Olaparib tablets significantly prolonged PFS compared with placebo among patients with BRCA1
-positive high-grade serous ovarian cancer, according to results of the randomized phase 3 SOLO2/ENGOT Ov-21 clinical trial.
“To our knowledge, SOLO2/ENGOT Ov-21 provides the first phase 3 data for olaparib tablets as maintenance treatment [among] patients with platinum, sensitive, relapsed, serous ovarian cancer,” Eric Pujade-Lauraine, MD, from the medical oncology department at Université Paris Descartes, AP-HP in Paris, and colleagues wrote. “Our results confirm that olaparib can achieve a significant prolongation of PFS [for] this patient population with no appreciable detrimental effect observed for patients’ quality of life.”
Olaparib (Lynparza, AstraZeneca) tablets are FDA approved for use — at 300 mg twice daily — as monotherapy to treat patients with deleterious or suspected deleterious germline BRCA–mutated advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy.
As HemOnc Today previously reported, the FDA granted regular approval to olaparib tablets for the maintenance treatment of adults with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer who achieved complete or partial response to platinum-based chemotherapy based on the results from the current trial.
In the Study 19 phase 2 trial, olaparib capsules given as maintenance monotherapy improved PFS compared with placebo among patients with platinum-sensitive, relapsed, high-grade serous ovarian cancer (HR = 0.35; 95% CI, 0.25-0.49).
Researchers sought to prospectively confirm these findings among patients with BRCA1/BRCA2 mutation using a tablet formulation of olaparib, which offers patients a reduced daily pill burden.
Researchers randomly assigned 295 women with BRCA-mutated metastatic ovarian cancer who received a minimum of two lines of previous chemotherapy to receive 300 mg olaparib (150-mg tablets twice daily; n = 196) or placebo (n = 99) for maintenance therapy.
Investigator-assessed PFS — which served as the primary endpoint — was 19.1 months among patients who received olaparib compared with 5.5 months among patients who received placebo (HR = 0.3; 95% CI, 0.22-0.41).
The Kaplan-Meier survival estimator showed 1-year PFS was 65% (95% CI, 57.8-71.4) in the olaparib group and 21% (95% CI, 13.3-29.6) in the placebo group. More patients assigned olaparib also achieved 2-year PFS (43% vs. 15%).
Sensitivity analysis showed 151 PFS events overall, with 81 events in the olaparib group and 70 events in the placebo group (51% maturity).
The most common grade 3 or higher adverse events included anemia (n = 38 of 195 patients in the olaparib group vs. n = 2 in the placebo group), fatigue or asthenia (n = 8 vs. n = 2); and neutropenia (n = 10 vs. n = 4).
Thirty-five patients in the olaparib group and eight in the placebo group experienced serious adverse events. The most common serious adverse events included anemia (4%), abdominal pain (2%) and intestinal obstruction (2%), and constipation (2%) in the olaparib group and intestinal obstruction (2%) in the placebo group.
One patient treated with olaparib developed acute myeloid leukemia with an outcome of death.
“The improvement in PFS seen using the olaparib tablet formulation in this disease setting is compelling because patients were able to maintain a good quality of life while experiencing a delay in disease progression and, therefore, a delay until the symptoms associated with subsequent chemotherapy treatments,” researchers wrote.
Despite the prolonged PFS, more mature data from the SOLO2 trial and other maintenance trials are crucial, according to Michael A. Bookman, MD, professor of medicine and section chief for hematology-oncology in the department of medicine at The University of Arizona, and Henry C. Kitchener, MD, professor of gynecological oncology at The University of Manchester, and honorary consultant at St. Mary’s Hospital in the United Kingdom.
“The distinction between maintenance and therapy of larger-volume disease is somewhat arbitrary,” Bookman and Kitchener wrote in a related editorial. “Indeed, more than half of the patients in the SOLO2 trial had achieved only a partial response to previous chemotherapy and were enrolled with larger-volume disease.”
Treatment with PARP inhibitors is not curative, they noted, and extended use may lead to patients developing treatment resistance through clonal BRCA1/BRCA2 revertant mutations and other pathways, potentially reducing the effectiveness of subsequent interventions.
“A better understanding of the optimal sequence and duration of therapy in women with small-volume asymptomatic residual disease could enhance the overall benefit of PARP inhibitors as part of an integrated approach to disease management,” Bookman and Kitchener wrote. – by Melinda Stevens
Disclosures: Pujade-Lauraine reports personal fees from AstraZeneca, Pfizer and Roche unrelated to the study. Please see the full study for all other researchers’ relevant financial disclosures. Bookman reports personal fees from AbbVie, AstraZeneca, Clovis, Endocyte, Mateon, McKesson Specialty Health and US Oncology Research, Pfizer and Tesaro; and nonfinancial support from Genentech/Roche unrelated to the study and editorial. Kitchener reports no relevant financial disclosures.
Editor's note: On Feb. 7, we corrected this article to specify that olaparib tablets are approved at a dose of 300 mg twice daily. The Editors regret this error.