Select patients for the treatment of HR-positive, HER2-negative advanced or metastatic breast cancer with TRUQAP, based on the presence of one or more of the following genetic alterations in tumor tissue: PIK3CA/AKT1/PTEN [see Clinical Studies (14)].

Information on FDA-approved tests for the detection of PIK3CA, AKT1, and PTEN alterations is available at: http://www.fda.gov/CompanionDiagnostics .

Evaluate fasting blood glucose (FG) and hemoglobin A1C (HbA1C) prior to starting TRUQAP and at regular intervals during treatment [see Warnings and Precautions (5.1)].

The recommended dosage of TRUQAP, in combination with fulvestrant, is 400 mg orally twice daily (approximately 12 hours apart) with or without food, for 4 days followed by 3 days off. Continue TRUQAP until disease progression or unacceptable toxicity.

TRUQAP dosing schedule for each week is provided in Table 1.

Table 1: TRUQAP Dosing Schedule for Each Week

Day	1	2	3	4	5 No dosing on day 5, 6 and 7.	6	7
Morning	2 x 200 mg	2 x 200 mg	2 x 200 mg	2 x 200 mg
Evening	2 x 200 mg	2 x 200 mg	2 x 200 mg	2 x 200 mg

Swallow TRUQAP tablets whole. Do not chew, crush, or split tablets prior to swallowing. Do not take tablets that are broken, cracked, or otherwise not intact.

If a patient misses a dose within 4 hours of the scheduled time, instruct the patient to take the missed dose. If a patient misses a dose more than 4 hours of the scheduled time, instruct the patient to skip the dose and take the next dose at its usual scheduled time.

If a patient vomits a dose, instruct the patient not to take an additional dose and take the next dose at its usual scheduled time.

Refer to the fulvestrant Full Prescribing Information for recommended fulvestrant dosing information.

For premenopausal and perimenopausal women, administer a luteinizing hormone-releasing hormone (LHRH) agonist according to current clinical practice standards.

For men, consider administering a LHRH agonist according to current clinical practice standards.

The recommended dose reductions for adverse reactions are listed in Table 2. Permanently discontinue TRUQAP if unable to tolerate the second dose reduction.

Table 2: Recommended Dose Reductions of TRUQAP for Adverse Reactions

TRUQAP	Dose and Schedule
First dose reduction	320 mg twice daily for 4 days followed by 3 days off
Second dose reduction	200 mg twice daily for 4 days followed by 3 days off

The recommended dosage modifications for adverse reactions are provided in Table 3.

Table 3: Recommended Dosage Modifications of TRUQAP for Adverse Reactions

Adverse Reaction	Severity Severity grading according to Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0.	TRUQAP Dosage Modification
Hyperglycemia (Fasting Glucose [FG]) [see Warnings and Precautions (5.1)]	FG > ULN‑160 mg/dL or FG > ULN‑8.9 mmol/L or HbA1C > 7%	Consider initiation or intensification of oral anti-diabetic treatment.
	FG 161‑250 mg/dL or FG 9‑13.9 mmol/L	Withhold TRUQAP until FG decrease ≤ 160 mg/dL (or ≤ 8.9 mmol/L). If recovery occurs in ≤ 28 days, resume TRUQAP at same dose. If recovery occurs in > 28 days, resume TRUQAP at one lower dose.
	FG 251‑500 mg/dL or FG 14‑27.8 mmol/L	Withhold TRUQAP until FG decrease ≤ 160 mg/dL (or ≤ 8.9 mmol/L). If recovery occurs in ≤ 28 days, resume TRUQAP at one lower dose. If recovery occurs in > 28 days, permanently discontinue TRUQAP.
	FG > 500 mg/dL or FG > 27.8 mmol/L or life-threatening sequelae of hyperglycemia at any FG level	For life-threatening sequelae of hyperglycemia or if FG persists at ≥ 500 mg/dL after 24 hours, permanently discontinue TRUQAP. If FG ≤ 500 mg/dL (or ≤ 27.8 mmol/L) within 24 hours, then follow the guidance in the table for the relevant grade.
Diarrhea [see Warnings and Precautions (5.2) ]	Grade 2	Withhold TRUQAP until recovery to ≤ Grade 1. If recovery occurs in ≤ 28 days, resume TRUQAP at same dose or one lower dose as clinically indicated. If recovery occurs in > 28 days, resume at one lower dose as clinically indicated. For recurrence, reduce TRUQAP by one lower dose.
	Grade 3	Withhold TRUQAP until recovery to ≤ Grade 1. If recovery occurs in ≤ 28 days, resume TRUQAP at same dose or one lower dose as clinically indicated. If recovery occurs in > 28 days, permanently discontinue TRUQAP.
	Grade 4	Permanently discontinue TRUQAP.
Cutaneous Adverse Reactions [see Warnings and Precautions (5.3) ]	Grade 2	Withhold TRUQAP until recovery to ≤ Grade 1. Resume TRUQAP at the same dose. Persistent or recurrent: reduce TRUQAP by one lower dose.
	Grade 3	Withhold TRUQAP until recovery to ≤ Grade 1. If recovery occurs in ≤ 28 days, resume TRUQAP at same dose. If recovery occurs in > 28 days, resume TRUQAP at one lower dose. For recurrent Grade 3, permanently discontinue TRUQAP.
	Grade 4	Permanently discontinue TRUQAP.
Other Adverse Reactions [see Adverse Reactions (6.1)]	Grade 2	Withhold TRUQAP until recovery to ≤ Grade 1. Resume TRUQAP at the same dose.
	Grade 3	Withhold TRUQAP until recovery to ≤ Grade 1. If recovery occurs in ≤ 28 days, resume TRUQAP at same dose. If recovery occurs in > 28 days, resume TRUQAP at one lower dose.
	Grade 4	Permanently discontinue TRUQAP.

Avoid concomitant use with strong CYP3A inhibitors. If concomitant use with a strong CYP3A inhibitor cannot be avoided, reduce the dosage of TRUQAP to 320 mg orally twice daily for 4 days followed by 3 days off [see Drug Interactions (7.1)].

When concomitantly used with a moderate CYP3A inhibitor, reduce the dosage of TRUQAP to 320 mg orally twice daily for 4 days followed by 3 days off.

After discontinuation of a strong or moderate CYP3A inhibitor, resume the TRUQAP dosage (after 3 to 5 half-lives of the inhibitor) that was taken prior to initiating the strong or moderate CYP3A inhibitor.

Severe hyperglycemia, associated with ketoacidosis, occurred in patients treated with TRUQAP. The safety of TRUQAP has not been established in patients with Type I diabetes or diabetes requiring insulin. Patients with insulin dependent diabetes were excluded from CAPItello-291.

Hyperglycemia occurred in 18% of patients treated with TRUQAP. Grade 3 (insulin therapy initiated; hospitalization indicated) or Grade 4 (life-threatening consequences; urgent intervention indicated) hyperglycemia occurred in 2.8% of patients. Diabetic ketoacidosis occurred in 0.3% of patients and diabetic metabolic decompensation in 0.6% of patients. Dose reduction for hyperglycemia was required in 0.6% of patients and permanent discontinuation was required in 0.6% of patients. The median time to first occurrence of hyperglycemia was 15 days (range: 1 to 367).

In the 65 patients with hyperglycemia, 45% required treatment with anti-hyperglycemic medication (insulin in 15%, and metformin in 29%). Of the 29 patients who required anti-hyperglycemic medication during treatment with TRUQAP, 66% (19/29) remained on these medications at treatment discontinuation or last follow up.

Evaluate fasting blood glucose (FG) and hemoglobin A1C (HbA1c) and optimize blood glucose prior to treatment. Before initiating TRUQAP, inform patients about TRUQAP’s potential to cause hyperglycemia and to immediately contact their healthcare professional if hyperglycemia symptoms occur (e.g., excessive thirst, urinating more often than usual or greater amount of urine than usual, increased appetite with weight loss). Evaluate FG at least every two weeks during the first month and at least once a month starting from the second month, prior to the scheduled dose of TRUQAP. Monitor HbA1c every three months. Monitor FG more frequently during treatment with TRUQAP in patients with a medical history of diabetes mellitus and in patients with risk factors for hyperglycemia such as obesity (BMI ≥ 30), elevated FG of > 160 mg/dL (> 8.9 mmol/L), HbA1c at or above the upper limit of normal, use of concomitant systemic corticosteroids, or intercurrent infections.

If a patient experiences hyperglycemia after initiating treatment with TRUQAP, monitor FG as clinically indicated, and at least twice weekly until FG decreases to normal levels. During treatment with anti-hyperglycemic medication, continue monitoring FG at least once a week for 8 weeks, followed by once every 2 weeks and as clinically indicated. Consider consultation with a healthcare practitioner with expertise in the treatment of hyperglycemia and counsel patients on lifestyle changes.

Withhold, reduce dose, or permanently discontinue TRUQAP based on severity [see Dosage and Administration (2.4)].

Severe diarrhea associated with dehydration occurred in patients who received TRUQAP.

Diarrhea occurred in 72% of patients. Grade 3 or 4 diarrhea occurred in 9% of patients. The median time to first occurrence was 8 days (range 1 to 519). In the 257 patients with diarrhea, 59% required anti-diarrheal medications to manage symptoms. Dose reductions were required in 8% of patients, and 2% of patients permanently discontinued TRUQAP due to diarrhea. In patients with Grade ≥ 2 diarrhea (n=93) with at least 1 grade improvement (n=89), median time to improvement from the first event was 4 days (range: 1 to 154).

Monitor patients for signs and symptoms of diarrhea. Advise patients to increase oral fluids and start antidiarrheal treatment at the first sign of diarrhea while taking TRUQAP. Withhold, reduce dose, or permanently discontinue TRUQAP based on severity [see Dosage and Administration (2.4)].

Cutaneous adverse reactions, which can be severe, including erythema multiforme (EM), palmar-plantar erythrodysesthesia, and drug reaction with eosinophilia and systemic symptoms (DRESS), occurred in patients who received TRUQAP.

Cutaneous adverse reactions occurred in 58% of patients. Grade 3 or 4 cutaneous adverse reactions occurred in 17% of patients receiving TRUQAP. EM occurred in 1.7% of patients and DRESS occurred in 0.3% of patients. Dose reduction was required in 7% of patients and 7% of patients permanently discontinued TRUQAP due to cutaneous adverse reactions.

The median time to onset of cutaneous adverse reactions was 13 days (range 1 to 575 days). Among the 204 patients with cutaneous adverse reactions, 44% (90/204) required corticosteroid treatment. Of these, 37% (76/204) were treated with topical corticosteroids and 19% (39/204) with systemic corticosteroids. In patients with Grade ≥ 2 cutaneous adverse reaction (n= 116) with at least 1 grade improvement (n=104), median time to improvement from the first event was 12 days (range 2 to 544).

Monitor patients for signs and symptoms of cutaneous adverse reactions. Early consultation with a dermatologist is recommended. Withhold, reduce dose, or permanently discontinue TRUQAP based on severity [see Dosage and Administration (2.4)].

Based on findings from animals and mechanism of action, TRUQAP can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. In an animal reproduction study, oral administration of capivasertib to pregnant rats during the period of organogenesis caused adverse developmental outcomes, including embryo-fetal mortality, and reduced fetal weights at maternal exposures 0.7 times the human exposure (AUC) at the recommended dosage of 400 mg twice daily.

Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with TRUQAP and for 1 month after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with TRUQAP and for 4 months after the last dose [see Use in Specific Populations (8.1, 8.3)].

TRUQAP is used in combination with fulvestrant. Refer to the Full Prescribing Information of fulvestrant for pregnancy and contraception information.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety population described in WARNINGS and PRECAUTIONS reflects exposure to TRUQAP 400 mg orally, twice a day for 4 days followed by 3 days off, in combination with fulvestrant, in 355 patients in CAPItello-291 until disease progression or unacceptable toxicity. Among the 355 patients who received TRUQAP, 52% were exposed for 6 months or longer, and 27% were exposed for greater than one year. In this safety population, the most common (≥ 20%) adverse reactions including laboratory abnormalities were diarrhea (72%), cutaneous adverse reactions (58%), increased random glucose (57%), decreased lymphocytes (47%), decreased hemoglobin (45%), increased fasting glucose (37%), nausea and fatigue (35% each), decreased leukocytes (32%), increased triglycerides (27%), decreased neutrophils (23%), increased creatinine (22%), vomiting (21%), and stomatitis (20%).

CAPItello-291

The safety of TRUQAP was evaluated in CAPItello-291, a clinical trial including 288 adult patients (155 patients in TRUQAP with fulvestrant arm and 133 patients in placebo with fulvestrant arm) whose breast cancer had one or more PIK3CA/AKT1/PTEN-alterations [see Clinical Studies (14)]. Among patients who received TRUQAP, 61% were exposed for 6 months or longer and 30% were exposed for greater than one year.

Of the 155 patients who received TRUQAP with fulvestrant, the median age was 58 years (range 36 to 84); female (99%); White (48%), Asian (31%), Black (1.3%), American Indian/Alaska Native (0.6%), and other races (19%).

Serious adverse reactions occurred in 18% of patients receiving TRUQAP with fulvestrant. The most common serious adverse reactions (≥ 1%) were cutaneous adverse reaction (3.9%), diarrhea and pneumonia (2.6% each), vomiting and pyrexia (1.9% each), hyperglycemia, hypersensitivity, fatigue, renal injury and second malignancy (1.3% each).

Fatal adverse reactions occurred in 1.3% of patients who received TRUQAP with fulvestrant, including sepsis (0.6%), and acute myocardial infarction (0.6%).

Permanent TRUQAP discontinuation due to an adverse reaction occurred in 10% of patients. The most common adverse reaction (≥ 2%) leading to permanent discontinuation of TRUQAP was cutaneous adverse reactions (6%). Dosage interruptions of TRUQAP due to an adverse reaction occurred in 39% of patients. Adverse reactions leading to dosage interruption in ≥ 2% of patients included cutaneous adverse reactions (14%), diarrhea (10%), pyrexia (4.5%), vomiting and nausea (3.2% each), and fatigue (2.6%).

Dose reductions of TRUQAP due to adverse reactions occurred in 21% of patients receiving TRUQAP with fulvestrant. Adverse reactions leading to TRUQAP dose reductions in ≥ 2% of patients were diarrhea and cutaneous adverse reactions (8% each).

The most common (≥ 20%) adverse reactions including laboratory abnormalities were diarrhea (77%), increased random glucose (58%), cutaneous adverse reaction (56%), decreased lymphocytes (49%), decreased hemoglobin (47%), fatigue (38%), increased fasting glucose (37%), nausea and decreased leukocytes (35% each), increased triglycerides (30%), stomatitis (25%), decreased neutrophils (25%), and vomiting (21%). Adverse reactions and laboratory abnormalities are listed in Table 4 and Table 5, respectively.

Table 4: Adverse Reactions ≥ 10% in Patients who Received TRUQAP with Fulvestrant [with a Difference Between Arms of ≥ 3%] in CAPItello-291

Adverse Reaction	TRUQAP with Fulvestrant N=155		Placebo with Fulvestrant N=133
	All Grades %	Grade 3 or 4 %	All Grades %	Grade 3 or 4 %
Gastrointestinal Disorders
Diarrhea	77	12	19	0.8
Nausea	35	1.3	14	0.8
StomatitisIncludes other related terms.	25	1.9	5	0
Vomiting	21	1.9	7	0.8
Skin and Subcutaneous Tissue Disorders
Cutaneous adverse reactionsCutaneous adverse reaction includes butterfly rash, dermatitis, allergic dermatitis, dry skin, eczema, erythema multiforme, hand dermatitis, palmar-plantar erythrodysesthesia syndrome, pruritus, rash, erythematous rash, maculo-papular rash, papular rash, skin discoloration, skin fissures, skin reaction, skin ulcer, urticaria, purpura, erythema and drug eruption.	56	15	16	0.8
General Disorders and Administration Site Conditions
Fatigue*	38	1.9	27	1.5
Metabolism and Nutrition Disorders
HyperglycemiaHyperglycemia includes hyperglycemia, blood glucose increased, glycosylated hemoglobin increased, glucose tolerance impaired and diabetes mellitus.	19	1.9	4.5	0
Decreased appetite	17	0	8	0.8
Nervous System Disorders
Headache	17	0	13	0.8
Infections and Infestations
Urinary tract infection	14	0.6	5	0
Renal and Urinary disorders
Renal injuryRenal injury includes acute kidney injury, renal failure, renal impairment, glomerular filtration rate decreased, increased creatinine and proteinuria.	11	2.6	1.5	0.8

Clinically relevant adverse reactions occurring in < 10% of patients treated with TRUQAP included anemia, hypersensitivity (including anaphylactic reaction), dysgeusia, dyspepsia, pneumonia and pyrexia.

Table 5: Laboratory Abnormalities (≥ 10%) in Patients who Received TRUQAP with Fulvestrant [With a Difference Between Arms ≥3%] in CAPItello-291

Laboratory Abnormality	TRUQAP with Fulvestrant The denominator used to calculate the rate varied from 129 to 155 based on the number of patients with a baseline value and at least one post-treatment value.		Placebo with Fulvestrant The denominator used to calculate the rate varied from 109 to 131 based on the number of patients with a baseline value and at least one post-treatment value.
	All Grades (%)	Grade 3 or 4 (%)	All Grades (%)	Grade 3 or 4 (%)
Glucose Metabolism
Increased random glucose	58	9	17	0
Increased fasting glucose	37	0.6	29	0
Hematology
Decreased lymphocytes	49	11	14	2.3
Decreased hemoglobin	47	2	22	2.3
Decreased leukocytes	35	0.6	23	0
Decreased neutrophils	25	1.9	16	0.8
Decreased platelets	12	1.9	6	0.8
Other Categories
Increased triglycerides	30	0.7	22	0.9
Increased alanine aminotransferase	23	2.6	13	0
Electrolytes/Renal
Decreased corrected calcium	19	0.6	8	0
Increased creatinine	19	1.3	4.6	0.8
Decreased potassium	17	4.5	8	0

Table 6 describes drug interactions where concomitant use of another drug affects TRUQAP.

Table 6: Drug Interactions with TRUQAP

Strong CYP3A Inhibitors
Clinical Impact	Capivasertib is a CYP3A substrate. Strong CYP3A inhibitors increase capivasertib exposure [see Clinical Pharmacology (12.3)], which may increase the risk of TRUQAP adverse reactions.
Prevention or Management	Avoid concomitant use with a strong CYP3A inhibitor. If concomitant use cannot be avoided, reduce the dose of TRUQAP and monitor patients for adverse reactions [see Dosage and Administration (2.5) ].
Moderate CYP3A Inhibitors
Clinical Impact	Capivasertib is a CYP3A substrate. Moderate CYP3A inhibitors increase capivasertib exposure [see Clinical Pharmacology (12.3)], which may increase the risk of TRUQAP adverse reactions.
Prevention or Management	When concomitantly used with moderate CYP3A inhibitor, reduce the dose of TRUQAP and monitor patients for adverse reactions [see Dosage and Administration (2.5) ].
Strong and Moderate CYP3A Inducers
Clinical Impact	Capivasertib is a CYP3A substrate. Strong and moderate CYP3A inducers decrease capivasertib exposure [see Clinical Pharmacology (12.3)], which may reduce the effectiveness of TRUQAP.
Prevention or Management	Avoid concomitant use of TRUQAP with strong or moderate CYP3A inducers.

Risk Summary

TRUQAP is used in combination with fulvestrant. Refer to the Full Prescribing Information of fulvestrant for pregnancy information.

Based on findings in animals and mechanism of action, TRUQAP can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data on the use of TRUQAP in pregnant women. In an animal reproduction study, oral administration of capivasertib to pregnant rats during the period of organogenesis caused adverse developmental outcomes, including embryo-fetal mortality and reduced fetal weights at maternal exposures 0.7 times the human exposure (AUC) at the recommended dose of 400 mg twice daily (see Data). Advise pregnant women and females of reproductive potential of the potential risk to a fetus.

The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies in the U.S. general population.

Data

Animal Data

In an embryo-fetal development study, pregnant rats received oral doses of capivasertib up to 150 mg/kg/day during the period of organogenesis. Administration of capivasertib resulted in maternal toxicities (reduced body weight gain and food consumption, increased blood glucose) and adverse developmental outcomes, including embryo-fetal deaths (post-implantation loss), reduced fetal weights, and minor fetal visceral variations at a dose of 150 mg/kg/day (0.7 times the human exposure at the recommended dose of 400 mg twice daily based on AUC).

In a pre- and post-natal assessment, pregnant rats received oral doses of capivasertib up to 150 mg/kg/day from gestation day 6 through at least lactation day 6. Administration of 150 mg/kg/day resulted in reduced litter and pup weights.

Risk Summary

TRUQAP is used in combination with fulvestrant. Refer to the Full Prescribing Information of fulvestrant for lactation information.

There are no data on the presence of capivasertib or its metabolites in human milk or their effects on milk production or the breastfed child. Capivasertib was detected in the plasma of suckling rat pups (see Data). Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with TRUQAP.

Data

Animal Data

In a pre- and post-natal assessment, when capivasertib was administered to maternal rats during the lactation period, capivasertib was detected in plasma of suckling rat pups on lactation day 7 to 8 [see Use in Specific Populations (8.1)]. Plasma concentrations in pups were up to 0.6% of concentrations in maternal plasma in the 150 mg/kg/day group.

TRUQAP is used in combination with fulvestrant. Refer to the Full Prescribing Information of fulvestrant for contraception and infertility information.

TRUQAP can cause fetal harm when administered to pregnant women [see Use in Specific Populations (8.1)].

Pregnancy Testing

Verify pregnancy status of females of reproductive potential prior to initiating TRUQAP [see Use in Specific Populations (8.1)].

Contraception

Females

Advise females of reproductive potential to use effective contraception during treatment with TRUQAP and for 1 month after the last dose.

Males

Advise male patients with female partners of reproductive potential to use effective contraception during treatment with TRUQAP and for 4 months after the last dose.

The safety and effectiveness of TRUQAP have not been established in pediatric patients.

Of the 355 patients who received TRUQAP in CAPItello-291, 115 (32%) patients were ≥ 65 years of age and 24 (7%) patients were ≥ 75 years of age. No overall differences in the efficacy of TRUQAP were observed between patients ≥ 65 years of age and younger patients. Analysis of the safety of TRUQAP comparing patients ≥ 65 years of age to younger patients suggest a higher incidence of Grade 3 to 5 adverse reactions (57% versus 36%), dosage reductions (30% versus 15%), dose interruptions (57% versus 30%), and permanent discontinuations (23% versus 8%), respectively.

No dosage modification is recommended for patients with mild to moderate (creatinine clearance (CLcr) 30 to 89 mL/min) renal impairment [see Clinical Pharmacology (12.3)].

TRUQAP has not been studied in patients with severe (CLcr 15 to 29 mL/min) renal impairment.

No dosage modification is recommended for patients with mild hepatic impairment (bilirubin ≤ upper limit of normal (ULN) and AST > ULN or bilirubin > 1 to 1.5x ULN and any AST) [see Clinical Pharmacology (12.3)].

Monitor patients with moderate (bilirubin > 1.5 to 3x ULN and any AST) hepatic impairment for adverse reactions due to potential increased capivasertib exposure [see Warnings and Precautions (5.1, 5.2, 5.3)].

TRUQAP has not been studied in patients with severe (bilirubin > 3x ULN and any AST) hepatic impairment.

Capivasertib is an inhibitor of all 3 isoforms of serine/threonine kinase AKT (AKT1, AKT2 and AKT3) and inhibits phosphorylation of downstream AKT substrates. AKT activation in tumors is a result of activation of upstream signaling pathways, mutations in AKT1, loss of phosphatase and tensin homolog (PTEN) function and mutations in the catalytic subunit alpha of phosphatidylinositol 3-kinase (PIK3CA).

In vitro, capivasertib reduced growth of breast cancer cell lines including those with relevant PIK3CA or AKT1 mutations or PTEN alteration. In vivo, capivasertib alone and in combination with fulvestrant inhibited tumor growth of mouse xenograft models including estrogen receptor positive breast cancer models with alterations in PIK3CA, AKT1, and PTEN.

Exposure-Response Relationships

The exposure-response relationship and time course of pharmacodynamic response for the effectiveness of capivasertib have not been fully characterized. Exposure-response relationships were observed for diarrhea (CTCAE Grade 2 to 4), rash (CTCAE Grade 2 to 4) and hyperglycemia (CTCAE Grades 3 or 4) at doses of 80 to 800 mg (0.2 to 2 times the approved recommended dosage).

Cardiac Electrophysiology

At the recommended TRUQAP dose, a mean increase in the QTc interval > 20 ms was not observed.

Capivasertib pharmacokinetic parameters are presented as the mean [%coefficient of variation (%CV)], unless otherwise specified. The capivasertib steady-state AUC is 8,069 h·ng/mL (37%) and C_max is 1,371 ng/mL (30%). Steady-state concentrations are predicted to be attained on the 3^rd and 4^th dosing day of each week, starting week 2.

Capivasertib plasma concentrations are approximately 0.5% to 15% of the steady state C_max during the off-dosing days.

Capivasertib AUC and C_max are proportional with dose over a range of 80 to 800 mg (0.2 to 2 times the approved recommended dosage).

Absorption

T_max is approximately 1-2 hours. The absolute bioavailability is 29%.

Effect of Food

No clinically meaningful differences in capivasertib pharmacokinetics were observed following administration of TRUQAP with a high-fat meal (approximately 1,000 kcal; fat 60%) or a low-fat meal (approximately 400 kcal; fat 26%).

Distribution

The steady state oral volume of distribution is 1,847 L (36%). Capivasertib plasma protein binding is 78% and the plasma-to-blood ratio is 0.71.

Elimination

The half-life is 8.3 hours and the steady-state oral clearance is 50 L/h (37% CV). Renal clearance was 21% of total clearance.

Metabolism

Capivasertib is primarily metabolized by CYP3A4 and UGT2B7.

Excretion

Following a single radiolabeled oral dose of 400 mg, the mean total recovery was 45% from urine and 50% from feces.

Specific Populations

No clinically significant differences in capivasertib pharmacokinetics were observed based on race/ethnicity (including White, Asian, Black, American Indian or Alaskan Native, and Native Hawaiian or Other Pacific Islander), sex (88% females), body weight (32 to 150 kg), age (26 to 87 years), mild hepatic impairment (bilirubin ≤ ULN and AST > ULN or bilirubin > 1 to 1.5x ULN), or mild to moderate renal impairment (CLcr 30 to 89 mL/min).

The effect of moderate (bilirubin > 1.5 to 3x ULN and any AST) hepatic impairment is not fully characterized.

TRUQAP has not been studied in patients with severe (bilirubin > 3x ULN and any AST) hepatic impairment or severe renal impairment (CLcr 15 to 29 mL/min).

Drug Interaction Studies

Clinical Studies and Model-Informed Approaches

Effect of Strong and Moderate CYP3A Inhibitors on Capivasertib: Itraconazole (strong CYP3A4 inhibitor) is predicted to increase capivasertib AUC by up to 1.7-fold and C_max by up to 1.4-fold.

Erythromycin and verapamil (moderate CYP3A inhibitors) are predicted to increase capivasertib AUC by up to 1.5-fold and C_max by up to 1.3-fold.

Effect of Strong and Moderate CYP3A Inducers on Capivasertib: Rifampicin (strong CYP3A4 inducer) is predicted to decrease capivasertib AUC by 70% and C_max by 60%.

Efavirenz (moderate CYP3A4 inducer) is predicted to decrease capivasertib AUC by 60% and C_max by 50%.

Effect of UGT2B7 Inhibitors on Capivasertib: Probenecid (UGT2B7 inhibitor) is not predicted to have a clinically meaningful effect on capivasertib pharmacokinetics.

Effect of Acid Reducing Agents on Capivasertib: Rabeprazole (gastric acid reducing agent) did not have a clinically meaningful effect on capivasertib pharmacokinetics.

Effect of Capivasertib on CYP3A Substrates: Concomitant use of TRUQAP increased midazolam (CYP3A substrate) AUC by 1.8-fold on day 4 and by 1.2-fold on day 7.

Effect of Capivasertib on CYP2D6 Substrates: TRUQAP is predicted to increase desipramine (CYP2D6 substrate) AUC by up to 2.1-fold on day 4.

Effect of Capivasertib on CYP2C9 Substrates: Concomitant use of TRUQAP with warfarin (CYP2C9 substrate) is not predicted to have a clinically meaningful effect on warfarin pharmacokinetics.

Effect of Capivasertib on UGT1A1 Substrates: TRUQAP is predicted to increase raltegravir (UGT1A1 substrate) AUC by up to 1.7-fold on day 4.

In-Vitro Studies

Capivasertib inhibits BCRP, OATP1B1, OATP1B3, OAT3, MATE1, MATE2-K, and OCT2.

Carcinogenicity studies have not been conducted with capivasertib.

Capivasertib was genotoxic in the in vivo rat bone marrow micronucleus assay through an aneugenic mechanism. Capivasertib was not mutagenic in vitro in a bacterial reverse mutation (Ames) assay or mouse lymphoma gene mutation assay.

In repeat-dose toxicity studies up to 26 weeks duration in rats and 39 weeks duration in dogs, tubular degeneration in the testes and cellular debris in the epididymides were observed at oral capivasertib doses of 100 mg/kg/day in rats and 15 mg/kg/day in dogs (approximately 1 time the human exposure at the recommended dose of 400 mg twice daily based on AUC). In a male fertility study, capivasertib had no effect on fertility in male rats at oral doses up to 100 mg/kg/day following 10 weeks of treatment. Effects of capivasertib on female fertility have not been studied in animals.