Regulatory Decision Summary for LYNPARZA

Review decision

The Regulatory Decision Summary explains Health Canada’s decision for the product seeking market authorization. The Regulatory Decision Summary includes the purpose of the submission and the reason for the decision.


Product type:

Drug

Medicinal ingredient(s):

olaparib

Therapeutic area:

Antineoplastic agent

Type of submission:

New Drug Submission (New Active Substance)

Control number:

182823
What was the purpose of this submission?

 

This New Drug Submission (NDS) was filed to seek marketing authorization of Lynparza (olaparib) monotherapy for the maintenance treatment of adult patients with platinum-sensitive relapsed breast cancer susceptibility gene (BRCA)-mutated (germline and/or somatic) high grade serous ovarian cancer (including fallopian tube or primary peritoneal) who are in response (complete response or partial response) to platinum-based chemotherapy.

This NDS was also filed to seek marketing authorization of Lynparza monotherapy in patients with deleterious or suspected deleterious germline BRCA-mutated advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy.

 

Why was the decision issued?

 

Due to the promising evidence of efficacy and the acceptable safety profile, this submission is considered to be conditionally acceptable for only the first of the above proposed indications. Lynparza was authorized under the Guidance Document: Notice of Compliance with Conditions (NOC/c) (NOC/c Guidance) on the basis of the promising nature of the clinical evidence, the acceptable safety profile and the need for further follow-up to confirm the clinical benefit.

This benefit-risk assessment pertains to the following Lynparza indication that was authorized:

  • Lynparza (olaparib) is indicated as monotherapy for the maintenance treatment of adult patients with platinum-sensitive relapsed BRCA-mutated (germline or somatic) high grade serous epithelial ovarian, fallopian tube or primary peritoneal cancer who are in response (complete response or partial response) to platinum-based chemotherapy.
  • Platinum sensitivity is defined as disease progressing at least 6 months after completion of the penultimate platinum chemotherapy.

Harm-Uncertainty

The safety of olaparib at the recommended dose of 400 mg twice daily has been studied in 766 patients with various solid tumours. The safety profile is generally consistent across olaparib studies of patients receiving olaparib capsules 400 mg twice daily including patients with BRCA-mutated ovarian cancer.

In the pivotal study, almost all patients reported an adverse event (97.1% in the olaparib group and 93.0% in the placebo group). More patients in the olaparib group reported grade 3 and higher adverse events compared to the placebo group (41.2% versus 21.9% respectively).

Common adverse events, including haematologic toxicities, were managed with dose interruptions and reductions.

Myelodysplastic Syndrome/Acute myeloid leukemia (MDS/AML) have been reported in a small number of all patients exposed to olaparib. The majority of MDS/AML cases were fatal. Based on evidence currently available, it is not possible to exclude the contribution of olaparib to the development or acceleration of MDS/AML. Non-clinical studies have shown that olaparib has a clastogenic effect, which is consistent with the mechanism of action of olaparib. This genotoxic potential likely translates into a carcinogenic risk in humans.

Benefits

The goals of maintenance therapy are:

  1. to start treatment when the disease burden has been reduced after completion of chemotherapy;
  2. to further delay the return of disease; and
  3. to maintain patients in a well state as long as possible.

The efficacy and safety data presented in support of olaparib capsules for the maintenance treatment of patients with platinum-sensitive relapsed BRCA-mutated high grade serous epithelial ovarian, fallopian tube or primary peritoneal cancer who are in response to platinum-based chemotherapy is promising.

The efficacy data supporting the maintenance indication is derived from one Phase II pivotal study (study 19) and one supporting Phase II study (study 41). In the pivotal study, 265 patients were randomised (136 in the olaparib arm and 129 in the placebo arm). The phase II data provide limited patient numbers in the BRCA-mutated subgroup. In study 19, the BRCA-mutated subgroup contained 136 patients (74 patients received olaparib and 62 patients received placebo). In study 41, 162 patients were randomised, but only 25 % of the study population had a known BRCA-mutation. The pivotal study was well designed and well conducted.

Subgroup analyses demonstrated that patients with a BRCA mutation received the greatest progression-free survival (PFS) benefit from treatment with Lynparza maintenance therapy (hazard ratio [HR] 0.18; 95% confidence interval [CI] 0.10, 0.31; p<0.00001), with a statistically significant and clinically meaningful improvement in median PFS of 6.9 months over placebo. The median PFS was 11.2 months in the Lynparza group compared to 4.3 months in the placebo group.

Although the submitted results do not suggest a detrimental effect on the overall survival (OS) in the subgroup of BRCA-mutated patients treated with olaparib, the interim OS analysis failed to show a statistically significant difference between the arms (Hazard Ratio [HR] = 0.73, 95% Confidence Interval [CI]: 0.45, 1.17; p = 0.19175).

Olaparib maintenance therapy appears to be well tolerated. There were few dose modifications due to Adverse Drug Reactions (ADRs) and the median duration of treatment was approximately 11 months.

Although promising, there are limitations to these phase II data. The Progression Free Survival (PFS) improvement has not been associated with an OS or a quality of life (QoL) advantage. The surrogacy of PFS for patients with platinum-sensitive ovarian cancer in the maintenance setting has not been determined yet. Nevertheless, the improved PFS observed in the olaparib arm of the BRCA-mutated subgroup of patients is considered reasonably likely to predict clinical benefit in this group of patients. However, considering that the targeted population has a reduced tumor burden and is asymptomatic, the clinical benefit of maintenance therapy should preferably be confirmed by OS and/or quality of life data. Due to the promising evidence of efficacy and the acceptable safety profile of olaparib for the proposed indication, this submission is considered to be conditionally acceptable.

A Scientific Advisory Committee on Oncology Therapies (SAC-OT) meeting was held on February 5, 2016 for seeking advice on the clinical merit of olaparib for the proposed indication. In summary, the Committee considered that the benefit of prolonging PFS, in the absence of OS or QoL advantage, outweighs the toxicity associated with olaparib. However, the clinical benefit should be preferably confirmed with further trial data, such as the SOLO-2 trial (mentioned below).

Conclusion

Lynparza has been issued marketing authorization with conditions, pending the results of studies to verify its clinical benefit. Olaparib has the potential to provide significant clinical benefits to patients with ovarian, fallopian tube or primary peritoneal cancer. Olaparib is associated with significant potential for harms. However, the clinical benefits outweigh the risk associated with olaparib for the specified maintenance therapy indication.

In contrast, the proposed indication for use in patients with deleterious or suspected deleterious germline BRCA-mutated advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy, was not authorized as it was found that the data in the submission did not support a positive benefit risk determination.

In order to confirm the clinical benefit of olaparib for the proposed maintenance indication, Astrazeneca Canada Inc. has committed to supply the following reports:

Confirmatory trials

  1. The report of the final overall survival analysis from Study D0810C00019 (study 19)
  2. The final study report of the study D0816C00002 (SOLO-2)

The results of SOLO-2 would be used to support the efficacy of olaparib in the proposed maintenance setting.

AstraZeneca Canada Inc. will also provide the results of targeted pharmacovigilance activities that are designed to effectively monitor the risk of MDS/AML in patients treated with olaparib.

For more information on Health Canadas decision, please view the Summary Basis of Decision.

 

Decision issued

Approved; issued Notice of Compliance in accordance with the Food and Drug Regulations.