Maintenance Olaparib Data Published as FDA Weighs Approval

Eric Pujade-Lauraine, MD, PhD

Maintenance olaparib (Lynparza) reduced the risk of risk of progression or death by 70% compared with placebo for patients with platinum-sensitive, relapsed, BRCA-mutant ovarian cancer, according to results from the phase III SOLO2/ENGOT Ov-21 trial published in The Lancet Oncology.

Based on data from the SOLO2 trial, the FDA granted a priority review in March to a new drug application for maintenance olaparib. The agency is scheduled to make its final decision on the PARP inhibitor before the end of the year.

“Our results confirm that olaparib can achieve a significant prolongation of progression-free survival in this patient population with no appreciable detrimental effect observed for patients’ quality of life,” lead author Eric Pujade-Lauraine, MD, PhD, University of Paris Descartes, and co-investigators wrote. “The favorable safety profile in SOLO2 enabled most patients receiving olaparib to maintain full dosing throughout their maintenance treatment.”

Between September 2013 and November 2014, investigators recruited 295 women for the international, double-blind, randomized SOLO2/ENGOT Ov-21 trial. Eligible patients had a performance status of 0 or 1, and histologically confirmed, relapsed, high-grade serous ovarian cancer or high-grade endometrioid cancer, including primary peritoneal or fallopian tube cancer.

Patients were required to have a predicted deleterious, or suspected deleterious BRCA1/2 mutation based on either blood or tumor testing, and all patients had to consent to provide 2 blood samples for confirmatory germline BRCA1/2 mutation testing. Overall, 78% of patients assigned to olaparib and 84% of those assigned to placebo had a BRCA1/2 mutation previously determined by local testing. All patients received a confirmatory BRCA test as part of the trial, which confirmed a germline BRCA1/2 mutation in 97% of both arms.

Patients were randomly assigned in a 2:1 ratio to 300 mg of olaparib twice daily (n = 196) or placebo (n = 99). Treatment continued until disease progression or until the investigator deemed that a patient was no longer benefiting from treatment. PFS was the primary endpoint.

Overall, 86 patients assigned to placebo discontinued the study, including 76 due to progression and 2 due to toxicity. A total of 112 patients in the experimental arm discontinued, including 75 due to progression and 22 due to toxicity. Eighty-three patients in the experimental group and 13 in the control group remained on-study at the September 19, 2016, data cutoff.

Investigators performed efficacy analysis after 187 deaths or progression events. Median follow-up for PFS was 22.1 months in the olaparib group and 22.2 months with placebo.

Progression-free survival was 19.1 months for the olaparib arm compared with 5.5 months for the placebo group (hazard ratio [HR], 0.30; 95% CI, 0.22-0.41; P <.0001).

According to the Kaplan-Meier survival estimator, 12-month PFS was 65% (95% CI, 57.8-71.4) in the olaparib group versus 21% (95% CI, 13.3-29.6) in the placebo group. PFS also favored olaparib at 24 months (43% vs 15%).

For patients with confirmed or suspected deleterious BRCA1/2 mutations (n = 286), PFS was, again, superior for olaparib compared with placebo (19.3 vs 5.5 months; HR, 0.33; 95% CI, 0.24-0.44; P <.0001).

The investigators reported that the incidence of grade ≥3 adverse events (AEs) was low in both groups. Thirty-five patients (18%) in the olaparib group experienced serious AEs compared with eight (8%) patients in the placebo group. The most common serious AEs in the olaparib group were anemia (4%), abdominal pain (2%), and intestinal obstruction (2%). The most common serious AEs in the placebo group were constipation (2%) and intestinal obstruction (2%).

A total of 45 patients (23%) in the olaparib group died during the study, including 1 patient who died of grade 5 acute myeloid leukemia. Twenty-seven (27%) patients died in the placebo arm.

Four patients in the both groups experienced acute myeloid leukemia, myelodysplastic syndrome, and/or chronic myelomonocytic leukemia during the study and long-term follow-up. Overall, the incidence of all secondary malignancies during the study and long-term follow-up was 6 patients (3%) in the olaparib group and 5 patients (5%) in the placebo group.

Pujade-Lauraine E, Ledermann JA, Selle F, et al. Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial [published online July 25]. Lancet Oncol. doi: 10.1016/S1470-2045(17)30469-2.