Summary Basis of Decision for Talzenna

Review decision

The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.


Product type:

Drug

Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Talzenna is located below.

Recent Activity for Talzenna

SBDs written for eligible drugs approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. PAATs will be updated regularly with post-authorization activity throughout the product's life cycle.

Summary Basis of Decision (SBD) for Talzenna

Date SBD issued: 2020-01-21

The following information relates to the new drug submission for Talzenna.

Talazoparib (supplied as talazoparib tosylate)

Drug Identification Number (DIN):

  • DIN 02492032 - 0.25 mg capsule, oral administration
  • DIN 02492040 - 1 mg capsule, oral administration

Pfizer Canada ULC

New Drug Submission Control Number: 220584

On September 6, 2019, Health Canada issued a Notice of Compliance to Pfizer Canada ULC for the drug product Talzenna.

The market authorization was based on quality (chemistry and manufacturing), non-clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada's review, the benefit-risk profile of Talzenna is favourable as a monotherapy for the treatment of adult patients with a deleterious or suspected deleterious germline breast cancer susceptibility gene (BRCA)-mutated human epidermal growth factor receptor 2 (HER2)-negative locally advanced (not amenable to curative radiation or surgery) or metastatic breast cancer, who have previously been treated with chemotherapy in the neoadjuvant, adjuvant or metastatic setting, unless patients were inappropriate for these treatments.

1 What was approved?

Talzenna, an antineoplastic agent, was authorized as a monotherapy for the treatment of adult patients with a deleterious or suspected deleterious germline breast cancer susceptibility gene (BRCA)-mutated human epidermal growth factor receptor 2 (HER2)-negative locally advanced (not amenable to curative radiation or surgery) or metastatic breast cancer, who have previously been treated with chemotherapy in the neoadjuvant, adjuvant or metastatic setting, unless patients were inappropriate for these treatments.

The safety and efficacy of Talzenna in children and adolescents younger than 18 years of age have not been established. Therefore, Health Canada has not authorized an indication for pediatric use.

Of the 494 patients who received Talzenna, 85 patients were 65 years of age or older. No overall differences in safety or effectiveness of Talzenna were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Talzenna is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container.

Talzenna was approved for use under the conditions stated in its Product Monograph, taking into consideration the potential risks associated with the administration of this drug product.

Talzenna (0.25 mg and 1 mg talazoparib, supplied as talazoparib tosylate) is presented as a capsule. In addition to the medicinal ingredient, talazoparib tosylate, the capsule contains hypromellose, pharmaceutical grade printing ink, red iron oxide, silicified microcrystalline cellulose, titanium dioxide, and yellow iron oxide.

For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

Additional information may be found in the Talzenna Product Monograph, approved by Health Canada and available through the Drug Product Database.

2 Why was Talzenna approved?

Breast cancer is a heterogeneous, life-threatening disease, especially in the locally advanced and metastatic stage. Some hereditary factors that significantly influence the development of breast cancer are germline mutations in the breast cancer susceptibility genes (BRCA1 or BRCA2). Germline BRCA mutations are present in 5-10% of all breast cancer patients.

Current treatment for hereditary BRCA-positive locally advanced or metastatic breast cancer patients with hormone receptor (HR)-positive disease includes hormone therapy prior to chemotherapy, unless there is extensive visceral spread. For BRCA mutation-positive patients with HR-negative disease, chemotherapy is the main option. Recent approval of targeted therapies (i.e., cyclin-dependent kinase 4/6 inhibitors) has provided another option for the aforementioned patient populations. Nevertheless, the current treatments and treatment guidelines for this cancer type do not specifically address the presence of BRCA mutations, and treatment options specifically tailored for BRCA-mutated breast cancer remain limited.

Talzenna is a poly [adenosine diphosphate] ribose polymerase (PARP) inhibitor. Inhibition of PARP results in deoxyribonucleic acid (DNA) damage that can lead to synthetic lethality in the DNA repair-deficient BRCA-mutated breast cancer cells.

Talzenna has been shown to be efficacious in patients with germline BRCA-mutated HER2-negative locally advanced or metastatic breast cancer who received no more than three prior cytotoxic chemotherapy regimens for their metastatic or locally advanced disease. The market authorization was based on a pivotal, Phase III, open-label, randomized, parallel, two-arm, multicentre study of Talzenna compared with physician's choice of chemotherapy (PCT).

Talzenna treatment demonstrated a clinically meaningful and statistically significant improvement in progression-free survival (PFS) compared with the PCT arm (8.6 months versus 5.6 months) (hazard ratio [HR] 0.54; 95% confidence interval [CI]: 0.41, 0.71; p<0.0001) as determined by the blinded independent central review (BICR). Additionally, the PFS was supported by the BICR-assessed subgroup analyses, investigator-assessed sensitivity analyses, as well as the achievement of confirmed objective response rates of 50% versus 18% favouring the Talzenna arm over the PCT arm. Overall survival data were immature, but suggested no overt detriment to patients in the Talzenna arm.

The safety profile of Talzenna was based on the pivotal and supportive clinical studies involving 494 patients with germline BRCA-mutated HER2-negative locally advanced or metastatic breast cancer. The identified significant risks were hematologic toxicity, embryo-fetal toxicity, and secondary primary malignancies. Other important toxicities include hepatotoxicity and gastrointestinal toxicity. The identified safety concerns have been addressed through appropriate labelling in the Talzenna Product Monograph, and are generally manageable by dose interruption, dose reduction, dose discontinuation and/or standard medical practice. These mitigation strategies are clearly outlined in the Product Monograph. A Serious Warnings and Precautions box has also been added to the Product Monograph to highlight the more severe, fatal and/or life-threatening risks including embryo-fetal toxicity and secondary primary malignancy of myelodysplastic syndrome and acute myeloid leukemia.

A Risk Management Plan (RMP) for Talzenna was submitted by Pfizer Canada ULC to Health Canada. Upon review, the RMP was considered to be acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product.

The submitted inner and outer labels, package insert, and Patient Medication Information section of the Talzenna Product Monograph meet the necessary regulatory labelling, plain language and design element requirements.

Look-alike Sound-alike brand name assessment was performed and the proposed name Talzenna was accepted.

Overall, the therapeutic benefits of Talzenna seen in the pivotal study are positive and are considered to outweigh the potential risks. The pivotal study met its primary endpoint demonstrating a superior PFS benefit favouring Talzenna over PCT. The efficacy of Talzenna was coupled with an acceptable and manageable safety profile. Therefore, the benefit-risk profile of Talzenna is considered positive under the proposed conditions of use.

This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

3 What steps led to the approval of Talzenna?

Submission Milestones: Talzenna

Submission MilestoneDate
Pre-submission meeting:2018-07-10
Submission filed:2018-09-28
Screening
Screening Acceptance Letter issued:2018-11-15
Review
Biostatistics Evaluation complete:2019-06-17
Biopharmaceutics Evaluation complete:2019-07-12
Review of Risk Management Plan complete:2019-07-19
Quality Evaluation complete:2019-08-26
Labelling Review complete, including Look-alike Sound-alike brand name assessment:2019-09-05
Clinical/Medical Evaluation complete:2019-09-06
Notice of Compliance issued by Director General, Therapeutic Products Directorate:2019-09-06

The Canadian regulatory decision on the review of Talzenna was based on a critical assessment of the data package submitted to Health Canada. Foreign reviews conducted by the United States Food and Drug Administration were used as added references.

For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.

4 What follow-up measures will the company take?

Requirements for post-market commitments are outlined in the Food and Drugs Act and Regulations.

5 What post-authorization activity has taken place for Talzenna?

Summary Basis of Decision documents (SBDs) for eligible drugs authorized after September 1, 2012 will include post-authorization information in a table format. The Post-Authorization Activity Table (PAAT) will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. The PAAT will continue to be updated during the product life cycle.

At this time, no PAAT is available for Talzenna. When available, the PAAT will be incorporated into this SBD.

For the latest advisories, warnings and recalls for marketed products, see MedEffect Canada.

6 What other information is available about drugs?

Up to date information on drug products can be found at the following links:

7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical basis for decision

Clinical Pharmacology

Talzenna (talazoparib) is an inhibitor of poly [adenosine diphosphate] ribose polymerase (PARP) enzymes, PARP1 and PARP2. The PARP enzymes are involved in cellular deoxyribonucleic acid (DNA) damage response signaling pathways such as DNA repair, gene transcription, cell cycle regulation, and cell death. Inhibitors of PARP (PARPi) exert cytotoxic effects on cancer cells by two mechanisms, inhibition of PARP catalytic activity and by PARP trapping, whereby PARP protein bound to a PARPi does not readily dissociate from a DNA lesion, thus preventing DNA repair, replication, and transcription and ultimately leading to apoptosis and/or cell death. Treatment of cancer cell lines that are harbouring defects in DNA repair genes with single agent talazoparib leads to double-strand DNA breaks, resulting in decreased cell proliferation and increased apoptosis. The cytotoxicity observed with talazoparib against multiple tumour cell lines harbouring mutations in the DNA damage response pathways can be attributed to its inhibition of PARP catalytic activity and PARP trapping. Talazoparib antitumour activity was also observed in the patient-derived xenograft breast cancer susceptibility gene BRCA1- or BRCA2-mutant breast cancer models.

The clinical pharmacology data included reports of the human pharmacodynamic and pharmacokinetic studies. Overall, the clinical pharmacology data support the use of Talzenna for the specified indication.

Renal and hepatic impairment studies are ongoing and will be submitted upon completion.

Two formulations were used in the pivotal Phase III clinical study. Both were similar based on the evaluated pharmacokinetic parameters and the key clinical pharmacology findings. The related risks are properly labelled in the Talzenna Product Monograph.

The information related to food effect supported the recommendation to administer the proposed Talzenna capsules without regard to food intake.

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

Clinical Efficacy

The clinical efficacy of Talzenna was evaluated in a Phase III, open-label, randomized, parallel, two-arm, multicentre study (EMBRACA) of Talzenna versus (vs.) physician's choice of chemotherapy (PCT; capecitabine, eribulin, gemcitabine, vinorelbine) in patients with germline BRCA-mutated human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer who received no more than three prior cytotoxic chemotherapy regimens for their metastatic or locally advanced disease. Patients were required to have received prior chemotherapy treatment with an anthracycline and/or a taxane (unless contraindicated) in the neoadjuvant, adjuvant and/or metastatic setting. Patients with prior platinum therapy for advanced disease were required to have no evidence of disease progression during platinum therapy and no relapse within six months. A majority (>90%) of patients with hormone receptor-positive (HR+) breast cancer were treated with a prior endocrine-based therapy. No prior treatment with a PARP inhibitor was permitted.

There were 431 patients randomized 2:1 to receive Talzenna 1 mg capsules once daily or PCT at standard doses until disease progression or unacceptable toxicity. Of the 431 patients, 287 were randomized to the Talzenna arm and 144 to the PCT arm. Randomization was stratified by prior use of chemotherapy for metastatic disease (0 vs. 1, 2, or 3), by triple-negative disease status (triple-negative breast cancer [TNBC] vs. non-TNBC), and history of central nervous system metastasis (yes vs. no). The majority of patients (408/431, 95%) were selected using the BRACAnalysis test and the BRCA mutation status (BRCA1 positive or BRCA2 positive) was similar across both treatment arms. The remainder of the patients were confirmed at experienced local laboratories using validated testing methods.

The primary efficacy endpoint was progression-free survival (PFS) evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, as assessed by blinded independent central review (BICR). Secondary endpoints were objective response rate (ORR), overall survival (OS), safety, and pharmacokinetics. Exploratory objectives included duration of response (DOR).

In the primary analysis of the primary efficacy endpoint, PFS, Talzenna treatment resulted in a consistent, clinically meaningful and statistically significant median PFS of 8.6 months (95% confidence interval [CI]: 7.2, 9.3) compared with 5.6 months (95% CI: 4.2, 6.7) in the PCT arm, with a hazard ratio (HR) of 0.54 (95% CI: 0.41, 0.71; p<0.0001). These results translate into a 46% decreased risk of disease progression in patients treated with Talzenna vs. PCT. The BICR-assessed PFS results were supported by the investigator assessment of PFS, and consistent with the investigator-assessed sensitivity analysis and BICR-assessed subgroup analyses. The primary efficacy endpoint was also supported by key secondary endpoints, including confirmed ORR of 50.2% (95% CI: 43.4, 57.0) vs. 18.4% (95% CI: 11.8, 26.8) and DOR of 6.4 months (95% CI: 5.4, 9.5) vs. 3.9 months (95% CI: 3.0, 7.6) in the Talzenna arm and the PCT arm, respectively.

Overall survival was a key secondary endpoint in the pivotal study. The OS data were immature at the time of the final PFS analysis (38% of patients had died). However, there was a positive trend suggesting no overt detriment for patients in the Talzenna arm.

Indication

The New Drug Submission for Talzenna was filed by the sponsor with the following indication:

  • Talzenna is indicated for the treatment of adult patients with germline breast cancer susceptibility gene (BRCA)-mutated human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer.

Health Canada revised the proposed indication to reflect the key inclusion criteria and the conditions of use in the pivotal study. Accordingly, Health Canada approved the following indication:

  • Talzenna is indicated as a monotherapy for the treatment of adult patients with a deleterious or suspected deleterious germline breast cancer susceptibility gene (BRCA)-mutated human epidermal growth factor receptor 2 (HER2)-negative locally advanced (not amenable to curative radiation or surgery) or metastatic breast cancer, who have previously been treated with chemotherapy in the neoadjuvant, adjuvant or metastatic setting, unless patients were inappropriate for these treatments.

For more information, refer to the Talzenna Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The clinical safety of Talzenna (talazoparib) in patients with germline BRCA-mutated, HER2-negative locally advanced or metastatic breast cancer was evaluated in the Phase III pivotal study EMBRACA (described in the Clinical Efficacy section). Study results included data from 286 patients treated with Talzenna and 126 patients treated with chemotherapy (the physician's choice of chemotherapy [PCT] arm). Chemotherapy included capecitabine (number of patients [n] = 55), eribulin (n = 50), gemcitabine (n = 12), and vinorelbine (n = 9). The median duration of study treatment was 6.1 months in patients who received Talzenna and 3.9 months in patients who received chemotherapy. None of the adverse reactions were adjusted for the longer exposure to therapy in the Talzenna arm.

The most common (≥10%) adverse reactions (all grades) were fatigue (62%), anemia (53%), nausea (49%), neutropenia (35%), headache (33%), thrombocytopenia (27%), alopecia (25%), vomiting (25%), decreased appetite (21%), abdominal pain (19%), leukopenia (17%), dizziness (17%), dysgeusia (10%), and dyspepsia (10%). The overall frequency of grade ≥3 adverse events was 68%. Based on the Common Terminology Criteria for Adverse Events (CTCAE), the most common (≥10%) adverse reactions grade ≥3 were anemia (39%), neutropenia (21%), and thrombocytopenia (15%). The overall frequency of serious adverse events (SAEs) was 32%. The most common SAEs were anemia (6%) and pyrexia (2%).

Dose modifications (dose reductions or dose interruptions) due to any adverse reaction occurred in 66% of patients receiving Talzenna. Common adverse reactions (≥5%) leading to dose modifications were anemia (38%), neutropenia (19%), thrombocytopenia (11%), and decreased platelet count (7%). In the study, 13 (5%) patients in the Talzenna arm and 7 (6%) patients in the PCT arm had an adverse reaction that was the primary reason for permanent study drug discontinuation. Anemia was the only adverse event reported in more than one patient that led to discontinuation in the Talzenna arm. Adverse events leading to death occurred in 2% of the patients treated with Talzenna. The adverse events leading to death included general physical health deterioration (2 patients), cerebral hemorrhage, liver disorder, neurological symptom, and veno-occlusive liver disease (1 patient each).

The toxicities of special interest for Talzenna, and PARP inhibitors in general, include secondary primary malignancies (i.e., myelodysplastic syndrome and acute myeloid leukemia [MDS/AML]), myelosuppression, reproductive toxicity, pneumonitis, and embryo-fetal toxicity. Except for pneumonitis, all of the toxicities have been included in the Warnings and Precautions section of the Talzenna Product Monograph. Also, based on the mechanism of action and the carcinogenic and teratogenic potential of Talzenna, MDS/AML and embryo-fetal toxicity have been listed in a Serious Warnings and Precautions box. Pneumonitis was not observed in the pivotal study.

Overall, the risks associated with Talzenna 1 mg once a day, although significant, were generally tolerable and predominantly mitigated in the pivotal study by dose reduction, dose interruption, dose discontinuation and/or standard medical practice. The key gastrointestinal, hematologic, reproductive and carcinogenic toxicities are adequately labelled in the Talzenna Product Monograph. Appropriate warnings and precautions are in place in the Talzenna Product Monograph to address the identified safety concerns.

For more information, refer to the Talzenna Product Monograph, approved by Health Canada and available through the Drug Product Database.

7.2 Non-Clinical Basis for Decision

Exposure to talazoparib in animals was sufficient to identify that talazoparib was able to target the gastrointestinal, hematological, hepatobiliary, and both male and female reproductive systems. Additionally, talazoparib was genotoxic, carcinogenic, able to induce embryo-fetal toxicity, and able to accumulate following repeat dosing. The safety margins in the animal findings were identified at subtherapeutic thresholds, thus preventing a full characterization of the potential toxicity of talazoparib. Nevertheless, the identified toxicities were considered to be manageable, generally supportive of clinical findings, and acceptable risks for the proposed disease setting of locally advanced or metastatic breast cancer with a germline deleterious or suspected deleterious BRCA mutation.

The results of the non-clinical studies as well as the potential risks to humans have been included in the Talzenna Product Monograph.

For more information, refer to the Talzenna Product Monograph, approved by Health Canada and available through the Drug Product Database.

7.3 Quality Basis for Decision

The Chemistry and Manufacturing information submitted for Talzenna has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes. Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the proposed shelf life of 24 months is acceptable when the drug product is stored at room temperature (15ºC to 30ºC).

The clinical lots have been found to be representative of the proposed commercial lots. Several batches of both strengths, manufactured at the proposed commercial site, have been used as clinical supplies in the pivotal Phase III study.

The sites involved in production are compliant with Good Manufacturing Practices.

All non-medicinal ingredients (i.e., excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. None of the excipients used in the manufacture of Talzenna capsules are of human or animal origin.

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