Evaluating Olaparib for BRCA Wild-Type Platinum-Resistant Ovarian Cancer

Single-agent olaparib showed favorable responses in women with platinum-recurrent ovarian cancer, including those with BRCA wild-type disease, according to the results of a phase II study (abstract 5507) presented at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago.

Women with ovarian cancer who have relapsed within 6 months of last platinum chemotherapy are eligible for four chemotherapy agents, with overall response rates around 15%: paclitaxel, pegylated liposomal doxorubicin (PLD), topotecan, and gemcitabine, explained presenter Adriaan Vanderstichele, MD, PhD, of BGOG & Department of Gynaecology and Obstetrics, University Hospitals Leuven, Leuven Cancer Institute.

Single-agent PARP inhibition is approved for BRCA1/2-mutated relapsed ovarian cancer. Among these patients, the overall response rate varies from 6% with niraparib to 31% with olaparib; however, there are limited data on the efficacy of these agents in BRCA wild-type disease.

In the phase II CLEO study, patients were randomly assigned 2:1 to olaparib 300 mg twice daily or physician’s choice of chemotherapy. In platinum-sensitive patients (n = 60), physician’s choice could include carboplatin/gemcitabine, carboplatin/paclitaxel, or carboplatin/PLD. Women with germline or somatic BRCA mutations were excluded.

For women with platinum-resistant disease (n = 100), physician’s choice included paclitaxel, PLD, topotecan, or gemcitabine. Germline or somatic BRCA mutation were allowed. In addition, patients assigned to chemotherapy were permitted to cross over to the olaparib arm.

Vanderstichele presented data on platinum-resistant patients only, as data from the platinum-sensitive cohort is not yet mature. Of these patients, 67 were assigned to olaparib and 33 to chemotherapy; 16% of patients had prior exposure to a PARP inhibitor. Median follow-up time was 16.5 months.

There was an imbalance between treatment arms in frequency of known BRCA mutations (P = .03). For the olaparib arm, 19% of patients had germline BRCA mutations compared with 3% of patients in the chemotherapy arm.

Overall response rate was three times greater in patients assigned olaparib compared with chemotherapy, but the difference was not statistically significant (18% vs 6%; P = .13). Patients with BRCA-mutated disease had a 36% response rate with olaparib compared with 0% with chemotherapy. Among patients with wild-type disease, the response rate was 13% compared with 6%.

Hereditary breast/ovarian cancer (HBOC) gene panel screening was also performed in all patients. In addition to BRCA1 and BRCA2, this panel includes RAD51C, RAD51D, and BRIP1. In the olaparib arm, 25.4% of patients had germline HBOC mutation, but unlike BRCA mutations, no responses were observed in the four platinum-resistant patients with BRIP1 or RAD51C/D mutations.

No difference in progression-free survival occurred between olaparib and chemotherapy (2.9 vs 3.4 months; hazard ratio, 1.18). Additionally, analysis of the clinical benefit rate-complete remission, partial remission, and stable disease-showed similar rates for chemotherapy and olaparib (45% vs 36%). There was also a similar duration of clinical benefit between the two arms.

According to Vanderstichele, there were no treatment-emergent adverse events. Treatment-emergent adverse events leading to dose reduction occurred in 21% of patients assigned olaparib compared with 15% of those who received chemotherapy. Only 7% of patients assigned olaparib discontinued due to adverse events.

Discussant Don S. Dizon, MD, FACP, FASCO, of Lifespan Cancer Institute, discussed the differences in response rate seen in the CLIO trial, but called attention to the imbalance in the study arms in terms of BRCA mutations.

“Women who got olaparib were far more likely to harbor mutations compared with the one volunteer in [the] control arm who had [a] mutation and received chemotherapy,” Dizon said.