Regulatory Decision Summary for Truqap

The purpose of this New Drug Submission (NDS) was to seek market authorization for Truqap (capivasertib), an oral inhibitor of serine/threonine kinase AKT. The sponsor, AstraZeneca Canada Inc. proposed Truqap is indicated in combination with fulvestrant for the treatment of adult patients with hormone receptor (HR) positive, human epidermal growth factor receptor 2 (HER2) negative (defined as IHC 0 or 1+, or IHC 2+/ISH-) locally advanced or metastatic breast cancer following recurrence or progression on or after an endocrine-based regimen. Upon review, 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.

The evaluation of efficacy and safety for this submission was supported by CAPItello-291, a Phase 3, randomized, double-blind, placebo-controlled study of Truqap plus fulvestrant versus placebo plus fulvestrant in adult females (pre- or post-menopausal) and adult males with locally advanced (inoperable) or metastatic HR-positive, HER2-negative breast cancer following recurrence or progression on or after an aromatase inhibitor (AI) based treatment.

Advanced breast cancer is a serious and life threatening condition. Although breast cancer-associated survival rates have dramatically improved over the past decades, once metastatic, breast cancer still represents an incurable condition and advanced stage breast cancer remains the largest cause of cancer death in women worldwide. Treatment options are palliative and the development of resistance to therapies is frequent. There remains an unmet need for novel therapies in this population.

Evidence to support market authorization of Truqap was provided by CAPItello-291, a Phase III international, multicenter, randomized, double blind, placebo-controlled trial which enrolled pre- and postmenopausal women and men with HR-positive, HER2-negative advanced breast cancer who had disease progression following aromatase inhibitor therapy. A total of 708 patients were randomized to receive either capivasertib 400 mg twice daily and fulvestrant 500 mg (355 patients) or placebo and fulvestrant (353 patients). The study specified dual primary endpoints of progression free survival (PFS) in an overall population and PFS in an altered population (defined as patients with breast tumour harbouring an alteration in PIK3CA/AKT1/PTEN genes). Overall, 40.8% of patients (n = 289) had tumours with alterations of PIK3CA/AKT/PTEN. Of the non-altered patients (419 patients; 59.2%), 44.2% were confirmed non-altered and 15% were ‘unknown’.

CAPItello-291 met its co-primary endpoints with a statistically significant improvement in PFS for capivasertib plus fulvestrant when compared to fulvestrant plus placebo control. In the overall population, a 40% risk reduction in disease progression or death was observed in favour of capivasertib plus fulvestrant treatment (hazard ratio [HR]: 0.60; 95% confidence interval [CI]: 0.51 – 0.71; p < 0.001). Median PFS was prolonged to 7.2 months in the capivasertib + fulvestrant arm compared with 3.6 months in the placebo + fulvestrant arm. In the altered population, results were more pronounced, with an estimated 50% risk reduction in disease progression or death (HR: 0.50; 95% CI: 0.38 – 0.65; p < 0.001). Median PFS was prolonged by 4.2 months to 7.3 months in the capivasertib + fulvestrant arm compared with 3.1 months in the placebo + fulvestrant arm. Importantly, in the known non-altered population the result was less robust, with only a 21% reduction in the risk of progression in favour of capivasertib + fulvestrant (HR: 0.79; 95% CI: 0.61 – 1.02). The median PFS was 5.3 months in the capivasertib + fulvestrant arm compared with 3.7 months in the placebo + fulvestrant arm. Exploratory evaluation of PFS by blinded independent central review (BICR) in the known non-altered population supported these results with a PFS of 3.9 months in the capivasertib plus fulvestrant arm compared with 3.7 months in the placebo plus fulvestrant arm (HR: 0.81; 95% CI 0.61 - 1.06). This modest increase in PFS is not considered to be clinically meaningful. Overall, the efficacy in the intent-to-treat population appears to be driven primarily by the altered population.

The PFS benefit for the dual primary endpoints were generally consistent across pre-planned sensitivity and supportive analyses, indicative of the robustness of the results, including the 71% of patients who had previously received treatment with a CDK4/6 inhibitor. The overall survival (OS) data in the altered population were only approximately 30% mature at the first OS data cut off, however did not suggest a detrimental effect on survival of treatment with capivasertib + fulvestrant compared with placebo + fulvestrant in the overall population or the altered population.

The safety profile of Truqap was supported primarily by the pivotal CAPItello-291 trial, which included 705 patients (355 who received capivasertib with fulvestrant and 350 who received placebo with fulvestrant). Data from the non-altered and altered cohorts were combined for a more robust safety evaluation with no significant differences observed between these populations. Capivasertib in combination with fulvestrant demonstrated increased toxicity compared to fulvestrant alone with all grade adverse events (AE) (96.6%), treatment related AE (88.2%), grade >3 AE (37.4%) and AE leading to dose modifications (44.5%) all reported at higher rates in the capivasertib/fulvestrant. AEs were considered manageable with clinical monitoring and appropriate supportive therapy or intervention, including dose interruptions (38.9%), reduction (19.7%) or discontinuation (13%).

Frequent adverse reactions (>2%, grouped terms) in the capivasertib/fulvestrant arm (vs. placebo/fulvestrant) 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%), blood creatinine increased (2.5% vs. 0%), dyspepsia (2.5% vs. 1.1%), hypokalemia (2.3% vs. 0%) and urinary tract infection (2% vs. 0.6%). Important additional adverse reactions include severe cutaneous adverse reactions including erythema multiforme (1.7%), palmar plantar erythrodysesthesia (0.8%) and drug reaction with eosinophilia and systemic symptoms (DRESS) (0.3%), diabetic ketoacidosis (0.3%) or severe hypoglycemia (2.3%), and severe diarrhea (9.3%) leading to both severe dehydration and acute kidney injury (1.1%). Serious adverse reactions were reported more frequently in the capivasertib plus fulvestrant arm (6.2% vs. 1.1%).

Hyperglycemia, cutaneous adverse reactions and diarrhea are included as Serious Warnings and Precautions in the Product Monograph and recommendations for monitoring and management of these reactions are included. Four patients died during the treatment with capivasertib plus fulvestrant due to causes other than the underlying disease: one of sepsis, aspiration pneumonia, cerebral hemorrhage and acute myocardial infarction. Overall, the safety profile of Truqap is considered acceptable in the setting of a serious and life-threatening disease.

The data is limited by the finding that the overall population is largely driven by those patients with alterations and the magnitude of improvement in PFS in the non-altered population is not considered sufficiently large in light of the substantial added toxicities of capivasertib treatment when compared to fulvestrant alone. As such, the risk-benefit analysis in the overall population is considered unfavorable and the indication was limited to include those patients with alterations only (AKT1/PTEN/PIK3CA). Further, limited data regarding the efficacy and safety of capivasertib in males were available given that few male patients were enrolled in CAPItello-291 (n = 7). Although too limited to draw conclusions, PFS in males treated with capivasertib was very short (mean 2.1 months) compared to fulvestrant monotherapy (mean 12.9 months) and this finding coupled with the differences in biology in endocrine sensitive breast cancer between males and females, leads to considerable uncertainty regarding the efficacy of capivasertib in males. Although no differences in regards to safety are anticipated between males and females, given the known increased toxicity of capivasertib when compared to fulvestrant, the risk-benefit analysis of Truqap in males is considered unfavourable at this time.

The food effects on capivasertib exposure were not considered to be clinically significant by the Sponsor and capivasertib tablets are proposed to be administered with or without food which is reflected in the Product Monograph (PM). Capivasertib was teratogenic in an animal studies. It is unknown whether capivasertib or its metabolites are excreted into human milk. A cautionary statement was included in the PM. There is uncertainty about the risk of QTc prolongation in patients with moderate/severe renal or hepatic impairment, which could show increased plasma levels of capivasertib. Capivasertib was not mutagenic in vitro, but showed genotoxic potential via an aneugenic mode of action. The carcinogenic potential of capivasertib has not been assessed. Additional clinical assessment is required to determine the potential effect of capivasertib on CYP1A2 and CYP2B6 substrates, as well as the effect of P-gp inhibitors on capivasertib exposure. Population PK analysis suggests that no dose modification is warranted for patients with mild or moderate renal impairment, mild hepatic impairment or in the case of concomitant administration of acid reducing agents or weak CYP3A4 inducers. However, dedicated clinical studies are required to determine the safety and tolerability of capivasertib in patients with moderate or severe hepatic impairment. 

A Risk Management Plan (RMP) for Truqap (capivasertib) was submitted by the Sponsor 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.

Taken together, there is substantial evidence to demonstrate a favorable benefit-risk profile for capivasertib in combination with fulvestrant for the treatment of adult female patients 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. On the basis of the information reviewed, Truqap presents an acceptable and manageable safety profile in consideration of the intended population. Based on the benefit-risk-uncertainty profile of the product, it is recommended that Truqap be granted authorization.

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