Regulatory Decision Summary for Lynparza

Approximately 5% of breast cancers are associated with a mutation in the breast cancer susceptibility gene (BRCA). Germline BRCA-mutated (gBRCAm), human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (mBC) is a life-threatening, incurable disease. Patients with gBRCAm, HER2-negative mBC who have received previous chemotherapy and are considered inappropriate for endocrine therapy have limited treatment options and poor survival outcome.

The marketing authorization recommendation for Lynparza (olaparib) in gBRCAm HER2-negative mBC is primarily based on results of a phase III, open-label, randomized controlled multicentre study OlympiAD. This study assessed the efficacy and safety of Lynparza monotherapy versus physicians choice of chemotherapy (capecitabine, vinorelbine or eribulin at standard doses) in patients with gBRCAm, HER2-negative mBC who had previously received chemotherapy in the neoadjuvant, adjuvant or metastatic setting. Patients with hormone receptor (HR)-positive tumor must have received and progressed on at least one endocrine therapy or had disease that the treating physician considered to be inappropriate for endocrine therapy.

The study met its primary objective and demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) for Lynparza compared with physicians choice of chemotherapy with a hazard ratio of 0.58 (95% confidence interval [CI] 0.43-0.80; p=0.0009; median 7.0 and 4.2 months for Lynparza and chemotherapy arms, respectively). In patients with measurable disease, objective response rate (ORR) was higher in the Lynparza arm (60%) compared with the chemotherapy control arm (29%). Overall survival (OS) was immature with 46% of events at the data cut-off date and there was no signal of detrimental effect of Lynparza on OS compared with chemotherapy (HR 0.90; 95% CI 0.63-1.29; median 19.3 versus 19.6 months).

The most commonly (≥20%) reported adverse drug reactions (ADRs) in the Lynparza arm were nausea, anemia, vomiting, fatigue (including asthenia), neutropenia, leukopenia, diarrhea and headache. These ADRs were generally consistent with the known safety profile of Lynparza. Gastroesophageal reflux disease, pyrexia and cystitis were identified as new ADRs during the review. Severe adverse events were reported in 36.6% of patients in the Lynparza arm compared to 50.5% in the chemotherapy arm. Anemia was the only serious ADR reported in more than one patient in the Lynparza arm (2.4%); the following serious ADRs were reported in a single patient: dermatitis allergic, neutrophil count decreased and platelet count decreased. One patient in the Lynparza arm died due to an adverse event (AE) of sepsis, which in the opinion of the investigator was not related to Lynparza. In most cases, ADRs of Lynparza were manageable through dose modification or symptomatic treatment. Dose modification (dose reduction or interruption) due to an AE occurred in 38.0% of patients in the Lynparza arm versus 41.8% in the chemotherapy arm. The most commonly reported (>10% in Lynparza versus comparator arm) AEs leading to dose modification were anemia (17.6% versus 3.3%) and neutropenia (8.3% versus 16.5%). The proportion of patients who permanently discontinued Lynparza due to an AE was 4.9% in the Lynparza arm compared with 7.7% in the chemotherapy arm. Anemia and platelet count decreased were the only ADRs leading to discontinuation of Lynparza in more than one patient. These safety findings are adequately labelled in Lynparza Product Monograph.

Overall, Lynparza monotherapy demonstrated a clinically meaningful improvement in PFS with a safety profile that was different from physicians choice of chemotherapy and is considered acceptable for the proposed indication; the benefit-harm-uncertainty profile is considered favourable for Lynparza.