Regulatory Decision Summary for Zoladex LA

This Supplement to a New Drug Submission (SNDS) for Zoladex Long Acting (LA) was filed to obtain market authorization for a new indication in early and advanced breast cancer. Upon review, the approved Zoladex LA indication was for the management of estrogen receptor (ER)-positive early breast cancer with a high risk of recurrence or advanced breast cancer in pre- and perimenopausal women. Conversion of the product monograph to the master PM template was also implemented.

This SNDS for Zoladex LA 10.8 mg depot was filed to seek market authorization for a new indication in early and advanced breast cancer. The active pharmaceutical ingredient of Zoladex is goserelin, a decapeptide analogue of naturally occurring luteinising hormone-releasing hormone that causes suppression of sex hormones production. The longer acting formulation of Zoladex LA is administered by subcutaneous injection every 12 weeks instead of every 4 weeks as for Zoladex 3.6 mg. Zoladex 3.6 mg is already approved early and advanced breast cancer.

In support of the new indication, the sponsor conducted one pivotal Phase II and one pivotal Phase III clinical trials comparing the Safety and Efficacy of Zoladex LA with that of Zoladex 3.6 mg depot in premenopausal, estrogen receptor (ER)-positive breast cancer patients when administered concomitantly with 20 mg of tamoxifen daily. Study D8664C00004 was a Phase II, open-label, randomized, non-inferiority trial conducted in 170 patients with early breast cancer. The primary variable was the area under the curve (AUC) (4-24 week) of estradiol (E₂) serum concentration. The E₂ AUC ratio of Zoladex LA group/3.6 mg group was 0.974 (95% confidence interval [CI]: 0.799 to 1.188) and the 95% CI upper limit was below the non-inferiority margin of 1.25. Therefore, non-inferiority of Zoladex LA to Zoladex 3.6 mg in terms of E₂ suppression was shown. All the secondary variables including E₂ and follicle-stimulating hormone (FSH) serum levels, % of patients with mean E₂ levels below 30 pg/mL (considered the menopausal level threshold), absence of menstruation, and disease-free survival (DFS) at the 24-week time point, showed comparability in efficacy between the Zoladex LA and 3.6 mg goserelin depots. Study D8666C00001 was a Phase III open-label, randomized, non-inferiority trial conducted in 222 patients with advanced breast cancer. The study primary objective was progression-free survival (PFS) at 24 weeks. Sixty seven patients (61.5%) in the Zoladex LA group and 68 patients (60.2%) in the 3.6 mg group were progression free at the 24-week time point. The 95% CI for the difference of 1.29 was -11.40 to 13.90. Therefore, non-inferiority of Zoladex LA to Zoladex 3.6 mg was shown. Secondary variables, including objective response rate (ORR), defined as either a complete or partial response based on Response Evaluation Criteria in Solid Tumors (RECIST) criteria at 24 weeks, mean serum E₂ concentration and mean serum FSH concentration, showed comparability in efficacy between the Zoladex LA and the 3.6 mg depots. Importantly, the rate of E₂ levels breakthrough or hormonal escape was very low in both arms of both studies.

Given that the majority of patients in the 2 pivotal clinical trials were from Asian countries, the sponsor presented results from an additional Phase III trial, Study D8664C00008, that enrolled both Asian and European advanced breast cancer patients; however, this trial was discontinued because of insufficient recruitment. While the primary endpoint of progression-free survival failed to reach statistical significance due to the insufficient sample size, results suggested similarly effective E₂ suppression among Zoladex LA and Zoladex 3.6 mg treated patients and among different ethnicity subgroups. The population pharmacokinetic (popPK) analysis of goserelin exposure conducted on data from the 3 trials was deemed inconclusive on its own to address the ethnicity concerns. A totality of evidence approach can be used to address these uncertainties. Given that the noninferiority of Zoladex LA compared to Zoladex 3.6 mg was shown in the two Asian trials, and the approved use of Zoladex 3.6 mg for early and advanced breast cancer was based on studies conducted in European and North American patients, along with the limited but supportive results of Zoladex LA use in study D8664C00008 showing similarly effective E2 suppression among Zoladex LA and Zoladex 3.6 mg and among different ethnicity subgroups, as well as the considerable global marketing history of Zoladex LA and Zoladex 3.6 mg for the treatment of early and advanced breast cancer, it was concluded that Zoladex LA would be expected to perform as well as the Zoladex 3.6 mg depot in the Canadian early and advanced breast cancer population.

Safety evaluation conducted in all 3 trials showed that Zoladex LA was well tolerated and displayed a similar safety and tolerability profile to Zoladex 3.6 mg depot in pre- and perimenopausal women with ER-positive early and advanced breast cancer. The most common adverse events reported in all 3 trials included hot flush (ranging from 13.9 to 70.6%), nasopharyngitis (8 to 60%), headache (6.2 to 27.1%), arthralgia (0.9 to 21.2%), hyperidrosis (1.8 to 17.6%), musculoskeletal stiffness (0.9% to 17.6%) dizziness (0 to 14.1%), back pain (2% to 15.3%).

The indication initially proposed for early breast cancer was considered slightly broader than the current indication for Zoladex 3.6 mg. However, recent shifts in medical practice and in the medical guidelines from main professional medical oncology networks recommend inclusion of ovarian suppression in the treatment of early breast cancer. Revisions to the proposed indication were proposed based on the strong consensus among these guidelines that the use of ovarian suppression should only be limited to patients with high-risk of recurrence in the early breast cancer setting and those revisions were accepted by the sponsor.

The Risk Management Plan (RMP) was considered acceptable following a level 1 review. The RMP did not warrant a full review as there were no significant changes to the safety profile of Zoladex LA compared to other gonadotropin-releasing hormone (GnRH) agonists, that would warrant revisions to the risk minimization plan, or that could impact the risk-benefit balance of the product for the proposed indication.

The inner and outer labels, Part III Patient Medication Information and Package Insert documents conformed to the necessary regulatory requirements and are consistent with the labelling guidance documents. They were therefore considered acceptable.

Taken together, the data from the submitted studies demonstrated a favorable benefit-risk balance of Zoladex LA for the treatment of pre-menopausal patients with early breast cancer with a high risk of recurrence or advanced breast cancer.

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