Regulatory Decision Summary for Lynparza

The benefit of olaparib was evaluated in the Phase 3 OlympiA study, a randomized, double-blind, placebo controlled, multi-centre trial. The study enrolled 1,836 participants with gBRCAm HER2-negative high risk early breast cancer (EBC) previously treated with adjuvant or neoadjuvant chemotherapy. The enrolled population primarily reflected the triple negative breast cancer (TNBC) molecular subtype while a minority represented the hormone receptor positive (HR+)/HER2- subtype. Subjects were randomized 1:1 to receive either 300 mg of olaparib tablets twice daily or placebo for 1 year, or until disease recurrence or unacceptable toxicity. The primary efficacy endpoint was invasive disease-free survival (iDFS). Secondary endpoints included distant disease-free survival (DDFS) and overall survival (OS). The study met the primary endpoint early at the pre-specified superiority interim analysis, and demonstrated a clinically and statistically significant improvement in iDFS and DDFS in the intent-to-treat (ITT) population. After a median duration of follow-up of 2.3 years in the olaparib arm and 2.5 years in the placebo arm , the iDFS stratified hazard ratio was 0.58 (95% confidence interval [CI]: [0.41, 0.82], p<0.0001), demonstrating a 42% reduction in the risk of invasive disease recurrence for Olaparib compared to placebo. In the ITT population, the 3-year IDFS rate was 86% in the olaparib arm compared to 77% in the placebo arm, with an absolute benefit of 9%. The majority of iDFS events were distant recurrences. The 3-year DDFS rate was 88% in the olaparib arm compared to 80% in the placebo arm, the stratified hazard ratio was 0.57 (95% CI: [0.39, 0.83, p<0.0001]. The difference in overall survival was not statistically significant, however, a positive trend in favour of the olaparib arm was observed (6% vs. 9% deaths in the olaparib vs. placebo arm).

The majority of adverse reactions associated with olaparib were manageable with supportive care and/or dose modifications and consistent with the known safety profile of olaparib. The most common adverse events (≥20%) were anemia, vomiting, nausea, fatigue and headache. A majority of these adverse events were Grade 1 or 2. Grade ≥3 Adverse Events (AEs) occurred in 25% of participants in the olaparib arm compared to the 11% of patients in the placebo arm. Grade ≥3 AEs with higher incidence of ≥2% in the olaparib compared to placebo arms were anemia, neutrophil count decreased and WBC count decreased. Grade ≥3 AEs and Serious Adverse Events of anemia occurred in 8.7% and 1.6% of participants. Adverse events of special interest include myelodysplastic syndrome (MDS)/ acute myeloid leukemia (AML) and pneumonitis. MDS/AML occurred in 2 patients (0.2%) in the olaparib arm and 3 patients (0.3%) in the placebo arm during the study treatment period or 30 days after discontinuation. Pneumonitis risk was similar across both arms at 1%. AEs leading to dose reduction occurred in 23% and 3.7% in the olaparib vs. placebo arm, and AEs leading to dose interruption occurred in 31% and 11% of the olaparib vs. placebo arms. Adverse reactions that led to permanent discontinuation occurred in 11% of the population. The most common adverse reactions leading to dose reduction/interruption/discontinuation of the treatment were nausea, anaemia and fatigue.

There is potential risk of genotoxicity to sperm or oocytes in males and females of child-bearing potential administered olaparib. Risk mitigation measures include an increased contraception period to eliminate damaged sperm or oocytes, and for women to use 2 highly effective forms of contraception.

The magnitude of clinical benefit of olaparib in the HR+/HER2- subpopulation is uncertain. Limitations in study design include the underrepresentation of HR+/HER2- subjects (18% of ITT population) and lack of statistical power to efficacy differences in this subgroup. In an exploratory subgroup analysis, the absolute 3-year iDFS benefit in the HR+/HER2- population was 6.3%, with a hazard ratio of 0.70 (95% CI: 0.281-1.27). The iDFS and DDFS hazard ratios for the in the HR+/HER2- had wide 95% CI’s which exceeded 1. Furthermore, the Kaplan-Meier iDFS curves crossed at approximately 3.5 years in the HR+/HER2- subgroup, while this was not observed in the TNBC subgroup. Thus, a detrimental impact on invasive disease recurrence in patients with a late relapse cannot be ruled out. The OS data is immature with a subgroup specific HR of 1.04 (95% CI: 0.46-2.4), thus a detrimental impact on survival cannot be ruled out in the HR+/HER2- subgroup. Overall, the clinical benefit of olaparib in the HR+/HER2- subgroup is promising. Long-term efficacy follow-up data is requested to address these uncertainties as a post-market requirement.

The sponsor requested an expanded indication to include somatic BRCAm (sBRCAm) tumours in the adjuvant treatment setting. Given the lack of sBRCAm participants in the OlympiA trial, the indication was restricted to the gBRCAm population.

A risk management plan (RMP) was submitted by AstraZeneca Canada Inc. to Health Canada. Upon review, the RMP was considered to be acceptable. Routine pharmacovigilance for the identified risk of MDS/AML, and the potential risks of New Primary Malignancies and Effects on embryofoetal survival and abnormal development were proposed.

Patients with gBRCAm HER2- EBC are at high risk of local and distant disease recurrence after adjuvant/neoadjuvant chemotherapy. In this submission, there is substantial evidence of clinical benefit of olaparib as an adjuvant treatment for the TNBC population. On the other hand, given the uncertainties in the magnitude of clinical benefit in the HR+/HER2- subpopulation, a conditional approval (NOC/c) for the overall gBRCAm HER2- high risk EBC indication was granted. In the Letter of Undertaking (LOU), the sponsor has agreed to all the requested commitments listed in the Qualifying Notice (QN). The LoU is consider acceptable.

For further details about Lynparza, please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.