Patients with relapsed, advanced, high-grade ovarian cancer achieved durable responses with the PARP inhibitor niraparib (Zejula) as fourth-line therapy and beyond, the phase II QUADRA trial showed.
Kathleen N. Moore, MD
Patients with relapsed, advanced, high-grade ovarian cancer achieved durable responses with the PARP inhibitor niraparib (Zejula) as fourth-line therapy and beyond, the phase II QUADRA trial showed.1
Treatment with niraparib led to an overall response rate of 27% in the target population: fourth-line therapy or beyond for homologous recombination deficiency (HRD)-positive, platinum-sensitive tumors. The PARP inhibitor demonstrated activity inBRCA-mutant andBRCAwild-type tumors.
The median duration of response (DoR) for the target population was 9.2 months, lead study author Kathleen N. Moore, MD, reported at the 2018 ASCO Annual Meeting in Chicago, Illinois.
“The duration of responses exceeded what we are accustomed to seeing in patients treated in fourth line and beyond,” said Moore, director of the OKLAHOMA TSET Phase I Clinical Trials Program at the University of Oklahoma, and associate director of clinical research for the Stephenson Cancer Center in Oklahoma City. “This was a very difficult population, and responses to niraparib were durable across the entire population.”
A growing population of patients with heavily pretreated ovarian cancer represents a high unmet clinical need. Limited data on cytotoxic chemotherapy in fourth line or later suggests a response rate of ≤10% and a median overall survival (OS) of 5 to 9 months. Use of platinum-based chemotherapy beyond third relapse is uncommon, and most patients are considered platinum ineligible by this point, Moore and colleagues stated in a poster presentation.
Several PARP inhibitors have been approved for the treatment of patients withBRCA-mutant ovarian cancer. Single-agent activity beyond that population is not well defined, although a phase I trial of niraparib in patients with heavily pretreated ovarian cancer demonstrated activity inBRCA-mutant and wild-type disease.2
Moore and colleagues reported findings from the large, open-label, single-arm QUADRA study, which involved patients with relapsed, advanced, high-grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer. Eligible patients had received at least 3 prior chemotherapy regimens and had undergone tumor HRD and blood germlineBRCAmutation testing. Patients received oral niraparib 300 mg daily in 28-day cycles.
The primary endpoint was objective response rate (ORR) in HRD-positive patients with platinum-sensitive tumors and no prior PARP inhibitor therapy. After enrollment of 292 patients, the study protocol was amended to limit enrollment to patients with 3 or 4 prior chemotherapy regimens and who had a response to first-line platinum-based chemotherapy lasting ≥6 months.
Investigators enrolled and treated a total of 463 patients, who had a median age of 65 (range, 29-91), with 13% over the age of 75. Data on baseline characteristics showed that 161 patients were platinum refractory, 151 were platinum resistant, 120 were platinum sensitive, and 31 had unknown platinum sensitivity status.
Moore reported that 188 patients received niraparib as fourth-line therapy, 144 as fifth line, and 126 as sixth line or later, with a median number of prior therapies of 4 (range, 2-16). Patient records showed that 37 of the 463 patients (8%) had received 1 prior course of platinum therapy, 235 (51%) had received 2, 147 (32%) had received 3, 37 (8%) had received 4, and 7 (2%) had received 5 or more prior platinum regimens.
Molecular test results showed that 19% of patients hadBRCA-mutant tumors, including 58 with germline mutations and 29 with somatic mutations, and 48% were HRD positive.
In the target population of patients with platinum-sensitive, HRD-positive tumors receiving niraparib as fourth or fifth-line therapy, the ORR was 29% (95% CI, 16%-44%;P= .0003) in 45 patients. In the expanded primary population (n = 51) that included patients treated in fourth line or later and who had sensitivity to the last platinum regimen, the ORR was 27%.
An additional 21 patients (41%) in the expanded population had stable disease for at least 16 weeks, resulting in a disease control rate of 69%. The expanded target population had a median DoR of 9.2 months and a median OS of 19.0 months.
Benefit with niraparib was also seen across patient subgroups. Among patients with platinum-resistant or refractory disease, the clinical benefit rate was 43% in those withBRCAmutations, 33% in those with HRD-positive disease (includingBRCAmutations); 28% in the HRD-positive,BRCAmutant-excluded group, and 18% in patients who had HRD-negative or unknown disease.
For all evaluable patients treated in fourth line or beyond, the ORR was 10%, and the clinical benefit rate was 35%. The median DoR was 9.4 months (95% CI, 6.6-18.3), and 44% of patients had responses lasting 12 months or longer. The median OS was 17.2 months (95% CI, 14.9-19.8).
Treatment-emergent adverse events (TEAEs) were consistent with prior clinical experience with niraparib, Moore reported. TEAEs were managed with dose interruption (62.2%), dose reduction (47.1%), or withdrawal (21.2%).
The most common grade ≥3 TEAEs were anemia (26.3%), thrombocytopenia (20.5%), nausea (9.7%), decreased platelet count (9.1%), neutropenia (8.2%), vomiting (8.0%), small intestinal obstruction (6.5%), abdominal pain (6.3%), and fatigue (6.3%).