The European Medicines Agency’s Committee for Medicinal Products for Human Use has recommended approval of olaparib tablets (Lynparza) as a maintenance therapy for patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer.
Sean Bohen, MD, PhD
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval of olaparib tablets (Lynparza) as a maintenance therapy for patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, who are in a complete or partial response to platinum-based chemotherapy, regardless of BRCA status.
A capsule formulation of olaparib is currently approved in the European Union for use in this setting; however, its use is limited to patients with BRCA mutations. AstraZeneca and Merck, the developers of olaparib, noted in a press release that the new formulation will lower dosing from 8 capsules twice daily to 2 tablets twice daily. The positive CHMP opinion will now be sent to the European Commission for a final regulatory decision.
The CHMP recommendation is based on data from the phase III SOLO2 trial and the phase II Study 19 trial. In SOLO2, maintenance treatment with olaparib tablets showed a 70% reduction in the risk of progression or death compared with placebo for patients with platinum-sensitive, relapsed, BRCA-mutant ovarian cancer. In Study 19, the risk of progression or death was reduced by 65% with maintenance olaparib versus placebo for women with ovarian cancer, regardless of BRCA status. Based on these findings, the FDA approved olaparib in this setting in August 2017.
“The data show that Lynparza provides long-term disease control, delaying the need for further chemotherapy for this broader group of women with platinum-sensitive relapsed ovarian cancer, irrespective of their BRCA status. It also offers a well-characterized safety and tolerability profile, which is critical to help enable patients to stay on treatment,” Sean Bohen, MD, PhD, executive vice president, Global Medicines Development, and chief medical officer at AstraZeneca, said in a statement.
In the SOLO2 trial,1 patients were randomized 2:1 to olaparib as a 300-mg tablet twice daily (n = 196) or placebo (n = 99). All patients had relapsed ovarian cancer, confirmed BRCA1/2 mutation, and were in response to their most recent platinum-containing regimen following 2 or more prior systemic regimens. The primary endpoint was investigator-assessed progression-free survival (PFS).
The median age of patients was 56 years and baseline characteristics did not differ substantively between treatment groups. Most patients had an ECOG performance status of 0 (83% with olaparib vs 78% for placebo) and 47% of patients had a complete response to prior chemotherapy. Prior bevacizumab was received by 17% of those in the olaparib group and for 20% of those in the placebo arm. Approximately 40% of patients had received 3 or more prior lines of therapy.
The median investigator-assessed PFS was 19.1 months compared with 5.5 months in the placebo arm (HR, 0.30; 95% CI, 0.22-0.41; P <.0001). A prespecified analysis of PFS by a blinded central review committee showed a median PFS of 30.2 months for the olaparib group versus 5.5 months for placebo, a 75% reduction in the hazard for progression and death (HR, 0.25; 95% CI, 0.18-0.35; P <.0001).
The 12-month PFS rate was 65% in the olaparib group (95% CI, 57.8%-71.4%) versus 21% in the placebo arm (95% CI, 13.3%-29.6%). PFS also favored olaparib at 24 months (43% vs 15%). For patients with confirmed or suspected deleterious BRCA1/2 mutations (n = 286), PFS was superior for olaparib compared with placebo (19.3 vs 5.5 months; HR, 0.33; 95% CI, 0.24-0.44; P <.0001).
In Study 19,2 patients with platinum-sensitive, recurrent high-grade serous ovarian cancer (n = 265) were randomized to olaparib capsules as 400 mg twice daily (n = 136) or placebo (n = 129).Patients had received 2 or more prior regimens of platinum-based chemotherapy and experienced complete response or partial response to their most recent regimen.
The median PFS for patients taking maintenance olaparib was 8.4 months, compared to 4.8 months for the control group (HR, 0.35; 95% CI, 95% CI, 0.25-0.49; P <.0001). For those with BRCA mutations, the median PFS was 11.2 versus 4.3 months for placebo, representing an 82% reduction in the risk of progression or death (HR, 0.18; P <.0001).
In the third interim analysis of Study 19, across the full study the median OS was 29.8 months in the olaparib group and 27.8 months in the placebo group (HR, 0.73; 95% CI, 0.55-0.95; nominal P = .02138). In the BRCA mutation group (n = 136), median OS was 34.9 months for the olaparib group and 30.2 months for placebo (HR, 0.62; 95% CI, 0.41-0.94; nominal P = .02480). However, these were not considered to be statistically significant.
The most commonly observed adverse events (AEs) for olaparib were anemia, nausea, fatigue (including asthenia), vomiting, nasopharyngitis, diarrhea, arthralgia/myalgia, dysgeusia, headache, dyspepsia, decreased appetite, constipation, and stomatitis. The most common laboratory abnormalities were decrease in hemoglobin, increase in mean corpuscular volume, decrease in lymphocytes, decrease in leukocytes, decrease in absolute neutrophil count, increase in serum creatinine, and decrease in platelets.
In the SOLO2 trial, which assessed the tablets specifically, grade ≥3 AEs were reported for 36.9% of patients treated with olaparib versus 18.2% with placebo. The most common nonhematologic AEs for olaparib were nausea (75.9%), fatigue/asthenia (65.6%), vomiting (37.4%), diarrhea (32.8%), and abdominal pain (24.1%). The incidence of serious hematologic AEs included anemia (19.5%), neutropenia (5.1%), and thrombocytopenia (1.0%).
The median duration of treatment was 19.4 months for olaparib versus 5.6 months with placebo. Forty-five percent of patients required a dose interruption in the olaparib group versus 18% in the placebo arm and dose reductions were required for 27% and 3% of patients, respectively. The most frequent AEs leading to dose interruption or reduction were anemia (22%), neutropenia (9%), and fatigue/asthenia (8%).