucaparib and 11% for olaparib), which most often occurs during the first 4 to 6 weeks of treatment. Hypertension and palpitations are also common with niraparib because of an off-target effect on norepinephrine, dopamine and serotonin transporters. Meanwhile, olaparib and rucaparib are associated with elevated serum creatinine due to effects on organic cation transporters and multidrug and toxin extrusion proteins.
Other notable toxicities include pneumonitis, particularly with olaparib, and an increase in cholesterol, phonosensitivity and rash with rucaparib, according to Matulonis. Although rare, there is also a risk for myelodysplastic syndrome and acute myeloid leukemia, which occurs in 0.5% to 2% of patients treated with a PARP inhibitor.
“When prescribing treatment, each physician must understand the most common side effects, but also the more rare toxicities associated with each of these agents,” Matulonis said.
Patients must be carefully monitored for low blood counts before and during treatment with PARP inhibitors, she added.
“When a patient is finishing up platinum-based chemotherapy, it is really important that physicians wait until platelet and neutrophil counts become normal and for the red blood-cell count to be as optimal as possible before starting a PARP inhibitor,” she said.
After starting treatment with a PARP inhibitor, Matulonis said patients’ complete blood counts (CBC) should be frequently monitored for cytopenias. According to the package insert for niraparib, CBCs should be assessed weekly during the first month of therapy, monthly for the next 11 months and periodically thereafter.¹⁴ Meanwhile, the package inserts for rucaparib and olaparib recommend screening CBCs at baseline and monthly thereafter. However, Matulonis said patients receiving rucaparib and olaparib should potentially be screened more often.
“If you were concerned with a patient’s blood count while she was on chemotherapy, then I would check her CBC weekly for at least the first month after she starts treatment with any PARP inhibitor, just to make sure the patient’s blood counts are sufficient,” she said.
Pharmacokinetic profiles
The pharmacokinetics of each inhibitor varies. Niraparib (300 mg) has a 36-hour half-life, allowing for once-daily dosing, whereas the half-lives of olaparib (300 mg) and rucparib (600 mg) are 12 hours and 18 hours, respectively, and therefore require twice-daily dosing.¹⁴,¹⁵,¹⁶
Olaparib is primarily metabolized by CYP3A4/5 and should not be co-administered with other strong CYP3A4 inhibitors. If co-administration with another CYP3A4 inhibitor cannot be avoided, physicians should reduce the dose of olaparib to 100 mg twice daily. Patients should also avoid consuming grapefruit, Seville oranges and their juices since these inhibit CYP3A4.
Rucaparib is primarily metabolized by CYP2D6 and, to a smaller extent, by CYP1A2 and CYP3A4. Co-administration with CYP1A2, CYP3A, CYP2C9 and CYP2C19 substrates can increase the risk for toxicities. If co-administration is unavoidable, the dosage of these substrates should be adjusted as needed.
Niraparib is metabolized by carboxylesterase enzymes. To date, no formal drug interaction studies have been conducted, so there are currently no known interactions with the agent.
Cost-effectiveness
In a previous interview with Healio, Jai N. Patel, PharmD, BCOP, chief of pharmacology research and associate professor at Atrium Health’s Levine Cancer Institute, said there are not enough data on the pharmacokinetics, indications, toxicity profiles and efficacy of PARP inhibitors to determine whether one should be prescribed over another. As a result, the market could drive selection.
Juliet E. Wolford, MD, of the University of California, Irvine, and colleagues used a Markov chain model to estimate the cost effectiveness of FDA-approved PARP inhibitors as maintenance therapy for advanced ovarian cancer. Their analysis was adjusted for pretreatment medication costs, infusion center charges and costs to manage adverse events. The findings, presented at ASCO 2017, revealed that olaparib was the most cost-effective PARP inhibitor at $16,469 per month of PFS, followed by rucaparib at $16,781 per month of PFS and niraparib at $18,157 per month of PFS.
The results further showed that PARP inhibitors cost 7.1 to 8.3 times more than platinum-based combinations, which were estimated to be $1,672 per month of PFS. In most cases, however, insurance companies will cover the cost of PARP inhibitors, according to Matulonis.
“The question is, what copay will patients have?” she said. “Some patients may have a $30 copay, which is certainly reasonable. But when they start having a copay of $1,000 to $2,000, that is just not acceptable.”
To ease the burden, Matulonis said patients can apply for aid through patient assistance programs.
“My nursing team and prior authorization team focus on accessing PARP inhibitors so that patients are not left with large copays when they are being prescribed treatment,” she said.
PARP inhibitors, combinations in the pipeline
There are several PARP inhibitors for ovarian cancer in the pipeline, according to Matulonis:
- veliparib (ABT-888, Abbvie), which is being investigated for newly-diagnosed advanced ovarian cancer, as well as non-small cell lung cancer and BRCA-mutated breast cancer;
- 2X-121 (Oncology Venture), which is currently being tested in women with advanced and recurrent ovarian cancer; and
- talazoparib (Talzenna, Pfizer), which is being assessed as treatment and maintenance therapy in combination with avelumab (Bavencio; EMD Serono, Pfizer).
As physicians become more familiar with PARP inhibitors and managing associated toxicities, the next obstacle will be to administer the agents with other therapeutic strategies, Roisin E. O'Cearbhaill, MD, medical oncologist at Memorial Sloan Kettering Cancer Center, wrote in Oncology. Researchers are currently investigating combinations of PARP inhibitors with immunotherapies and other targeted drugs, including MEK, MYC, PI3K, WEE1, ATR and CHEK1/2 inhibitors.
Trials that have reached phase 3 development include the PAOLA-1 trial, which is testing olaparib plus bevacizumab (Avastin, Genentech) as maintenance therapy for patients with newly-diagnosed, advanced ovarian cancer, regardless of BRCA status; the ICON 9 trial, which is comparing maintenance therapy with olaparib plus cediranib (AZD2171, AstraZeneca) vs. olaparib alone in women with relapsed, platinum-sensitive ovarian, fallopian tube or peritoneal cancer; and a trial evaluating avelumab plus chemotherapy followed by maintenance therapy with avelumab plus talazoparib in patients with previously untreated advanced ovarian cancer.
“While these combinations will add to the formidable array of choices with which patients and their clinicians already must contend, they will also allow clinicians to provide more effective treatments, more closely tailored to the individual needs of each patient,” O’Cearbhaill wrote.
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FDA. FDA approved olaparib (LYNPARZA, AstraZeneca Pharmaceuticals LP) for the maintenance treatment of adult patients with deleterious or suspected deleterious germline or somatic BRCA-mutated (gBRCAm or sBRCAm) advanced epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete or partial response to first-line platinum-based. https://www.fda.gov/drugs/fda-approved-olaparib-lynparza-astrazeneca-pharmaceuticals-lp-maintenance-treatment-adult-patients. Accessed May 6, 2019.
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