Both Germline, Somatic BRCA Mutations Benefit from Maintenance Olaparib in Platinum-Sensitive Relapsed Ovarian Cancer

Sandro Pignata, MD, PhD

Benefit from maintenance therapy with olaparib (Lynparza) in terms of progression-free survival (PFS) was achieved in patients with platinum-sensitive relapsed ovarian cancer, even among patients who have somatic BRCA mutations and those with non-BRCA homologous recombination repair (HRR) mutations, according to results from the phase 4 ORZORA (NCT02476968) trial.1

“ORZORA showed again that olaparib showed clinical activity in platinum-sensitive ovarian cancer and in particular the activity in the somatic BRCA–mutated patients is fairly similar to those that carry the germline mutation,” Sandro Pignata, MD, PhD, of the Istituto Nazionale Tumori ‘Fondazione G Pascale,’ IRCCS, in Napoli, Italy, said in a presentation during the Society of Gynecologic Oncology (SGO) 2021 Virtual Annual Meeting on Women’s Cancer.

Patients with platinum-sensitive relapsed ovarian cancer have demonstrated benefit from maintenance therapy in past studies, including Study 19 (NCT00753545), which showed PFS benefit for the PARP inhibitor over placebo in patients regardless of BRCA mutation status.2 In a further retrospective analysis from the study, a small group of patients with somatic BRCA mutations even showed PFS benefit that was similar to that of the germline BRCA cohort.3 

The open-label, single-arm, multicenter ORZORA trial further explored the benefit of maintenance olaparib in platinum-sensitive relapsed ovarian cancer among subgroups of patients, including those with germline or somatic tumor BRCA mutations, and those with non-BRCA HRR mutations. All patients had achieved a complete response (CR) or partial response (PR) after at least 2 lines of prior platinum-based chemotherapy.

Patients were screened for 2 cohorts, a BRCA-mutant group and a non-BRCA HRR mutant group. Both groups started maintenance olaparib 400 mg twice daily within 8 weeks of their last chemotherapy dose and were treated until disease progression or discontinuation. The primary end point in the BRCA cohort was investigator-assessed PFS in the whole cohort as well as in the somatic group. Secondary end points included second PFS, overall survival (OS), time to study treatment discontinuation or death, time to first subsequent anti-cancer therapy or death, time to second subsequent anti-cancer therapy or death, health-related quality of life, and safety. Exploratory end points included PFS, OS, and safety in the non-BRCA HRR mutant cohort.

Participants were enrolled between September 2015 and October 2018 and the primary PFS analysis was conducted in April 2020 at 60% data maturity. At this time point, 32.6% of patients were still on study treatment. The primary reason for discontinuation across the subgroups was the worsening of underlying condition in 73.7% of patients.

A total of 872 patients were screened, though only 181 were enrolled, and 177 were treated and included in the safety analysis set. This included 33 patients with non-BRCA HRR mutations, 87 with germline BRCA mutations, 55 with somatic BRCA mutations, and 3 with unknown BRCA classification.

Pignata explained that although the baseline characteristics were similar between the subgroups, there was a slightly higher age in the patients with somatic mutations.

Among patients with somatic BRCA mutations, the median age was 67 and there was a median of 2.93 years from diagnosis, the primary tumor location was in the ovaries in 78.2%, 65.5% had a BRCA1 mutation, 54.5% had achieved a CR on prior platinum-based chemotherapy, and 61.8% had received 2 prior lines of therapy whereas 16.4% had received at least 4.

In the germline group, the median age was 56 years, median time from diagnosis was 3.37 years, the ovary was the primary tumor location for 89.7%, 63.6% had BRCA1 mutation, but 1 patient had both a BRCA1 and BRCA2 mutation. Additionally, 50.6% had achieved a CR on prior platinum-based chemotherapy, 51.7% had received 2 prior lines of chemotherapy, 32.2% had received 3, and 16.1% had received 4 or more lines.

In the small non-BRCA HRR cohort, the median age was 54 years, the median time from diagnosis was 3.52 years, the ovary was the primary tumor location for 81.8%, 34.4% achieved a CR to prior platinum-based chemotherapy, and 54.5% had received 2 prior lines of therapy whereas 12.1% had received at least 4.

At a median of 22.3 months follow-up, the median PFS in the overall BRCA-mutant cohort was 18.0 months (95% CI, 14.3-22.1). At 1 year, the PFS rate was 67% and 39% at 2 years.

Regarding the median PFS observed in the BRCA-mutant population, Pignanta said: “This was “very similar to the previous experienced published from Study 19.”

Among patients with somatic BRCA mutations, the median PFS was 16.6 months (95% CI, 12.4-22.2). The PFS rate at 1 year was 65% and 33% at 2 years. Pignata commented that this is the largest somatic BRCA cohort to date to show a benefit from treatment with maintenance olaparib.

In patients with non-BRCA HRR mutations, the median PFS was 16.4 months (95% CI, 10.9-19.3). The PFS rates at 1 and 2 years were 68% and 26%, respectively.

The majority of patients with BRCA mutations (68%) reported no change in quality of life during the study, only 21% reported an improvement in quality of life. There was no difference in responses for the somatic BRCA mutation cohort.

Patients were treated for a median of 17.71 months (range, 0-53.8). During this time, treatment-emergent adverse events (TEAEs) of any grade were reported in 93.8% of all BRCA-mutant patients, grade ≥3 TEAEs were observed in 35.0%, and serious events in 25.4%. Patients with somatic mutations demonstrated similar rates at 94.5%, 38.2%, and 23.6%, respectively. Two cases of myelodysplastic syndrome/acute myeloid leukemia and 2 cases of new primary malignancies were reported in the germline BRCA–mutant cohort. Dose interruptions were required in 48.6% of patients due to TEAEs, and 4.5% of patients discontinued treatment due to TEAEs.

The most common TEAEs of any grade in the safety analysis set were nausea (53.7%), fatigue/asthenia (53.7%), anemia (42.4%), and vomiting (27.7%). The most common grade ≥3 TEAE was anemia in 15.8% of patients.

_References

_{1. Pignata S, Oza A, Hall G, et al. ORZORA: maintenance olaparib in patients with platinum sensitive relapsed ovarian cancer: outcomes by somatic and germline BRCA and other homologous recombination repair gene mutation status. Presented at: Society of Gynecologic Oncology 2021 Virtual Annual Meeting on Women’s Cancer; March 19-25; 2021; Virtual. Abstract 46.}

_{2. 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. doi:10.1056/NEJMoa1105535}

_{3. Ledermann J, Harter P, Gourley C, et al. Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial. Lancet Oncol. 2014;15(8):852-861. doi:10.1016/S1470-2045(14)70228-1}