Summary Basis of Decision for Truqap

As outlined in the What steps led to the approval of Truqap? section, the review of the clinical component of the New Drug Submission for Truqap was completed by Health Canada as part of an international partnership with the United States Food and Drug Administration as a Project Orbis Type A submission. The clinical review of the New Drug Submission for Truqap applied multiple methods for use of foreign reviews, described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.

Clinical Pharmacology

Capivasertib, the medicinal ingredient in Truqap, is an inhibitor of the kinase activity of all 3 isoforms of serine/threonine kinase AKT (AKT1, AKT2 and AKT3). In tumours, AKT activation is a result of upstream activation by other signalling pathways, genetic alterations in AKT1, phosphatase and tensin homolog (PTEN) and the catalytic subunit of phosphatidylinositol 3-kinase (PIK3CA).

The pharmacokinetics of capivastertib has been characterized in healthy subjects and in participants with solid tumours. When following the recommended dosing regimen (400 mg twice daily, 4 days on and 3 days off), steady-state levels are predicted to be attained every third and fourth dosing day each week, starting from Week 2. During the off-dosing days, plasma concentration of capivasertib is low (approximately 0.5% to 15% of the maximum concentration [C_max] at steady state). The systemic exposure of capivasertib, as measured by the area under the plasma concentration-time curve (AUC) and the C_max, increased approximately proportionally to the dose over the dose range of 80 mg to 800 mg.

In humans, capivasertib reached the C_max approximately 1-2 hours after administration (median time: 1.74 hours), and the mean absolute bioavailability was 29%. No clinically significant differences in capivasertib exposure were observed after co-administration with food.

Following intravenous administration of capivasertib to healthy subjects, the mean volume of distribution was 205 L (16% coefficient of variation [CV]). Following oral administration of capivasertib to participants, the steady-state volume of distribution was 322 L (111% CV). Capivasertib plasma protein binding was 78%, with preference towards albumin versus alpha 1-acid glycoprotein (AGP), and the plasma-to-blood ratio was 0.71.

Data from in vitro phenotyping experiments indicate that capivasertib is primarily metabolized by the cytochrome P450 (CYP) 3A4 and uridine 5'-diphospho-glucuronosyltransferase (UGT) 2B7 enzymes. The major metabolite identified in human plasma (accounting for 83% of the circulating material) and urine was the ether glucuronide metabolite AZ14102143 (M2). Capivasertib showed drug-drug interactions with strong or moderate CYP3A4 inhibitors (itraconazole, erythromycin, verapamil) and inducers (enzalutamide, rifampicin, and efavirenz). No clinically meaningful interaction was predicted between capivasertib and UGT2B7 inhibitors. Capivasertib is a substrate for P-glycoprotein (P-gp), and to a lesser extent, organic cation transporter (OCT) 2. Capivasertib showed potential to inhibit the drug transporters OCT2, multidrug and toxin extrusion protein (MATE) 1, MATE2K, organic anion transporting polypeptide (OATP) 1B1, OATP1B3, OAT3 and breast cancer resistance protein (BCRP). The effect of P-gp inhibition on capivasertib exposure was not assessed.

In participants, the effective half-life of capivasertib following multiple dosing was 8.3 hours. The steady-state oral clearance was 50 L/h (37% CV). Following single-dose oral administration of 400 mg capivasertib, the mean total recovery of radioactive dose was 45% from urine and 50% from feces. Renal clearance was 21% of total clearance.

The potential risk of QT prolongation in association with capivasertib treatment was assessed in 180 participants with advanced solid malignancies at doses ranging from 80 mg to 800 mg capivasertib. The model projects a linear relationship between capivasertib concentration and increases in the QT interval corrected using Fridericia’s formula (QTcF). At exposures close to the one anticipated in participants at the therapeutic dose, the predicted QTcF prolongation was 3.87 ms (90% confidence interval [CI]: 2.77, 4.97). Capivasertib is not expected to induce clinically relevant QT prolongation that is associated with proarrhythmic effects (i.e., > 20 ms) at the recommended dosage. However, in the pivotal study CAPItello-291, QT prolongation was reported in 11 (3.1%) participants treated with capivasertib plus fulvestrant, while no cases were noted in the control arm.

The pharmacokinetic parameters of capivasertib were analyzed in a population pharmacokinetic analysis using data pooled from Phase I/II and III studies. For a patient of 66 kg and 57 years following a dosing schedule of 400 mg twice daily (4 days on, 3 days off), exposure as measured by the area under the drug plasma concentration-time curve at steady state, over a 12-hour period (AUC_12h,ss) was 7,280 µg·h/L and the C_max at steady state was 1,380 µg/L. Based on the data, capivasertib clearance was predicted to increase with body weight and decrease with age.

Based on a critical review of the clinical pharmacology package, no safety issues were identified which would preclude the approval of Truqap.

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

Clinical Efficacy

The results of the Phase III study CAPItello-291 provided evidence supporting the clinical efficacy of Truqap in combination with fulvestrant. This study enrolled pre- and postmenopausal adult females and males with HR-positive, HER2-negative advanced breast cancer who had disease progression following aromatase-inhibitor therapy. Enrollment was open to all eligible participants regardless of the PIK3CA/AKT1/PTEN status of their tumour(s). However, collection of adequate tumour tissue prior to randomization was required for post-randomization central analysis of PIK3CA/AKT1/PTEN mutation status. Participants should have previously received treatment with an aromatase inhibitor (AI)-containing regimen and have:

• radiological evidence of breast cancer recurrence or progression while on, or within 12 months of the end of treatment with an AI, or

• radiological evidence of progression while on prior AI administered as a treatment line for locally advanced or metastatic breast cancer.

Participants were excluded from the study if:

• they had more than two lines of endocrine therapy or more than one line of chemotherapy for inoperable locally advanced or metastatic disease,

• they had prior treatment with an AKT, PI3K, mTOR inhibitor, fulvestrant and/or other selective estrogen receptor degraders (SERDs), or

• the disease burden made the patient ineligible for endocrine therapy (e.g., symptomatic visceral disease that is potentially life-threatening in the short term, or clinically significant abnormalities of glucose metabolism as defined by any of the following: participants with diabetes mellitus type 1 or diabetes mellitus type 2 requiring insulin treatment or hemoglobin A1C level ≥ 8.0%).

The dual primary endpoints of the study were progression-free survival (PFS) in an overall population, and PFS in the population of participants with a breast tumour harbouring an eligible alteration in the PIK3CA/AKT1/PTEN genes. The key secondary endpoints were overall survival (OS) and objective response rate (ORR) in the overall population and the population with PIK3CA/AKT1/PTEN-altered tumours.

In total, 708 participants were randomized to receive either Truqap (400 mg twice daily) and fulvestrant (500 mg), or placebo and fulvestrant. Randomization was stratified according to liver metastases, prior use of cyclin-dependent kinase (CDK) 4/6 inhibitors, and geographic location. Participants received treatment until radiographic disease progression or unacceptable toxicity. Tumour assessments were performed every 8 weeks (± 7 days) for the first 18 months, and every 12 weeks (± 7 days) thereafter.

There were no significant differences in the patient demographics between the Truqap arm and placebo arm in the overall study population and the study population with PIK3CA/AKT1/PTEN-altered tumours. The median age of participants in the population with PIK3CA/AKT1/PTEN-altered tumours was 59.3 years (range: 34 to 90 years), 99.3% of participants were adult females, 52.5% were White, and 28.7% were Asian. Most participants (81.3%) were postmenopausal. The majority of participants (99.3%) had metastatic disease and 71.3% of participants had received prior treatment with a CDK4/6 inhibitor. As expected, most participants (62.6%) had received one prior line of therapy for advanced disease. Use of prior chemotherapy was reported for 18.2% of participants. Participants were overall representative of the general population with the exception of race/ethnicity, as White and Asian participants were overrepresented when compared to the Canadian population of breast cancer participants. Likewise, the participants enrolled in the pivotal study had a younger median age (58 years) than those reported in the Canadian population at initial diagnosis of breast cancer (median age 63 years). Overall, 40.8% of participants (number of participants [n] = 289) had PIK3CA/AKT1/PTEN-altered tumours. Of the participants with non-altered tumours (n = 419; 59.2%), 44.2% had confirmed non-altered tumours and 15.0% had ‘unknown’ tumour status due mostly to preanalytical failure.

Baseline demographics and disease characteristics including Eastern Cooperative Oncology Group (ECOG) performance status, tumour burden, and prior antineoplastic therapy were generally balanced between the study arms. In the overall population, small differences in the number of pre- or perimenopausal adult females were observed between the two arms (21.6% in the Truqap-plus-fulvestrant arm versus 18.1% in the placebo-plus-fulvestrant arm) and in the proportion of participants with diabetes (6% in the Truqap-plus-fulvestrant arm versus 9% in the placebo-plus-fulvestrant arm).

At the clinical data cutoff (DCO) for final PFS analysis, the median duration of exposure to Truqap plus fulvestrant in the overall population was 5.29 months, with 52.4% of participants having completed 6 months of treatment or more, and 27.0% having completed 12 months of treatment or more. At DCO1, the median duration of follow-up of PFS in the Truqap-plus-fulvestrant arm was 13.0 months in the overall population and 16.4 months in the population with PIK3CA/AKT1/PTEN-altered tumours.

The dual primary endpoints of the pivotal study were met, with a statistically significant improvement in investigator-assessed PFS for Truqap plus fulvestrant over the fulvestrant plus placebo control in both the overall population and the population with PIK3CA/AKT1/PTEN-altered tumours. In the overall population, an estimated 40% risk reduction in disease progression or death was observed in favour of Truqap-plus-fulvestrant treatment (hazard ratio [HR]: 0.60; 95% confidence interval [CI]: 0.51, 0.71; p < 0.001). The median PFS was prolonged by 3.6 months in the Truqap-plus-fulvestrant arm (7.2 months), relative to the placebo-plus-fulvestrant arm (3.6 months). Similar results were reported for the population with PIK3CA/AKT1/PTEN-altered tumours, with an estimated 50% risk reduction in disease progression or death (HR: 0.50; 95% CI: 0.38, 0.65; p < 0.001). The median PFS was prolonged by 4.2 months in the Truqap-plus-fulvestrant arm (7.3 months) relative to the placebo-plus-fulvestrant arm (3.1 months). Evaluation by blinded independent central review supported this finding, with an estimated 49% risk reduction in disease progression or death (HR: 0.51; 95% CI: 0.38, 0.68; p < 0.001). The median PFS in the Truqap-plus-fulvestrant group and the placebo-plus-fulvestrant group were 7.3 months and 3.3 months, respectively. The magnitude of this benefit is considered clinically meaningful for this patient population.

Among the participants whose tumours did not have PIK3CA/AKT1/PTEN alterations or for whose tumours the alteration status was “unknown/no result”, a 30% reduction was observed in the risk of progression or death in favour of Truqap plus fulvestrant (HR: 0.70; 95% CI: 0.56, 0.88). The median PFS was 7.2 months in the Truqap-plus-fulvestrant arm, compared with 3.7 months in the placebo-plus-fulvestrant arm. In participants whose tumours had an “unknown/no result” alteration status, a 48% reduction was reported in the risk of progression or death in favour of Truqap plus fulvestrant (HR: 0.52; 95% CI: 0.32, 0.83). The median PFS was 10.0 months in the Truqap-plus-fulvestrant arm compared with 1.9 months in the placebo-plus-fulvestrant arm.

Data from exploratory analyses in the population of participants with non-altered tumours supported the efficacy of Truqap plus fulvestrant, but due to their exploratory nature, cannot be considered clinically meaningful. Based on observations from this study, efficacy in the overall population is expected to be driven by the patient population with PIK3CA/AKT1/PTEN-altered tumours. The data are not considered sufficient to clearly demonstrate a substantially large improvement in clinical efficacy to support an authorization of Truqap in the population of participants whose tumours do not harbour alterations in the PIK3CA/AKT1/PTEN genes considering the toxicity associated with the addition of Truqap to fulvestrant.

The PFS benefit for the dual primary endpoints was consistent across pre-planned sensitivity and supportive analyses, which is indicative of the robustness of the results. Hazard ratios estimated for predefined subgroups generally favoured the Truqap-plus-fulvestrant treatment. In the patient population with PIK3CA/AKT1/PTEN-altered tumours, efficacy was observed regardless of randomization stratification factors including baseline ECOG performance scores, visceral metastases, HR status, number of metastatic sites, bone lesions only, and importantly, prior treatment with a CDK4/6 inhibitor.

Hazard ratios crossed 1 in a small number of subgroups. This creates uncertainty regarding true differences between the groups, and was attributed to their small sample sizes.

Due to the rarity of breast cancer in men, recruitment into clinical studies is challenging. Although men were eligible to enroll in the pivotal study, only seven men were included: three men in the overall population who received Truqap plus fulvestrant (two of whom had PIK3CA/AKT1/PTEN-altered tumours), and four men who received placebo plus fulvestrant. The authorization of Truqap for treatment of men with PIK3CA/AKT1/PTEN-altered tumours is hindered by multiple factors. In the pivotal study, short PFS times were observed in the three male participants who received Truqap when compared to those who received placebo-plus-fulvestrant. Generally, the available data regarding the safety and efficacy of fulvestrant in males are limited. Whether the pathogenesis, biology, and genetics of breast cancer in males differ from breast cancer in females, particularly in endocrine-sensitive breast cancer, remains uncertain. Although common female breast cancer treatment practices are applied to the management of male breast cancer, the medical community recognizes male breast cancer as a distinct disease characterized by varied molecular and clinicopathologic features.

A number of agents have been approved in similar indications for the treatment of advanced HR-positive, HER2-negative breast cancer in men, with extrapolation of the results from female clinical study participants. The rationale of similar mechanism of disease for advanced HR-positive, HER2-negative breast cancer between males and females is generally considered reasonable, particularly given the current guidelines and recommendations for treatment of males with the same general strategies used in females. However, the PFS time in the three male participants treated with Truqap in combination with fulvestrant in the pivotal study was very short (mean of 2.1 months) when compared to that in the four participants receiving placebo-plus-fulvestrant (mean of 12.9 months). The data are limited by small sample size, and therefore insufficient to draw definitive conclusions. This finding, combined with the uncertainties regarding biological differences in endocrine-sensitive breast cancer between males and females, creates considerable uncertainty regarding the efficacy of Truqap in combination with fulvestrant in males. Although no differences in safety are anticipated between males and females, the risk-benefit profile of Truqap in combination with fulvestrant in males was ultimately considered unfavourable due to the known increased toxicity of Truqap compared to fulvestrant and the uncertainties surrounding the efficacy of this combination therapy in males. For these reasons, Health Canada restricted the indication to female participants, as stated below.

Indication

Sponsor's proposed indication

Health Canada-approved indication

Truqap (capivasertib tablets) is indicated, in combination with fulvestrant, for the treatment of adult participants with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative (defined as immunohistochemistry [IHC] 0 or 1+, or IHC 2+/in situ hybridization [ISH]-negative) locally advanced or metastatic breast cancer following recurrence or progression on or after an endocrine-based regimen.

Truqap (capivasertib tablets) in combination with fulvestrant is indicated for the treatment of adult females with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer with one or more AKT1/PTEN/PIK3CA alterations following progression on at least one endocrine-based regimen in the metastatic setting or recurrence on or within 12 months of completing adjuvant therapy.

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

Clinical Safety

The safety profile of Truqap was characterized mainly in the pivotal study, CAPItello-291, which included 705 participants (355 who received Truqap plus fulvestrant and 350 who received placebo plus fulvestrant). Data from the participants whose tumours harboured AKT1/PTEN/PIK3CA alterations and participants with non-altered tumours were combined for a more robust safety evaluation. The safety profile was generally similar across both populations. An additional 165 participants were exposed to Truqap monotherapy and 75 participants were exposed to Truqap plus fulvestrant in the Phase I and II trials FTIH (D3610C00001), the Japanese safety/pharmacokinetics study (D3610C00004), and the formulation/food study (D3610C00007). Safety data from the non-pivotal studies were not pooled due to the different study populations and regimens used (single agent and combination with fulvestrant).

In the pivotal study, the median treatment duration was 5.4 months in the Truqap-plus- fulvestrant arm and 3.6 months in the placebo-plus-fulvestrant arm. At the time of the safety analysis, 186 participants in the Truqap-plus-fulvestrant arm (52.4%) and 136 participants in the placebo-plus-fulvestrant arm (38.9%) had completed 6 months or more of treatment. Ninety-six participants in the Truqap-plus-fulvestrant arm (27.0%) and 61 participants in the placebo-plus-fulvestrant arm (17.4%) had completed 12 months or more of treatment.

The proportions of participants who reported adverse events, adverse events leading to discontinuation and to dose adjustment/interruption, adverse events requiring additional therapy, adverse reactions, severe adverse reactions, and serious adverse reactions were higher in the Truqap-plus-fulvestrant group than in the placebo-plus-fulvestrant group. This is consistent with the increased toxicity expected when adding a targeted agent to endocrine therapy. Almost all participants in the Truqap-plus-fulvestrant group (96.6%, compared to 82.3% in the placebo-plus-fulvestrant group) experienced at least one adverse event. The safety profile was generally similar across both the population with AKT1/PTEN/PIK3CA-altered tumours and the overall population.

The percentage of participants with adverse events considered by the investigator to be possibly related to Truqap or placebo was higher in the Truqap-plus-fulvestrant arm (88.2%) than in the placebo-plus-fulvestrant arm (37.7%). The most commonly reported adverse reactions in the Truqap-plus-fulvestrant arm (reported at a frequency of 2% or greater, and for which the frequency was at least 2% higher than that reported in the placebo-plus-fulvestrant arm) include diarrhea (67.3% vs. 13.1%), cutaneous reactions (46.5% vs. 10.9%), nausea (27.3% vs. 10.6%), fatigue (22% vs. 13.4%), stomatitis (16.3% vs. 3.1%), vomiting (15.8% vs. 2.6%), hyperglycemia (16.9% vs 4.0%), decreased appetite (10.7% vs. 2.3%), dysgeusia (5.6% vs. 0.9%), pyrexia (5.6% vs. 0.3%), headache (5.4% vs. 3.1%), dry mouth (4.2% vs. 1.4%), anemia (3.9% vs. 2.0%), increased blood creatinine (2.5% vs. 0%), dyspepsia (2.5% vs. 1.1%), hypokalemia (2.3% vs. 0%) and urinary tract infection (2% vs. 0.6%).

Severe (Grade 3 or 4) adverse reactions were more commonly reported in the Truqap-plus-fulvestrant group (30.7%) than in the placebo-plus-fulvestrant group (5.4%). Cutaneous adverse reactions (16.9%), diarrhea (9.3%) and hyperglycemia (2.3%) were the most common Grade 3 or higher adverse reactions (reported at a frequency of 2% or higher in the Truqap-plus-fulvestrant arm, with a higher frequency in the Truqap-plus-fulvestrant arm).

Serious adverse events were also reported more frequently in the Truqap-plus-fulvestrant arm (16.1%) than in the placebo-plus-fulvestrant arm (8%), and were assessed by the investigator as possibly related to the treatment in 6.2% and 1.1% of participants, respectively. The serious adverse events considered by the investigator as possibly related to Truqap and reported in more than one patient in the Truqap-plus-fulvestrant arm were diarrhea (6 participants, 1.7%), cutaneous adverse reaction (12 participants, 3.4%), acute kidney injury, hyperglycemia, fatigue and vomiting (each in 3 participants, 0.8%),.

There were 87 deaths in the Truqap-plus-fulvestrant arm (24.5%) and 108 deaths in the placebo-plus-fulvestrant arm (30.6%). Four participants in the Truqap-plus-fulvestrant arm died during treatment from causes other than the underlying disease: one patient from acute myocardial infarction, one patient from cerebral hemorrhage, one patient from aspiration pneumonia, and one patient from sepsis. Although all were assessed by the investigator as not causally related to study treatment, upon review, it is believed that association with Truqap cannot be ruled out in 3 of the 4 reported deaths (those attributed to myocardial infarction, aspiration pneumonia, and sepsis). One patient in the placebo-plus-fulvestrant arm died due to coronavirus disease 2019 (COVID-19).

Although the incidence of adverse events and adverse reactions was higher in the Truqap-plus-fulvestrant arm than in the placebo-plus-fulvestrant arm, most adverse events and reactions were manageable using concomitant medications and/or dose modifications. Adverse events leading to dose interruptions (38.9%) and dose reductions (19.7%) were more frequent in participants treated with Truqap plus fulvestrant. Adverse events leading to discontinuation occurred in 13% of participants. The most frequently reported adverse events leading to dose modification or discontinuation in the Truqap plus fulvestrant arm were diarrhea, rash, vomiting, nausea, hyperglycemia, and pyrexia.

Based on the mechanism of action of Truqap, the adverse events of special interest (AESI) were hyperglycemia, cutaneous reactions, diarrhea, hypersensitivity, pneumonitis, stomatitis, urinary tract infections, and prolongation of the corrected QT (QTc) interval. These events are consistent with previous experience in the dose-finding studies, and in line with reported toxicities for the PIK3CA inhibitor alpelisib. Hyperglycemia, cutaneous adverse reactions, and diarrhea are listed as Serious Warnings and Precautions in the Truqap Product Monograph, along with recommendations for monitoring and management of these reactions.

Non-clinical data suggest a potential risk for QTc prolongation, which was considered an AESI in this study. However, no notable increases in the mean or median QTc interval were observed in the pivotal study (CAPItello-291). Three adverse events of QTc prolongation (two Grade 1 events and one Grade 3 event) were reported in the Truqap-plus-fulvestrant arm. No cases of sudden death or torsade de pointes were reported.

Overall, Truqap in combination with fulvestrant demonstrated increased toxicity compared to fulvestrant alone. All grades of adverse events, treatment-related adverse events, adverse events of severity higher than Grade 3, and dose modifications were all reported at higher rates in the Truqap-plus-fulvestrant arm. However, the adverse events were generally reversible with standard clinical management, Truqap dose reduction, treatment interruption, or discontinuation. The aforementioned safety findings, appropriate clinical monitoring and management were updated in various sections of the approved Truqap Product Monograph.

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

As outlined in the What steps led to the approval of Truqap? section, the review of the non-clinical component of the New Drug Submission for Truqap was completed by Health Canada as part of an international partnership with the United States Food and Drug Administration as a Project Orbis Type A submission. Foreign reviews were used in accordance with multiple methods described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.

Capivastertib (the medicinal ingredient in Truqap) is an inhibitor of all 3 isoforms of the human AKT serine/threonine kinase family (AKT1, AKT2 and AKT3), and shows selectivity for these over other kinases such as p70S6K, protein kinase A (PKA), and Rho-associated protein kinase (ROCK). Capivasertib treatment reduced the growth of cells in vitro and showed dose-dependent antitumour activity in human cancer xenograft models. The efficacy of capivasertib treatment was also observed in animal models with and without PIK3CA/AKT1/PTEN alterations.

The safety pharmacology profile of capivasertib was evaluated in a number of in vitro and in vivo models. The key targets identified were the cardiovascular and renal systems, and the secondary pharmacodynamic assessment showed the selectivity of capivasertib against the primary targets.

In repeat-dose toxicity studies of up to 6 months’ duration in rats and up to 9 months’ duration in dogs, capivasertib was rapidly absorbed and widely distributed. The most significant accumulations of radioactively labeled drug were observed in excretory tissues and fluids, with the liver, bile, and kidneys exhibiting the highest levels. When administered to rats, unchanged capivasertib was the primary circulating component, accounting for approximately 63% of the total exposure as measured by the area under the plasma concentration-time curve (AUC) and the drug was mainly excreted in feces (90%). The toxicologic assessment of capivasertib was conducted in mice, rats, and dogs. Repeated oral administration of capivasertib led to a temporary rise in glucose and insulin plasma levels at clinically relevant exposures, accompanied by histopathological changes in liver, pancreas, thyroid, adrenal glands, and effects on the hematopoietic system. In line with safety studies, renal and cardiac functions were affected in rats and dogs, respectively. Degenerative changes were identified in the male reproductive organs of all non-clinical species studied; these changes were not fully reversible in rats and dogs within 28 days from the end of treatment.

No effects were observed on mating performance or fertility in male rats after 10 weeks of administration of capivasertib at doses up to 100 mg/kg/day (corresponding to exposures approximately 1.4 times the expected exposure in humans at the recommended dose of 400 mg twice daily, based on total AUC). The effects on female fertility were not assessed, although a reversible decrease in the weight of female reproductive organs (uterus and ovaries) was observed in rats. In an embryo-fetal development study, oral administration of capivasertib to pregnant and lactating rats caused maternal toxicity and fetal harm, including embryo-fetal mortality, reduced fetal weights, and minor fetal visceral variation at maternal exposures approximately 0.8 times the anticipated human exposure at the recommended clinical dose, based on total AUC. When capivasertib was administered to pregnant rats at 150 mg/kg/day (approximately 0.8 times the expected exposure in humans at the recommended dose) throughout gestation and through early lactation, there was a reduction in litter and pup weights. Exposure to capivasertib was confirmed in suckling pups, which may indicate the potential for excretion of capivasertib in human milk.

Carcinogenicity studies have not been conducted with capivasertib. Capivasertib was genotoxic in vivo in a rat bone marrow micronucleus test, mainly via an aneugenic mode of action. Capivasertib was not mutagenic in vitro in the bacterial mutation assay (Ames test) and was not genotoxic in the mouse lymphoma gene mutation assay.

The results of the non-clinical studies as well as the potential risks to humans have been included in the Truqap Product Monograph. Considering the intended use of Truqap, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product.

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

As outlined in the What steps led to the approval of Truqap? section, the review of the quality component of the New Drug Submission for Truqap was completed by Health Canada as part of an international partnership with the United States Food and Drug Administration as a Project Orbis Type A submission. Foreign reviews were used in accordance with Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.

The chemistry and manufacturing information submitted for Truqap 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 (15 ºC to 30 ºC).

Proposed limits of drug-related impurities are considered adequately qualified (i.e., within International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use limits and/or qualified from toxicological studies).

A risk assessment for the potential presence of nitrosamine impurities was conducted according to requirements outlined in Health Canada’s Guidance on Nitrosamine Impurities in Medications. No risk was identified of the formation or introduction of nitrosamines during the drug substance and drug product manufacturing processes. Accordingly, no confirmatory testing is required.

All sites involved in production are compliant with good manufacturing practices.

None of the non-medicinal ingredients (excipients, described earlier) found in the drug product are prohibited by the Food and Drug Regulations.

The excipients used in the formulation of Truqap are not of human or animal origin.