PARP Inhibitor Active in BRCA Subgroups

PARP Inhibitor Active in BRCA SubgroupsPatients with relapsed BRCA-mutated ovarian cancer had a similar progression-free survival (PFS) with the PARP inhibitor rucaparib (Rubraca) regardless of the type of mutation, according to subgroup analyses of a prospective, multicenter trial.

Results showed a median PFS of about 13 months among patients with germline or somatic BRCA mutations and a median of 11 to 12 months in patients with BRCA1– or BRCA2-mutant cancer. Patients with platinum-sensitive disease (defined as a platinum-free interval, PFI) had more prolonged PFS compared with patients who had platinum-resistant or refractory, as did those patients whose most recent treatment was platinum-based rather than non-platinum.

Treatment with rucaparib led to an objective response rate of 70% in patients with platinum-sensitive ovarian cancer and no prior non-platinum therapy but declined dramatically in patients treated with non-platinum agents and those who were platinum resistant or refractory, as reported here at the Society of Gynecologic Oncology meeting.

“I think the objective response rates with rucaparib in primary mutated ovarian cancer, both somatic and germline mutations, were extraordinary, ranging between 52% and 86%, depending on the number of prior therapies,” said Gottfried E. Konecny, MD, of the University of California Los Angeles.

“These are very promising data and are currently being validated in an ongoing prospective trial comparing rucaparib to standard care in patients with relapsed primary mutated ovarian cancer,” he added.

The results with rucaparib add to the evidence base for PARP inhibition in ovarian cancer established by olaparib (Lynparza), said invited discussant Jonathan Ledermann, MD, of University College London. A little more than 2 years ago, the FDA approved olaparib as maintenance therapy for previously treated BRCA-mutant ovarian cancer, followed late last year by approval of rucaparib for patients who received one or two prior therapies.

“There is a clear clinical benefit of olaparib or rucaparib in the treatment of BRCA-mutated recurrent, high-grade ovarian cancer,” said Ledermann. “Single-agent activity correlates with the platinum-free interval and number of prior lines of chemotherapy. BRCA status is the strongest determinant of benefit from treatment with a PARP inhibitor and should be assessed in all patients with high-grade tumors.

“We know from experience with olaparib that there is a long-term benefit with maintenance therapy with a PARP inhibitor, as 15% of patients remain progression-free for 5 years. Maintenance and single-agent strategies are both effective in the short term, and we will have to await results of the ARIEL3 and ARIEL4 trials with rucaparib to see whether long-term results are similar.”

ARIEL3 is evaluating rucaparib as maintenance therapy, and ARIEL4 compares rucaparib with standard therapy for ovarian cancer.

Konecny presented data from a subgroup analysis of the two-part ARIEL trial of rucaparib in patients with relapsed high-grade ovarian cancer. Part 1 included 206 patients who had received one or more prior lines of therapy, platinum sensitivity, and a platinum agent as their most recent therapy. Part 2 involved 287 patients who had received three or four prior lines of therapy. Both parts included patients with BRCA-mutated or wild-type disease.

The subgroup analysis focused on patients with BRCA-mutated disease, a total of 134 from the two trial components of ARIEL2. Three-fourths of the patients included in the analysis had received three or more prior lines of therapy, and 85% of the patients had received two or more prior platinum-based regimens. About 53% of patients had platinum-sensitive disease, and 10% had not received non-platinum therapy.

Among patients with platinum-sensitive disease, rucaparib led to an objective response rate of 70% in those without prior non-platinum therapy versus 43% among patients whose most recent treatment was non-platinum. The platinum-resistant group had a 25% response rate, and no patient with platinum-refractory disease responded to rucaparib.

In the subgroup with platinum-sensitive disease and platinum-based therapy as the most recent treatment, response rate increased to 83% for patients with one prior line of treatment and 86% for those with two prior lines, dropping off to 52% in patients with three or more prior lines of therapy. The disease-control rate was 81% in the platinum-sensitive/platinum prior therapy group, 57% in patients with platinum-sensitive/prior non-platinum therapy, 39% for platinum-resistant disease, and 29% for platinum-refractory disease.

Among patients with platinum-sensitive disease, the median PFS was 12.7 months with immediate prior platinum therapy and 7.4 months with immediate prior non-platinum therapy. Patients with platinum-resistant or refractory disease had a median PFS of 7.3 and 5.0 months, respectively. Among patients with platinum-sensitive disease and immediate prior platinum therapy, PFS increased with the duration of PFI: 12.7 months for PFI ≥6 months, 16.9 months for PFI ≥12 months, and 25.1 months for PFI ≥18 months.

Focusing on patients with platinum-sensitive disease and immediate prior platinum therapy, Konecny said the median PFS was 12.8 months for patients with BRCA germline mutations, 12.7 months for those with somatic mutations, and 7.1 months with BRCAindeterminate status. The median PFS was 12.8 months with BRCA1 mutation and 11.2 months with BRCA2.

Nausea and asthenia/fatigue were the most common adverse events (~80% of patients, all grades), and about half of the patients had episodes of vomiting and anemia. The most common grade 3/4 adverse events were anemia (29%), asthenia/fatigue (10%), and liver enzyme elevations (10%).

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