Summary Basis of Decision for Nubeqa

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 Nubeqa is located below.

Recent Activity for Nubeqa

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.

The following table describes post-authorization activity for Nubeqa, a product which contains the medicinal ingredient darolutamide. For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the list of abbreviations that are found in PAATs.

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

Updated: 2023-08-16

Drug Identification Number (DIN):

DIN 02496348 – 300 mg darolutamide, tablet, oral administration

Post-Authorization Activity Table (PAAT)

Activity/submission type, control number Date submitted Decision and date Summary of activities
SNDS # 262749 2022-03-24 Issued NOC 2022-09-29 Submission filed as a Level I – Supplement to add a new indication. The submission was reviewed under the Priority Review of Drug Submissions Policy. The indication authorized was for the treatment of patients with metastatic castration-sensitive prostate cancer (mCSPC) in combination with docetaxel. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Indications; Warnings and Precautions; Adverse Reactions; Drug Interactions; Dosage and Administration; Clinical Pharmacology; and Clinical Trials sections of the PM, and corresponding changes were made to Part III: Patient Medication Information. An NOC was issued. A Regulatory Decision Summary was published.
SNDS # 243046 2020-08-21 Issued NOC 2021-07-15 Submission filed as a Level I – Supplement to provide final analyses from Study 17712 (ARAMIS). The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions; Adverse Reactions; Drug Interactions; Action and Clinical Pharmacology; and Clinical Trials sections of the PM, and corresponding changes were made to Part III: Patient Medication Information. An NOC was issued.
Drug product (DIN 02496348) market notification Not applicable Date of first sale: 2020-03-24 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NDS # 226146 2019-03-27 Issued NOC 2020-02-20 NOC issued for New Drug Submission.
Summary Basis of Decision (SBD) for Nubeqa

Date SBD issued: 2020-06-29

The following information relates to the New Drug Submission for Nubeqa.

Darolutamide

Drug Identification Number (DIN):

  • DIN 02496348 - 300 mg tablet, oral administration

Bayer Inc.

New Drug Submission Control Number: 226146

 

On February 20, 2020, Health Canada issued a Notice of Compliance to Bayer Inc. for the drug product Nubeqa.

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-harm-uncertainty profile of Nubeqa is favourable for the treatment of patients with non-metastatic castration-resistant prostate cancer (nmCRPC).

Nubeqa has not been studied in patients with nmCRPC at low risk of developing metastasis. The benefit and risk profile in these patients is unknown.

 

1 What was approved?

 

Nubeqa, an anti-androgen, was authorized for the treatment of patients with non-metastatic castration-resistant prostate cancer (nmCRPC).

Nubeqa has not been studied in patients with nmCRPC at low risk of developing metastasis. The benefit and risk profile in these patients is unknown.

Data regarding the use of Nubeqa in patients younger than 18 years of age have not been submitted to Health Canada. Therefore, Health Canada has not authorized an indication for pediatric use.

Evidence from clinical studies do not suggest clinically relevant differences in safety or efficacy associated with the use of Nubeqa in the geriatric population (65 years of age and above).

Nubeqa 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.

Nubeqa 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.

Nubeqa (300 mg darolutamide) is presented as a tablet. In addition to the medicinal ingredient, the tablet contains calcium hydrogen phosphate, croscarmellose sodium, hypromellose 15 cP, lactose monohydrate, Macrogol 3350, magnesium stearate, povidone K 30, and titanium dioxide.

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 Nubeqa Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

2 Why was Nubeqa approved?

 

Health Canada considers that the benefit-harm-uncertainty profile of Nubeqa is favourable for the treatment of patients with non-metastatic castration-resistant prostate cancer (nmCRPC).

Nubeqa has not been studied in patients with nmCRPC at low risk of developing metastasis. The benefit and risk profile in these patients is unknown.

Among Canadian men, prostate cancer is the most common cancer (excluding non-melanoma skin cancers) and the third leading cause of death from cancer. In 2017, an estimated 21,300 men were diagnosed with prostate cancer in Canada, representing 21% of all new cancer cases in men. That same year, 4,100 Canadian men died from prostate cancer, representing 10% of all cancer deaths in men.

During the early stages of prostate cancer with localized disease (non-metastatic), the majority of patients have one of two treatment options: local treatment (e.g. surgery or radiotherapy) alone or local treatment combined with androgen deprivation therapy (ADT). Androgens, such as testosterone, are hormones that may stimulate prostate cancer cells to grow. Androgen deprivation therapy is a type of treatment that blocks the effects of androgens and can slow prostate cancer growth. Most patients initially benefit from ADT; however, nearly all patients will eventually become resistant to ADT and develop castration-resistant prostate cancer (CRPC). Signs of resistance to ADT include rising serum prostate-specific antigen (PSA) levels. Instances of CRPC with no evidence of metastatic disease are referred to as non-metastatic CRPC (nmCRPC).

Untreated, approximately 30% of patients with nmCRPC will develop bone metastases within two years, with a median overall survival of approximately 4 years. In the majority of nmCRPC patients, PSA doubling time has been shown to be a strong predictor of the development of metastasis. Those with a short PSA doubling time (≤10 months) are considered to have a higher risk of developing metastases. Metastases are a major cause of complications and death among men with prostate cancer. Most develop metastases to lymph nodes, bone or visceral sites, such as the lung and liver. Delaying the development of metastatic disease for as long as possible is clinically meaningful for patients with nmCRPC, and represents an important treatment goal. Castration-resistant prostate cancer remains mainly driven by the androgen receptor (AR) signaling pathway and high-level AR expression occurs commonly in these patients.

Despite recent advances in treatment of nmCRPC, clinical progression and drug resistance subsequently evolve and CRPC remains a disease with limited treatment options. In addition, available therapies and recent clinical data show that these patients suffer from central nervous system conditions, including, but not limited to, falls and seizures. Fatigue, hypertension, fractures, and rash are also commonly reported. Therefore, there remains a need for efficacious treatment options that offer differentiated or improved safety profiles for patients with nmCRPC.

Nubeqa (darolutamide) is an orally administered, non-steroidal AR inhibitor that binds to the ligand binding domain of the AR. Nubeqa competitively inhibits androgen binding, AR nuclear translocation, and AR mediated transcription. In xenograft animal models of prostate cancer, Nubeqa inhibited prostate cancer cell proliferation and resulted in tumour growth inhibition.

Nubeqa has been shown to be efficacious in nmCRPC patients who are at high risk for developing metastasis. The market authorization was based on a randomized, double-blind, placebo-controlled multicentre Phase III pivotal study known as ARAMIS. In this study, 1,509 nmCRPC patients considered to be at high risk of developing metastasis (PSA doubling time ≤10 months) were randomized 2:1 to receive either 600 mg Nubeqa orally twice daily (total daily dose of 1,200 mg) plus ADT with food, or a matching placebo plus ADT. Randomization was stratified by PSA doubling time (≤6 months or >6 months) and use of osteoclast-targeted therapy at study entry (yes or no). During the study, ADT was in the form of a gonadotropin-releasing hormone (GnRH) analog or a bilateral orchiectomy. Treatment with Nubeqa continued until confirmed metastasis, unacceptable toxicity, or withdrawal.

The primary endpoint was metastasis-free survival (MFS), defined as the time from randomization to confirmed evidence of distant metastasis, or death, whichever occurred first. Distant metastasis was defined as new bone or soft tissue lesions or enlarged lymph nodes above the aortic bifurcation. Treatment with Nubeqa resulted in a statistically significant improvement in MFS compared to placebo (median MFS of 40.4 and 18.4 months, respectively). The secondary endpoints of overall survival, time to pain progression, time to initiation of first cytotoxic chemotherapy for prostate cancer, and time to first symptomatic skeletal event were not statistically significant at the time of data cut-off for analysis of the primary endpoint. However, no reduction in these secondary endpoints was apparent in the Nubeqa arm compared to the placebo arm.

Adverse drug reactions reported at a higher incidence in the Nubeqa arm compared to the placebo arm (≥2 percentage point difference) were fatigue, rash, and pain in extremity. Incidences of adverse drug reactions were below 10% in both treatment arms, with the exception of fatigue (12.1% Nubeqa vs 8.7% placebo). Nubeqa was generally well tolerated, with treatment-emergent adverse events leading to permanent study drug discontinuation occurring at a similar rate in both study arms. These issues have been addressed through appropriate labelling in the Nubeqa Product Monograph.

All patients enrolled in the pivotal study were considered at high risk of developing metastatic disease. Based on the significant positive effect of Nubeqa, the AR target of darolutamide, and because the precise definition of high-risk nmCRPC is still evolving, Health Canada considered it reasonable not to limit the indication in a manner that would exclude treatment of low-risk patients. However, a caveat was added to the indication stating that the benefit and risk profile is unknown for patients with low risk of developing metastases.

A Risk Management Plan (RMP) for Nubeqa was submitted by Bayer Inc. to Health Canada. 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. Upon review, the RMP was considered to be acceptable.

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

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

Nubeqa has an acceptable safety profile based on the non-clinical data and clinical studies. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Nubeqa Product Monograph to address the identified safety concerns.

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 Nubeqa?

 

The New Drug Submission (NDS) for Nubeqa was reviewed as part of the New Chemical Entities Work Sharing Initiative (NCEWSI), a work-sharing initiative between Canada, Australia, Singapore, and Switzerland (ACSS). This partnership aims to promote collaboration between regulatory agencies, optimize the use of resources, reduce duplication, and enhance each agency's ability to ensure consumers have timely access to safe, effective, and high-quality therapeutic products.

For this submission, Health Canada completed the clinical and quality reviews of Nubeqa, while Australia's Therapeutic Goods Administration completed the non-clinical reviews. Although the review of the submission was collaborative, each jurisdiction made their regulatory decision independently of the other.

 

Submission Milestones: Nubeqa

Submission Milestone Date
Pre-submission meeting: 2018-11-20
New Drug Submission filed: 2019-03-27
Screening 1  
Screening Acceptance Letter issued: 2019-04-26
Review  
Quality Evaluation complete: 2019-12-19
Review of Risk Management Plan complete: 2020-01-14
Labelling Review complete, including Look-alike Sound-alike brand name assessment: 2020-02-17
Clinical/Medical Evaluation complete: 2020-02-19
Notice of Compliance issued by Director General, Therapeutic Products Directorate: 2020-02-20

 

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.

 

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

 

The clinical review of Nubeqa was completed by Health Canada as part of a work-sharing initiative with Australia, Singapore, and Switzerland. The review of the submission was collaborative, with each regulatory agency sharing the outcome of their review with the others. However, each regulatory agency made their decision regarding authorization independently.

Clinical Pharmacology

Darolutamide, the medicinal ingredient in Nubeqa, is an orally administered, non-steroidal androgen receptor (AR) inhibitor that binds to the ligand binding domain of the AR. Darolutamide competitively inhibits androgen binding, AR nuclear translocation, and AR mediated transcription. Darolutamide inhibited prostate cancer cell proliferation and resulted in tumor growth inhibition in xenograft animal models of prostate cancer. Treatment with darolutamide is expected to delay development of metastases in prostate cancer patients by inhibiting the AR signaling pathway.

A bioavailability study demonstrates that food significantly increases the rate (as measured by the peak plasma concentration [Cmax]) and extent of absorption (as measured by the area under the concentration-time curve to the time of the last quantifiable concentration [AUCT]) of darolutamide. Specifically, administration of darolutamide (2 x 300 mg) with a high-fat high-calorie meal resulted in a 2.5-fold increase in AUCT and a 2.0-fold increase in Cmax relative to administration of darolutamide (2 x 300 mg) under fasted conditions.

The recommended Nubeqa dose is 600 mg twice daily with food, for a total daily dose of 1200 mg. A dose escalation study over the 100 mg to 900 mg range suggests there is a saturation in absorption beyond the 700 mg dose. The Cmax is 4.79 mg/L following repeated administration of 600 mg twice daily with food, reached after approximately 4 hours. At steady state, the area under the plasma concentration-time curve from 0-12 hours (AUC[0-12]) was 52.8 mcg*h/mL. Darolutamide is metabolised by oxidation via cytochrome P450 (CYP) 3A4 and by glucuronidation via UGT1A9, UGT1A1, and UGT1A3. Darolutamide is mainly excreted in urine (~63%) and to a lesser extent in feces (~32%).

A dedicated organ dysfunction study has shown a 1.5-fold and a 1.9-fold increase in Cmax and AUC(0-48) in non-cancer patients with moderate hepatic impairment (Child-Pugh B). There are no data in patients with severe hepatic impairment (Child-Pugh C). Darolutamide Cmax and AUC(0-48) were increased by 1.6-fold and 2.5-fold in non-cancer patients with severe renal impairment (estimated glomerular filtration rate [eGFR] of 15 to 29 mL/min/1.73m2). The Nubeqa Product Monograph includes a recommendation to reduce the darolutamide dose to 300 mg twice daily for patients with moderate hepatic impairment or with severe renal impairment.

Darolutamide is primarily metabolized by CYP3A4, which can be induced or inhibited by concomitant medications. Darolutamide is also a substrate of P-glycoprotein and Breast Cancer Resistance Protein (BCRP). Concomitant use of darolutamide with combined P-glycoprotein and strong CYP3A4 inducers can decrease exposure to darolutamide. Concomitant use of darolutamide with combined P-glycoprotein, BCRP and strong CYP3A4 inhibitors can increase exposure to darolutamide.

Darolutamide is also an inhibitor of BCRP and P-glycoprotein in vitro. Co-administration of darolutamide with a BCRP substrate can significantly increase exposure to the BCRP substrate. Co-administration of darolutamide with a P-glycoprotein substrate does not result in a clinically significant drug-drug interaction.

Darolutamide is a weak inducer of CYP3A4. Co-administration of darolutamide with a CYP3A4 substrate does not result in a clinically significant drug-drug interaction.

In vitro data indicate darolutamide administration may inhibit organic anion transporting polypeptides (OATP) 1B1, OATP1B3, organic anion transporter (OAT) 3, multidrug and toxin extrusion protein (MATE) 1, MATE2K, and intestinal multidrug resistance-associated protein (MRP) 2. Darolutamide does not inhibit OATP2B1, bile salt export pumps (BSEP), OAT1, organic cation transporters (OCT), and sodium ion/bile acid cotransporters (NTCP) at clinically relevant concentrations.

In the pivotal ARAMIS study, the confirmed prostate-specific antigen (PSA) response rate (defined as a ≥50% reduction from baseline) was 83.6%. Darolutamide is poorly soluble in aqueous solvents over a large pH range and generally more soluble in organic solvents.

Overall, the clinical pharmacological data support the use of darolutamide for the recommended indication.

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

Clinical Efficacy

The clinical efficacy Nubeqa (darolutamide) for the treatment of patients with non-metastatic castration resistant prostate cancer (nmCRPC) is supported by the pivotal ARAMIS study, a randomized, double-blind, placebo-controlled multicentre Phase III study in patients with nmCRPC and a prostate-specific antigen doubling time (PSADT) of ≤10 months (considered to be at high risk of developing metastatic disease).

In the ARAMIS study, a total of 1,509 patients on androgen deprivation therapy (ADT) were randomized 2:1 to receive Nubeqa (955 patients) or matching placebo (554 patients). In the Nubeqa arm, patients were treated with 600 mg darolutamide (two tablets of 300 mg) orally twice daily, for a total of 1,200 mg/day. Randomization was stratified by PSADT (≤6 months or >6 months) and use of osteoclast-targeted therapy at study entry (yes or no). All patients received a gonadotropin-releasing hormone (GnRH) analog concurrently or had a bilateral orchiectomy.

The following patient demographics and disease characteristics were balanced between treatment arms. The median age was 74 years (range 48-95) and 9% of patients were 85 years of age or older. The racial distribution was 79% White, 13% Asian, and 3% Black. A majority (73%) of patients had a Gleason score of ≥7 at diagnosis. The median PSADT was 4.5 months. Nine percent (9%) of patients had prior orchiectomy, 25% of patients had prior prostatectomy, and 50% of patients had at least one prior radiotherapy. Seventy-three percent (73%) of patients received prior treatment with an anti-androgen (bicalutamide or flutamide). All patients had an Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0 (69%) or 1 at study entry.

The patients were to receive treatment until confirmed metastasis, unacceptable toxicity, or withdrawal. At the cut-off point for data collection, 64.4% of the patients in the Nubeqa arm and 36.1% of the patients in the placebo arm continued to receive their assigned study treatment. The median duration of treatment was 14.8 months in the Nubeqa arm and 11.0 months in the placebo arm. The most common reason for permanent treatment discontinuation was centrally confirmed metastasis, in 11.7% of patients in the Nubeqa arm and 23.3% of patients in the placebo arm.

The primary endpoint was metastasis-free survival (MFS), defined as the time from randomization to confirmed evidence of either distant metastasis, or death from any cause within 33 weeks after the last evaluable scan, whichever occurred first. Distant metastasis was defined as new bone or soft tissue lesions or enlarged lymph nodes above the aortic bifurcation. The secondary endpoints were overall survival (OS), time to pain progression, time to initiation of first cytotoxic chemotherapy for prostate cancer, and time to first symptomatic skeletal event.

Superiority of Nubeqa over placebo was shown with a hazard ratio (HR) of 0.413 (95% Confidence Interval [CI]: [0.341; 0.500]; p<0.000001), representing a 58.7% reduction in the risk of metastasis or death.

The median MFS was 40.4 months (95% CI: [34.33; not estimable]) in the Nubeqa arm compared to 18.4 months (95% CI: [15.51; 22.34]) in the placebo arm, which is a clinically meaningful difference of 21.9 months in favour of Nubeqa.

Metastasis-free survival results were consistent across patient subgroups regardless of PSADT, prior use of bone-targeting agents or loco-regional disease. Additional subgroups with consistent MFS results included PSA levels at baseline, Gleason score at diagnosis, age, geographical region, ECOG PS at baseline, race, and number of prior hormonal therapies.

Overall survival was the first secondary endpoint analyzed in a gated hierarchical analysis. At the time of the data cut-off, 136 out of the 240 OS events planned for the final OS analysis had occurred. The HR for the OS analysis was 0.706 (95% CI: [0.501; 0.994]; p = 0.045210). The median OS was not reached in either treatment arm. As the pre-specified alpha significance level for this interim analysis of OS was 0.0005, the result was not considered statistically significant at this time. However, a trend in improvement of survival was observed for patients treated with Nubeqa.

Conclusions could not be reached from the remaining secondary endpoints because the pre-specified hierarchical statistical analysis plan did not permit for formal testing if the OS analysis was not significant. However, the descriptive analyses were supportive of the MFS endpoints as follows:

  • The median time to pain progression was 40.3 months in the Nubeqa arm (95% CI: [33.21; 41.20]) compared to 25.4 months in the placebo arm (95% CI: [19.09; 29.63]).
  • The time to first cytotoxic therapy was not reached in the Nubeqa arm, and therefore the median could not be determined. The median in the placebo arm was 38.2 months (95% CI: [35.55; 41.89]).
  • The median time to first symptomatic skeletal event could not be accurately determined in either treatment arm due to a low number of events.

Overall, treatment with Nubeqa plus ADT in patients with nmCRPC and at high risk of developing metastases demonstrates significant improvement over ADT alone in delaying distant metastases or death. Treatment with Nubeqa plus ADT is well tolerated with a manageable safety profile. Taken together, the data provided in the submission establish a favourable benefit-harm-uncertainty profile for the use of Nubeqa in the treatment of patients with nmCRPC, with the caveat that Nubeqa has not been studied in patients with nmCRPC at low risk of developing metastases.

Indication

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

  • Nubeqa (darolutamide) is indicated for the treatment of patients with non-metastatic castration resistant prostate cancer (nmCRPC)

Health Canada revised the proposed indication to better reflect the patient population studied in the pivotal study. It was considered reasonable not to limit the indication in a manner that would exclude treatment of low-risk patients based on the significant positive effect of Nubeqa, the AR target of darolutamide, and because the precise definition of high-risk nmCRPC is still evolving. Accordingly, Health Canada approved the following indication:

  • Nubeqa (darolutamide) is indicated for the treatment of patients with non-metastatic castration resistant prostate cancer (nmCRPC).
    • Nubeqa has not been studied in patients with nmCRPC at low risk of developing metastasis. The benefit and risk profile in these patients is unknown.

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

Clinical Safety

The clinical safety profile of Nubeqa (darolutamide) was primarily derived from the pivotal Phase III study, ARAMIS, which is described in the Clinical Efficacy section. Patients in this study had nmCRPC, with a high risk of developing metastasis.

An independent Data and Safety Monitoring Board (DSMB), also called Data Monitoring Committee (DMC), was established to monitor the study periodically for safety and patient benefit-risk, and perform other functions. In cases of clinically significant toxicities, or if otherwise considered necessary for patient safety, the dose of study treatment could be delayed or reduced to 300 mg twice a day (600 mg daily total). Dosing of the study treatment below 300 mg twice a day was not allowed. Adverse reactions were graded from least severe (Grade 1) to most severe (Grade 4), with Grade 5 being a fatal outcome.

Adverse reactions leading to permanent study drug discontinuation occurred at a similar rate in both the Nubeqa and placebo arms, at 8.9% vs 8.7%, respectively. The most common adverse reactions leading to permanent study drug discontinuation in the Nubeqa arm were cardiac failure (0.4%) and death (with cause unspecified or unknown) (0.4%). In the placebo arm, these reactions were reported in 0.7% and 0.2% of patients, respectively. Cardiac failure was also the most commonly reported reason for discontinuation in the placebo arm.

Dose modifications (interruption, delay, or reduction) were required for 15.2% of patients in the Nubeqa arm and for 9.7% of patients in the placebo arm. The dose was re-escalated to 600 mg in the majority of the patients who had dose modification in both the Nubeqa and placebo arms.

Adverse reactions classified as Grade 3 or lower were reported for 22.5% of patients in the Nubeqa arm vs 17.9% of patients in the placebo arm. The most common adverse reaction in both treatment arms was hypertension (3.1% in the Nubeqa arm vs 2.2% in the placebo arm), followed by urinary retention (1.6% vs 2.0%) and hematuria (1.0% vs 1.3%).

Adverse reactions classified as Grade 4 or lower were reported for 2.2% of patients in the Nubeqa arm vs 1.6% of patients in the placebo arm. These included acute myocardial infarction, hyperglycemia, ischemic stroke, and respiratory failure, which each occurred in 0.2% of patients in the Nubeqa arm. No corresponding reactions were reported in the placebo arm.

Special topics were defined as reactions or disorders representing potential or known risks associated with ADT or with novel anti-androgens. There was no incremental risk with treatment with Nubeqa for adverse events such as fracture, fall, seizure, hypertension, weight decrease, mental impairment, diabetes and hyperglycemia, cardiovascular disorders, cerebrovascular disorders, vasodilatation and flushing, depressed mood disorders, and breast disorders, including gynecomastia.

A sub-study of the pivotal ARAMIS study assessed QTc prolongation. The results from this study, as well as preclinical and clinical studies included in the development program, support the conclusion that Nubeqa does not cause large mean increases in the QTc interval (i.e. ≥20 ms).

Health-related Quality of Life outcome endpoints were supportive of an acceptable toxicity profile of Nubeqa compared to placebo.

Overall, the safety profile of Nubeqa is considered acceptable. Intolerable adverse reactions can be adequately managed by dose reduction or discontinuation until symptoms improve. Appropriate warnings and precautions are in place in the approved Nubeqa Product Monograph to address the identified safety concerns.

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

 

 

 

7.2 Non-Clinical Basis for Decision

 

The non-clinical review of Nubeqa was completed by Australia's Therapeutic Goods Administration (TGA) as part of a work-sharing initiative with Canada, Singapore, and Switzerland. The review of the submission was collaborative, with each regulatory agency sharing the outcome of their review with the others. However, each regulatory agency made their decision regarding authorization independently.

Darolutamide competitively inhibits androgen binding, AR nuclear translocation, and AR mediated transcription. Darolutamide decreased tumour cell proliferation in vitro, and led to tumour growth inhibition in xenograft models of prostate cancer in vivo.

Exposure to darolutamide in vitro and in vivo was sufficient to identify hematologic, reproductive and clastogenic toxicity. Additionally, based on the mechanism of action, darolutamide is expected to induce embryo-fetal toxicity and impair fertility.

Overall, the identified toxicities were considered manageable and acceptable risks for the proposed disease setting of nmCRPC. The key non-clinical findings and related risks are appropriately labelled in the Nubeqa Product Monograph.

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

 

 

7.3 Quality Basis for Decision

 

The quality review of Nubeqa was completed by Health Canada as part of a work-sharing initiative with Australia, Singapore, and Switzerland. The review of the submission was collaborative, with each regulatory agency sharing the outcome of their review with the others. However, each regulatory agency made their decision regarding authorization independently.

The Chemistry and Manufacturing information submitted for Nubeqa 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 36 months is acceptable when the drug product is stored at room temperature (15ºC to 30ºC).

Proposed limits of drug-related impurities are considered adequately qualified (i.e. within International Council for Harmonisation [ICH] limits and/or qualified from toxicological studies).

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

All non-medicinal ingredients (described earlier) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations.

One excipient found in Nubeqa, lactose monohydrate, is of animal origin. In accordance with the European guideline "Note for guidance on minimizing the risk of transmitting animal spongiform encephalopathy agents via human and veterinary medicinal products" (EMA/410/01), the drug product can be regarded as safe with respect to transmissible spongiform encephalopathy (TSE). Consequently, there is no risk of transmission of spongiform encephalopathy from pharmaceutical use of the drug product.