Real-World Data Identify Significant Differences in Tolerability Among Approved PARP Inhibitors in Ovarian Cancer

David O’Malley, MD

Patients with ovarian cancer treated with FDA-approved PARP inhibitors had significant differences in the incidence of clinically relevant adverse events (AEs), according to results of a real-world analysis presented at the 2022 ASCO Annual Meeting.

The findings highlight differences in tolerability, use, and dose modifications associated with olaparib (Lynparza), niraparib (Zejula), and rucaparib (Rubraca) for patients treated with ovarian cancer between January 1, 2017, and December 31, 2020.

Crude results found that clinical events of interest (CEIs) were generally stable across calendar years, but were lower with olaparib vs niraparib for most years. Furthermore, the risk of any CEI, as well as time to PARP dose decrease and PARP dose discontinuation, was significantly different with niraparib compared with olaparib and with niraparib compared with rucaparib.

In a multivariable Cox regression analysis, the adjusted hazard ratio (HR) of any CEI with niraparib vs olaparib was 1.34 (95% CI, 1.19-1.52; P < .001), compared to 1.13 with rucaparib vs olaparib (95% CI, 0.96-1.33; P = .1318) and 1.19 with niraparib vs rucaparib (95% CI, 1.01-1.40; P = .0385). The risk of all-cause hospital admission with niraparib vs olaparib was 1.46 (95% CI, 1.15-1.84; P = .0016), compared to 1.38 with rucaparib vs olaparib (95% CI, 1.03-1.86; P = .0301) and 1.05 with niraparib vs rucaparib (95% CI, 0.79-1.40; P = .7257).

Adjusted HR for time to dose reduction with niraparib vs olaparib was 1.78 (95% CI, 1.43-2.22; P < .001), compared with 1.31 with rucaparib vs olaparib (95% CI, 0.97-1.75; P = .0744) and 1.37 with niraparib vs rucaparib (95% CI, 1.03-1.81; P = .0317). For treatment discontinuation, the adjusted HR was 1.73 with niraparib compared with olaparib (95% CI, 1.47-2.02; P < .001), 1.35 with rucaparib vs olaparib (95% CI, 1.09-1.66; P = .0056), and 1.28 with niraparib vs rucaparib (95% CI, 1.05-1.57; P = .0161).

“Tolerability, or how well patients cope with the [adverse] effects of treatment, is a key consideration when selecting a PARP [inhibitor],” David O’Malley, MD, professor in the Department of Obstetrics and Gynecology at The Ohio State University College of Medicine and the director of the Division of Gynecologic Oncology at the OSUCCC – James, and coinvestigators, wrote in a poster of the data. “Here we expand on earlier work to further explore real-world tolerability and dose changes in patients with ovarian cancer receiving PARP therapy in the [US]; we also investigate how many patients continue PARP [inhibitor] therapy without treatment gaps.”

Two US claims databases were used to identify evaluable patients. For each PARP inhibitor regimen, investigators described changes to dosing, frequency of clinical events of interest (CEIs), and the proportion of patients who continued therapy for at least 6 months with no treatment gaps greater than 90 days.

CEIs were based on adverse effects described in the agents’ prescribing information and included acute myeloid leukemia/myelodysplastic syndromes, anemia, leukopenia, neutropenia, thrombocytopenia, acute kidney injury, arthralgia, constipation, diarrhea, nausea, vomiting, dermatitis, rash, or photosensitivity, fatigue, hypertension, infection, insomnia, pneumonitis, and transaminitis.

Patient characteristics were generally balanced across the 3 treatment groups. The median age was 58.0 years, 59.0 years, and 58.0 years, among the olaparib (n = 637), niraparib (n = 538), and rucaparib (n = 227) groups, respectively.The mean National Cancer Institute–adapted Charlson Comorbidity Index scores were 0.7, 0.8, and 0.8, respectively. Furthermore, the percentage of patients with treatment history of systemic chemotherapy was 91.7%, 92.9%, and 91.6%, respectively. Evidence of metastatic disease was present in 82.1%, 84.8%, and 86.3% of patients, respectively.

In addition, 81.1% (n = 516), 79.6% (n = 428), and 83.7% (n = 190) of patients in the olaparib, niraparib, and rucaparib groups had insurance through commercial payers, and 19.0% (n = 121), 20.4% (n = 110), and 16.3% (n = 37) of patients, respectively, had a Medicare supplemental insurance.

At a median follow-up time of 10.1 months (interquartile range [IQR], 12.7), in the olaparib group, 9.6 months (IQR, 14.2) in the niraparib group, and 11.7 months (IQR, 13.3) in the rucaparib group, the percentage of dose reductions was 22.6% (n = 144/637), 34.8% (n = 187/538), and 28.6% (n = 65/227), respectively.

The highest indicated doses for each PARP inhibitor were 600 mg daily for olaparib, 300 mg daily for niraparib, and 1200 mg daily for rucaparib, and 800 mg daily for olaparib capsules.

In total, 89.2% of patients receiving olaparib, 57.6% of patients receiving niraparib, and 89.9% of patients receiving rucaparib, initiated treatment at the highest indicated dose. In both the olaparib and rucaparib treatment arms, 1 patient began treatment above the recommended dose, and all remaining patients began treatment below the recommended dose.

Overall, the crude number of patients impacted by a clinical event of interest (CEI) was significantly fewer in in the olaparib treatment group (65.9%), compared with the patients receiving niraparib (77.5%; P < .001) and rucaparib (79.3%; P < .001). Patients who began treatment with the highest recommended dose experienced a significantly lower number of CEI incidences with olaparib (66.4%; n = 337/568) compared with niraparib (82.3%; n = 255/310; P < .001) or rucaparib (80.9%; n = 165/204; P < .001).

The proportion of patients who experienced CEIs was numerically higher in patients taking niraparib (71.1%) below the recommended dose vs those taking olaparib at the highest recommended dose (66.4%) or below the recommended dose (63.2%).

“Regardless of whether patients started treatment at or below the recommended dose, the prevalence of CEIs differed across the PARP [inhibitor] treatments,” wrote study authors. “Differences were also seen in the proportions of patients persistent with treatment, the risk of experiencing CEIs and inpatient hospital admissions, and the time to dose decreases and ending treatment, even after variations in patient characteristics were taken into account.”

In regard to persistence, patients taking olaparib (83.4%) demonstrated the highest rates of treatment persistence compared with those taking niraparib (73.3%; P < .001) or rucaparib (80.2%; P = .341). This trend was consistent with observations among patients taking PARP inhibitors at the various recommended doses: persistence was significantly higher with olaparib treatment vs niraparib treatment (84.2% vs 71.1%; P < .001), and numerically higher with olaparib compared with rucaparib (84.2% vs 79.4%; P = .174).

Reference

O’Malley D, Arend RC, Alam N. Real-world use, tolerability, and dose modifications of PARP inhibitors in ovarian cancer. J Clin Oncol. 2022;40(suppl 16):5552. doi:10.1200/JCO.2022.40.16_suppl.5552