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Maintenance Therapy in Ovarian Cancer: Emerging Data on PARP Inhibitors

Cara Iacobellis, PharmD
Hematology/Oncology Clinical Pharmacist
Augusta University Medical Center (AUMC)
Augusta, GA

Using poly adenosine diphosphate–ribose polymerase (PARP) inhibitors in the treatment of ovarian cancer is not a new concept. The first PARP inhibitor to be used in this setting, olaparib, gained U.S. Food and Drug Administration (FDA) approval in 2014 for the treatment of patients with deleterious or suspected deleterious germline BRCA-mutated recurrent ovarian cancer. Since olaparib’s initial approval, PARP inhibitors have become an area of developing research and an attractive option for many patients because it is an oral agent. Multiple PARP inhibitors are now indicated as treatment (olaparib, rucaparib) and as maintenance therapy for recurrent ovarian cancer (olaparib, rucaparib, and niraparib).1 The role of PARP inhibitors in advanced ovarian cancer will continue to grow as new data emerge.

PARP inhibitors exhibit their clinical effect by arresting PARP proteins involved in several DNA repair processes, including single-strand repair.2 This action is of particular value in treating BRCA-mutated ovarian cancer because these mutations prevent the repair of double-strand DNA breaks and create reliance on the single-strand repair pathway, which is disrupted by PARP inhibition. This can result in the targeted death of BRCA-mutated cancer cells. BRCA mutation occurs in between 6% and 35% of the population with ovarian cancer, depending on the histology.3 Additionally, PARP inhibitors have been studied in BRCA wild-type patients. They still have a benefit over placebo in this setting, though the response is less pronounced than that found in BRCA-mutated ovarian cancer.4-6 Therefore, PARP inhibitors are indicated as maintenance therapy regardless of BRCA-mutation status in platinum-sensitive recurrent ovarian cancer.

In light of these FDA approvals, a large subset of patients with ovarian cancer will qualify for and potentially receive therapy with a PARP inhibitor. Pharmacists are in a unique position to provide education to physicians, patients, and caregivers on appropriate monitoring and side effect management for these agents.

Niraparib

Niraparib’s FDA approval in 2017 was based on results from a phase 3 trial, NOVA. This trial randomized 553 patients with platinum-sensitive relapsed ovarian cancer with or without a germline BRCA mutation who had received at least two prior lines of chemotherapy to receive either niraparib (300 mg by mouth [PO] daily) or placebo following platinum-based therapy. Of note, patients were required to start niraparib no later than 8 weeks after completing their last dose of platinum-based therapy. Patients treated with niraparib were demonstrated to have a significant improvement in progression-free survival (PFS), whether BRCA mutation–positive (median PFS 21 vs. 5.5 months; hazard ratio [HR] 0.27; 95% confidence interval [CI] 0.17–0.41; p < .001) or negative (median PFS 9.3 vs. 3.9 months; HR 0.45; 95% CI 0.34–0.61; p < .001).5 Niraparib was the first PARP inhibitor to be FDA approved for maintenance therapy of recurrent ovarian cancer, and it was the first PARP inhibitor to be approved for use regardless of BRCA-mutation status.

Olaparib

SOLO-2, published in July 2017, was the first phase 3 study to evaluate olaparib as maintenance treatment for recurrent ovarian cancer. This trial randomized 295 platinum-sensitive relapsed ovarian cancer patients with a BRCA mutation who had received at least two prior lines of chemotherapy to receive olaparib (300 mg twice daily) or placebo. PFS was evaluated as the primary endpoint, and it was found that treatment with olaparib resulted in a significantly longer PFS (19.1 months) compared to placebo (5.5 months; HR 0.30; 95% CI 0.22–0.41; p < .0001).7 These results, along with prior phase 2 results finding benefit regardless of BRCA-mutation status, were the basis of olaparib’s FDA approval as a maintenance treatment option for recurrent ovarian cancer regardless of BRCA-mutation status.8

In October 2018, a new phase 3 trial, SOLO-1, was published. This trial evaluated newly diagnosed patients with BRCA-mutated advanced ovarian cancer following a response to platinum-based chemotherapy. The trial randomized 391 patients to receive olaparib or placebo. The results showed that after a median of 40.7 months of follow-up, a median PFS was not reached in the olaparib group. Kaplan–Meier estimates of the rate of freedom from disease progression and death at 3 years was significantly higher in the olaparib group compared to placebo (60% vs. 27%; HR 0.30; 95% CI 0.23–0.41; p < .001).9

SOLO-1 is one of the first trials to evaluate PARP inhibitor maintenance therapy in newly diagnosed ovarian cancer. Although the data have not yet been given time to mature, maintenance therapy with olaparib introduced earlier in the treatment pathway could reveal a promising new role for PARP inhibitor therapy and a potential replacement to alternative maintenance therapies such as bevacizumab. It also reinforces the importance of identifying a patient’s BRCA-mutation status at diagnosis.

Rucaparib

Rucaparib was approved by the FDA for maintenance therapy in April 2018 on the basis of results from the ARIEL3 trial. This randomized double-blind trial enrolled 561 patients with platinum-sensitive recurrent ovarian cancer with or without a BRCA mutation who had been treated with at least two prior lines of therapy to receive either rucaparib (600 mg PO twice daily) or placebo. ARIEL3 demonstrated a statistically significant improvement in estimated PFS in patients receiving rucaparib compared with placebo (median PFS 10.8 vs. 5.4 months; HR 0.36; 95% CI 0.30–0.45; p < .0001).6 Rucaparib represents the newest option for maintenance therapy in advanced recurrent ovarian cancer.

Safety

PARP inhibitor therapy is administered as an oral tablet either once or twice daily, depending on the agent. Compared to alternative maintenance therapy options such as bevacizumab, an intravenous infusion given every 3 weeks, some patients prefer PARP inhibitor therapy because of convenience. However, using an oral dosage form has specific challenges. Prescribers must be judicious in their selection of an appropriate candidate, given that compliance cannot be monitored as readily as with clinician-administered intravenous therapies. Adverse effects like nausea and fatigue can also increase noncompliance and potentially affect the treatment efficacy of an oral agent. In addition, any recent history of small-bowel obstruction or extensive peritoneal disease creates a concern about malabsorption of oral therapy.

All three available PARP inhibitors have the potential to cause fatigue, myelosuppression, and gastrointestinal side effects. Comparative studies have found that all three PARP inhibitors have similar efficacy when used as maintenance therapy in BRCA-mutated ovarian cancer, but olaparib tends to be better tolerated and is associated with a lower incidence of dose interruption and discontinuation.10 Olaparib is also a major substrate of CYP3A4 and the only PARP inhibitor with CYP-related drug interactions requiring dose adjustment. It is recommended that patients avoid taking olaparib in combination with moderate to strong CYP3A4 inducers (e.g., rifampin, carbamazepine, phenobarbital, and phenytoin). Olaparib’s dose should be reduced to 150 mg twice daily or 100 mg twice daily for moderate to strong CYP3A4 inhibitors (e.g., amiodarone, diltiazem, ketoconazole, ritonavir, and clarithromycin), respectively.

It is imperative that all patients and providers be counseled on how to identify and manage such side effects. Typically, brief dose interruptions and supportive care medications allow the resumption of therapy. However, more severe or recurrent toxicities may require a dose reduction of the PARP inhibitor or its discontinuation.

Gastrointestinal Toxicity
Gastrointestinal (GI) side effects are fairly common, especially in the first few weeks of therapy. Nausea, vomiting, and diarrhea occur in around 70%, 35%, and 25% of patients, respectively. Taking the PARP inhibitor with food or immediately prior to bedtime may help ameliorate some of these side effects. Antiemetics should be prescribed with initiation of treatment and can be taken prophylactically 30–60 minutes prior to the dose. In patients with constipation, low-dose olanzapine has been used as an alternative to ondansetron.11 However, olanzapine is associated with sedation and may not be an appropriate option for all patients. Some data also suggest that rucaparib can be initiated at a lower dose to improve GI tolerability and then increased to full dosing after 3–4 weeks.12 If a dose of a PARP inhibitor is missed or vomited, an additional dose should not be taken.

For cases of diarrhea, patients should be counseled to maintain adequate fluid intake to avoid dehydration. Other causes for diarrhea, such as infection or progression of disease, should also be ruled out. In the absence of infection, antimotility agents such as loperamide can be considered in addition to dietary modifications.

Myelosuppression
Anemia, leukopenia, and thrombocytopenia are fairly common side effects. Between 20% and 40% of patients will develop myelosuppression, with the highest incidence occurring in those treated with niraparib, which has a dose-limiting toxicity of thrombocytopenia and more stringent monitoring parameters. Red blood cell or platelet transfusions may be appropriate in certain patients. In addition, underlying causes of anemia, such as iron, folic acid, and vitamin B12 deficiency, should be investigated. Erythropoiesis-stimulating agents are generally not recommended. Instead, treatment can be temporarily interrupted until count recovery. Complete blood cell counts (CBCs) should be checked monthly for rucaparib and olaparib, and weekly monitoring for the first 4–6 weeks is advised for niraparib. Some experts suggest starting niraparib at a reduced dose during the first 4–6 weeks of therapy in patients with baseline myelosuppression.11 Subgroup analyses have also revealed that patients with a baseline platelet count lower than 150,000 or weight less than 77 kilograms may be at a higher risk of developing thrombocytopenia, and a lower starting dose is warranted in these populations.5 Bleeding precautions and signs of severe bleeding should be reviewed with patients.

Fatigue
Fatigue is a common side effect that can occur in up to 60% of patients. This side effect warrants evaluation of other underlying causes such as anemia, depression, and sedation from concomitant medications as well as consultation with physical therapy or psychosocial intervention.

Serum Creatinine Elevation
Olaparib and rucaparib are associated with serum creatinine elevations due to an impact on the multidrug and toxin extrusion transporters.11 A rise in creatinine typically occurs early in treatment, but other causes should still be ruled out, such as administration of concomitant nephrotoxins or hydronephrosis (a fairly common complication in ovarian cancer because of the location of the tumor burden). Dose reduction for renal impairment is required for both olaparib and rucaparib.

Elevations of Transaminase Levels
Elevations in transaminase levels are typically benign and are not associated with organ dysfunction. They more commonly occur with rucaparib treatment, especially in the first 4 months of therapy. Transaminase elevations are often transient and resolve over time. Patients receiving rucaparib should be counseled to avoid hepatotoxic drugs and alcohol.

Hypertension and Palpitations
Treatment with niraparib can result in hypertension (20% of patients) and palpitations (10% of patients).11 Patients should be advised to obtain a blood pressure monitor and check their blood pressure at home regularly. Heart rate and blood pressure should also be monitored monthly in the clinic. Caution is advised for patients with preexisting cardiovascular disorders, and they should be closely monitored.

Rash
All PARP inhibitors can cause rash in up to 20% of patients. Rashes induced by rucaparib may be photosensitive, and patients should be counseled to reduce sun exposure and wear sunblock lotion.

Rare but Serious Toxicities
Myelodysplastic syndrome or acute myeloid leukemia can occur in 0.5%–2% of patients treated with PARP inhibitors. The development of a secondary malignancy is postulated to occur as a result of inhibition in compensatory repair pathways, especially in patients with germline BRCA mutations, in addition to prior exposure to cytotoxic agents.13 Patients with prolonged myelosuppression or a concern for development of a secondary malignancy should have PARP treatment discontinued and be referred promptly to a hematologist for further evaluation.

Pneumonitis has a less than 1% incidence, but it is an adverse event that pharmacists should watch for in patients who present with worsening dyspnea, cough, fever, or associated radiographic changes.

Future Directions

Multiple open studies have included PARP inhibitors. For example, the ongoing phase 3 trial PAOLA-1 is evaluating olaparib in combination with bevacizumab as maintenance treatment for patients with newly diagnosed advanced ovarian cancer, regardless of their BRCA-mutation status. A combination of olaparib and the vascular endothelial growth factor (VEGF) antagonist cediranib is being investigated as a treatment strategy for recurrent ovarian cancer. Trials with veliparib may also eventually establish PARP inhibitors as a front-line treatment option. As the indications for PARP inhibitor therapy expand, clinicians will be able to provide more effective treatment options to their patients, and PARP inhibitor therapy will continue to become more common. Pharmacists can ensure that the prescribing of PARP inhibitor therapy is accompanied by proper monitoring and education.

References

  1. U.S. Food and Drug Administration. FDA approves olaparib tablets for maintenance treatment in ovarian cancer. August 17, 2017. Available at https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm572143.htm
  2. O’Connor MJ. Targeting the DNA damage response in cancer. Mol Cell. 2015;60:547-560.
  3. Cecere SC, Pignata S. BRCA1 and BRCA2 in Ovarian Cancer: ESMO Biomarker Factsheet. July 25, 2016. Available at https://oncologypro.esmo.org/Education-Library/Factsheets-on-Biomarkers/BRCA1-and-BRCA2-in-Ovarian-Cancer
  4. Ledermann J, Harter P, Gourley C, et al. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N Engl J Med. 2012;366(15):1382-1392.
  5. Mirza MR, Monk BJ, Herrstedt J, et al., for the ENGOT-OV16/NOVA Investigators. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N Engl J Med. 2016;375:2154-2164.
  6. 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. Lancet. 2017;390:1949-1961.
  7. 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. Lancet Oncol. 2017;18:1274-1284.
  8. Ledermann J, Harter P, Gourley C, et al. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N Engl J Med. 2012;366(15):1382-1392.
  9. Moore K, Colombo N, Scambia G, et al. Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. 2018.;379(26):2495-2505.
  10. Sackeyfio A, Nussel F, Friedlander M, et al. Comparative efficacy and tolerability of the PARP inhibitors, olaparib 300 mg tablets BID, niraparib 300 mg capsules QD and rucaparib 600 mg tablets BID as maintenance treatment in BRCA-mutated (BRCAm) platinum-sensitive relapsed ovarian. Gynecologic Oncology. 2018;149:43-44.
  11. O’Cearbhaill RE. Using PARP inhibitors in advanced ovarian cancer. Oncology (Williston Park). 2018;32(7):339-343.
  12. Drew Y, Ledermann J, Hall G, et al. Phase 2 multicentre trial investigating intermittent and continuous dosing schedules of the poly(ADP-ribose) polymerase inhibitor rucaparib in germline BRCA mutation carriers with advanced ovarian and breast cancer. Br J Cancer. 2016;114:723-730.
  13. Ricks T, Chiu H, Pazdur R. Successes and challenges of PARP inhibitors in cancer therapy. Front Oncol. 2015;5:222.
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