The PARP inhibitor niraparib has shown durable clinical activity in later lines of therapy in patients with relapsed ovarian cancer who have BRCA mutations, according to a posthoc analysis of the phase II QUADRA study.
Kathleen N. Moore, MD
The PARP niraparib (Zejula) has shown durable clinical activity in later lines of therapy in patients with relapsed ovarian cancer who have BRCA mutations, according to a posthoc analysis of the phase II QUADRA study. When used in the fourth line or later, niraparib exhibited an overall response rate (ORR) of approximately 30% in this subset of patients,1 Kathleen N. Moore, MD, reported at the 2018 ESMO Congress.
The efficacy of niraparib in this setting appeared to be greater in patients who were sensitive to their last line of platinum therapy, with a longer median progression-free survival (PFS) in this subset compared with patients who were platinum-resistant or platinum-refractory.
“The QUADRA data provide a lot of support for use of niraparib in later lines of therapy,” said Moore, director of the Oklahoma TSET Phase I Program and an associate professor of gynecologic oncology at the Stephenson Cancer Center, University of Oklahoma. “The data presented at ESMO [and previously] show high response rates and durability of response that look very similar to that reported for olaparib [Lynparza] from Study 42.2 The highest efficacy is in platinum-sensitive patients, but we see nice efficacy in platinum-resistant patients as well.”
Study 42 investigated olaparib in a subgroup of patients with germline BRCA1/2 mutated advanced ovarian cancer who had received ≥3 prior lines of chemotherapy.2
Effective treatments in later lines of therapy are still needed for patients with recurrent ovarian cancer, as the estimated response rate to chemotherapy in the fourth or later line of therapy is only about 10% or less regardless of prior platinum sensitivity status,3 noted Moore.
“A gradient of clinical activity based on platinum sensitivity was demonstrated in the BRCA mutated population, with greatest activity demonstrated in patients with platinum-sensitive disease,” the authors indicated in their poster presentation. Platinum-sensitive patients with BRCA mutations, defined as those with a platinum-free interval (PFI) >6 months, had an ORR of 39%, compared with 33% in those who were platinum-resistant (PFI of 1 to 6 months), and 19% in those who were platinum-refractory (PFI <28 days).
The median PFS in the overall cohort of patients whose tumors harbored BRCA mutations was 6.3 months, which improved to a median of 11.0 months in those who were platinum-sensitive. By comparison, patients with tumors harboring BRCA mutations who were platinum-resistant and platinum-refractory had a median PFS of 5.4 months and 5.7 months, respectively.
Median overall survival (OS) was 26.0 months in the patients with BRCA mutations. When examined by platinum sensitivity status, median OS was not estimable in patients with platinum-sensitive disease and was 26.0 months and 23.3 months in patients with platinum-resistant and platinum-refractory disease, respectively.
QUADRA was a multicenter, open-label, single-arm study that evaluated the safety and efficacy of niraparib in patients with metastatic, relapsed, high-grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer who were treated previously with at least 3 lines of chemotherapy. QUADRA met its primary endpoint, demonstrating an ORR of 27.7% per RECIST v1.1 criteria (95% CI, 15.6-42.6; P = .0005) in patients who had homologous repair deficiency (HRD) and who received 3 or 4 prior lines of anticancer therapy, not to include a PARP inhibitor.
In single-agent PARP inhibitor trials, the ORRs in cancer patients with BRCA mutations were highly dependent on line of therapy. Among patients treated in later lines, the highest ORRs were seen in the platinum-sensitive population.
The data presented here were in a subgroup of 63 patients from QUADRA with BRCA mutations who were naïve to PARP inhibitor therapy. Thirty-six patients had germline BRCA mutations and 27 had somatic BRCA mutations.
In the overall study population with BRCA mutations, the ORR in QUADRA was 29%. The ORRs were similar between those with germline and somatic BRCA mutations (25% vs 33%).
Those who were sensitive to the last line of platinum therapy had a clinical benefit rate (CBR) of 72% at 16 weeks and 56% at 24 weeks. The CBRs in patients who were platinum-resistant were 38% at 16 weeks and 33% at 24 weeks, and the CBRs in the group that was platinum-refractory were 50% and 31% at 16 and 24 weeks, respectively.
Of the 20 patients with BRCA1 mutations, the ORR was 32%. The ORR was nearly identical (33%) in the 18 patients with BRCA2 mutations.
The median duration of response in all BRCA-mutant patients was 9.2 months. When examined by platinum sensitivity, the median duration of response was not estimable in those who were platinum-sensitive, was 7.4 months in the patients who were platinum-resistant, and not estimable in those who were platinum-refractory.
Efficacy of niraparib in later lines extends beyond patients with BRCA mutations, Moore said. The ORR was 20% in the 35 patients with non-BRCA-mutated tumors who were HRD-positive and platinum-sensitive. Patients with BRCA-mutated tumors regardless of platinum sensitivity or those with HRD-positive tumors without a BRCA mutation who had platinum-sensitive disease had an ORR of 25.5%, a median PFS of 5.5 months, a median duration of response of 8.3 months, and a median OS of 23.3 months.