Truqap Drug Information

Generic name: CAPIVASERTIB

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Uses of Truqap

HR-positive

HER2-negative locally advanced or metastatic breast cancer TRUQAP, in combination with fulvestrant, is indicated for the treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced or metastatic breast cancer with one or more PIK3CA/AKT1/PTEN -alteration as detected by an FDA-authorized test following progression on at least one endocrine-based regimen in the metastatic setting or recurrence on or within 12 months of completing adjuvant therapy.

PTEN-deficient metastatic androgen pathway modulation-naïve or -sensitive prostate cancer TRUQAP, in combination with abiraterone and prednisone, is indicated for treatment of adult patients with metastatic androgen pathway modulation-naïve or -sensitive (mAPMN/S) prostate cancer that is PTEN-deficient as detected by an FDA-authorized test.

Dosage & Administration of Truqap

Patient Selection

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. Select patients for the treatment of metastatic androgen pathway modulation-naïve or -sensitive (mAPMN/S) prostate cancer with TRUQAP based on PTEN deficiency in tumor tissue. Information on FDA-authorized tests for patient selection for the detection of PIK3CA, AKT1, and PTEN alterations or PTEN deficiency are available at: http://www.fda.gov/CompanionDiagnostics

Recommended Evaluation Before Initiating TRUQAP

Evaluate fasting blood glucose (FG) and hemoglobin A1C (HbA1C) prior to starting TRUQAP and at regular intervals during treatment.

Recommended Dosage The HR positive, HER2 negative locally advanced or metastatic breast cancer 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. 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. PTEN-deficient metastatic androgen pathway modulation-naïve or -sensitive (mAPMN/S) prostate cancer The recommended dosage of TRUQAP, in combination with abiraterone and prednisone, is 400 mg orally twice daily (approximately 12 hours apart) with or without food, for 4 days followed by 3 days off. Patients with mAPMN/S prostate cancer should also receive a gonadotropin-releasing hormone (GnRH) analog concurrently or should have had bilateral orchiectomy.

Refer to the Prescribing Information of the individual therapeutic agents used in combination with TRUQAP for dosing and administration information.

Administration

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

Dosage Modification for Adverse Reactions

The recommended dose reductions for adverse reactions are listed in Table 2. Permanently discontinue TRUQAP if unable to tolerate the second dose reduction. Table 3: Recommended Dosage Modifications of Hyperglycemia For the management of suspected or confirmed diabetic ketoacidosis (DKA) see Warnings and Precautions. (Fasting Glucose )

Dosage Modifications for Strong and Moderate CYP3A Inhibitors 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. 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.

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

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

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 For the management of suspected or confirmed diabetic ketoacidosis (DKA) see Warnings and Precautions (5.1). (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	Withhold TRUQAP. 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.

Side Effects of Truqap

Clinical Trials Experience

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 with metastatic breast cancer in CAPItello-291 until disease progression or unacceptable toxicity. The safety population described in WARNINGS and PRECAUTIONS also reflects exposure to TRUQAP 400 mg orally, twice a day for 4 days followed by 3 days off, in combination with abiraterone, in 503 patients with mAPMN/S prostate cancer with PTEN deficiency in CAPItello-281 until disease progression or unacceptable toxicity.

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. Among patients who received TRUQAP, 61% were exposed for 6 months or longer and 30% were exposed for greater than one year. Serious adverse reactions occurred in 18% of patients receiving TRUQAP with fulvestrant.

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

Table 5: Laboratory Abnormalities (≥ 10%) That Worsened from Baseline in Patients who Received TRUQAP with Fulvestrant in CAPItello- 8 0 CAPItello-281 The safety of TRUQAP was evaluated in CAPItello-281, a clinical trial including 1006 adult patients (503 patients in TRUQAP with abiraterone and prednisone/prednisolone arm and 503 patients in placebo with abiraterone and prednisone/prednisolone arm) with mAPMN/S prostate cancer with PTEN deficiency. Serious adverse reactions occurred in 47% of patients who received TRUQAP with abiraterone and prednisone. The most common adverse reactions (≥ 2%) leading to treatment discontinuation were cutaneous adverse reactions (8%) and hyperglycemia (2.4%).

Adverse reactions and laboratory abnormalities are listed in Table 6 and Table 7, respectively. Table 6: Adverse Reactions ≥ 10% in Patients who Received TRUQAP plus Abiraterone in CAPItello-281 0 Clinically relevant adverse reactions occurring in < 10% of patients treated with TRUQAP included vomiting, stomatitis, decreased weight, dyspepsia, dysgeusia, hypersensitivity, and diabetic ketoacidosis.

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
Adverse Reaction	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
Stomatitis Includes other related terms.	25	1.9	5	0
Vomiting	21	1.9	7	0.8
Skin and Subcutaneous Tissue Disorders
Cutaneous adverse reactions Cutaneous 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
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 injury Renal injury includes acute kidney injury, renal failure, renal impairment, glomerular filtration rate decreased, increased creatinine and proteinuria.	11	2.6	1.5	0.8

Table 5: Laboratory Abnormalities (≥ 10%) That Worsened from Baseline 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.
Laboratory Abnormality	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: Adverse Reactions ≥ 10% in Patients who Received TRUQAP plus Abiraterone [with a Difference Between Arms of ≥ 5% (All Grades) or ≥2% (Grade 3 or 4)] in CAPItello-281
Adverse Reaction	TRUQAP plus Abiraterone N=503		Placebo plus Abiraterone N=503
Adverse Reaction	All Grades %	Grade 3 or 4 %	All Grades %	Grade 3 or 4 %
Gastrointestinal Disorders
Diarrhea	53	6	9	0.4
Nausea	13	0.6	5	0.2
Skin and Subcutaneous Tissue Disorders
Cutaneous adverse reactions Cutaneous adverse reaction includes brachioradial pruritus, dermatitis, dermatitis acneiform, dermatitis allergic, dermatitis atopic, dermatitis exfoliative, dermatitis exfoliative generalized, drug eruption, dry skin, eczema, eczema asteatotic, eczema nummular, erythema, erythema ab igne, erythema multiforme, exfoliative rash, eye pruritus, eyelids pruritus, genital erythema, mucocutaneous rash, palmar-plantar erythrodysesthesia syndrome, pruritus, pruritus allergic, pruritus genital, purpura, rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic, rash pustular, skin exfoliation, skin fissures, skin ulcer, stoma site rash, urticaria, and urticaria papular.	53	17	16	0.4
General Disorders and Administration Site Conditions
Fatigue Includes other related terms.	26	1.2	19	1.2
Pyrexia	11	1.2	3.2	0
Infections and Infestations
Urinary tract infection	16	4.2	12	1.8
Pneumonia	11	6	6	2.4
Metabolism and Nutrition Disorders
Decreased appetite	10	1	4.2	0

Table 7: Selected Laboratory Abnormalities (≥ 10%) in Patients who Received TRUQAP plus Abiraterone With a Difference Between Arms ≥ 5% (All Grades) or ≥2% (Grade 3 or 4) in CAPItello-281
Laboratory Abnormality	TRUQAP plus Abiraterone The denominator used to calculate the rate varied from 472 to 500 based on the number of patients with a baseline value and at least one post-treatment value		Placebo plus Abiraterone The denominator used to calculate the rate varied from 485 to 500 based on the number of patients with a baseline value and at least one post-treatment value.
Laboratory Abnormality	All Grades (%)	Grade 3 or 4 (%)	All Grades (%)	Grade 3 or 4 (%)
Chemistry
Increased fasting glucose	70	14	50	3
Decreased potassium	51	19	36	10
Increased creatinine	49	7	24	3
Increased non-fasting glucose	49	23	31	2.3
Increased triglycerides	37	3	32	2.6
Increased alanine aminotransferase	38	9	36	6
Increased aspartate aminotransferase	36	7	37	4
Decreased sodium	30	5	23	3.6
Hematology
Decreased hemoglobin	61	8	46	3.2
Decreased lymphocytes	58	17	36	9

Warnings & Cautions for Truqap

Hyperglycemia TRUQAP can cause severe hyperglycemia, including diabetic ketoacidosis and fatal outcomes. Withhold TRUQAP in clinical situations known to increase the risk of severe hyperglycemia or ketoacidosis (e.g., suspected serious infection or acute illness). Before initiating treatment with TRUQAP, test fasting glucose levels (FPG or FBG), HbA1C levels, and optimize fasting glucose.

After initiating treatment with TRUQAP, monitor or self-monitor fasting glucose levels on Day 3 or 4 of the dosing week during weeks then monthly while on treatment with TRUQAP; and as clinically indicated. Monitor HbA1C levels every 3 months during treatment with TRUQAP and as clinically indicated and manage changes as appropriate. Patients with a history of well-controlled Type 2 diabetes mellitus may require intensified anti-hyperglycemic treatment and require close monitoring of fasting glucose levels.

For patients who experience hyperglycemia during treatment with TRUQAP, monitor fasting glucose at least twice weekly, on days on and off TRUQAP, until fasting glucose decreases to baseline levels. During treatment with anti-diabetic medications, monitor fasting glucose at least once a week for 2 months, followed by once every 2 weeks, or as clinically indicated. Consider consultation with a healthcare practitioner with expertise in the treatment of hyperglycemia and initiation of fasting glucose monitoring at home for patients who have risk factors for hyperglycemia or who experience hyperglycemia.

Advise patients of the signs and symptoms of hyperglycemia and counsel patients on lifestyle changes. Withhold TRUQAP immediately when ketoacidosis is suspected. If ketoacidosis is confirmed, permanently discontinue TRUQAP.

The safety of TRUQAP has not been established in patients with Type 1 diabetes or Type 2 diabetes that is uncontrolled or requiring insulin at baseline as these patients were excluded from clinical studies. Based on the severity of the hyperglycemia, withhold, reduce dose, or permanently discontinue TRUQAP. The median time to first occurrence of hyperglycemia was 15 days (range: 1 to 367).

Dose reduction for hyperglycemia was required in 0.6% of patients and permanent discontinuation was required in 0.6% of patients. Diabetic metabolic decompensation occurred in 0.6% of patients, including diabetic ketoacidosis in 0.3%. The median time to first occurrence of hyperglycemia was 71 days (range: 1 to 1454).

Dose reduction for hyperglycemia was required in 8.7% of patients and permanent discontinuation was required in 2.4% of patients. Diabetic ketoacidosis occurred in 1.2% of patients. 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. CAPItello-291 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.

The median time to first occurrence was 12 days (range: 3 to 48). In the 264 patients with diarrhea, anti-diarrheal medication was required in 64% (170/264) of patients to manage diarrhea symptoms.

Cutaneous Adverse Reactions TRUQAP can cause cutaneous adverse reactions, which can be severe, including erythema multiforme (EM), palmar-plantar erythrodysesthesia, and drug reaction with eosinophilia and systemic symptoms (DRESS). Monitor patients for signs and symptoms of cutaneous adverse reactions. Early consultation with a dermatologist is recommended.

CAPItello 291 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.

CAPItello 281 Cutaneous adverse reactions occurred in 53% of patients. The median time to onset of rash was 13 days (range: 11 to 63 days). 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.

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

Drug Interactions with Truqap

Effects of Other Drugs on TRUQAP Table 8 describes drug interactions where concomitant use of another drug affects TRUQAP. Table 8: Drug Interactions with TRUQAP Strong CYP3A Inhibitors Clinical Impact • Capivasertib is a CYP3A substrate. Strong CYP3A inhibitors increase capivasertib exposure, 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. Moderate CYP3A Inhibitors Clinical Impact • Capivasertib is a CYP3A substrate.

Prevention or Management • When concomitantly used with moderate CYP3A inhibitor, reduce the dose of TRUQAP and monitor patients for adverse reactions. Strong and Moderate CYP3A Inducers Clinical Impact • Capivasertib is a CYP3A substrate. Strong and moderate CYP3A inducers decrease capivasertib exposure, which may reduce the effectiveness of TRUQAP.

Prevention or Management • Avoid concomitant use of TRUQAP with strong or moderate CYP3A inducers.

Table 8: 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.

Pregnancy Safety for Truqap

Pregnancy 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.

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. 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.

Pediatric Use of Truqap

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

Contraindications for Truqap

TRUQAP is contraindicated in patients with severe hypersensitivity to TRUQAP or any of its components.

Clinical Studies of Truqap

Metastatic HR-Positive, HER2-Negative Breast Cancer

The efficacy of TRUQAP with fulvestrant was evaluated in CAPItello-291 (NCT04305496), a randomized, double-blind, placebo-controlled, multicenter trial that enrolled 708 adult patients with locally advanced (inoperable) or metastatic HR-positive, HER2-negative (defined as IHC 0 or 1+, or IHC 2+/ISH-) breast cancer of which 289 patients had tumors with eligible PIK3CA/AKT1/PTEN -alterations. Eligible PIK3CA/AKT1 activating mutations or PTEN loss of function alterations were identified in the majority of FFPE tumor specimens using FoundationOne®CDx next-generation sequencing (n=686). All patients were required to have progression on an aromatase inhibitor (AI) based treatment in the metastatic setting or recurrence on or within 12 months of completing (neo)adjuvant treatment with an AI.

Patients could have received up to two prior lines of endocrine therapy and up to 1 line of chemotherapy for locally advanced (inoperable) or metastatic disease. Patients were excluded if they had clinically significant abnormalities of glucose metabolism (defined as patients with diabetes mellitus Type 1, Type 2 requiring insulin treatment, or HbA1c ≥8%). Patients were randomized (1:1) to receive either 400 mg of TRUQAP (n=355) or placebo (n=353), given orally twice daily for 4 days followed by 3 days off treatment each week of 28-day treatment cycle.

Patients were treated until disease progression, or unacceptable toxicity. Randomization was stratified by presence of liver metastases (yes vs. no), prior treatment with CDK4/6 inhibitors (yes vs. no) and geographical region (region 1: US, Canada, Western Europe, Australia, and Israel vs region 2: Latin America, Eastern Europe and Russia vs Region 3: Asia). The major efficacy outcomes were investigator-assessed progression-free survival (PFS) in the overall population, and in the population of patients whose tumors have PIK3CA/AKT1/PTEN -alterations evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1.

Additional efficacy outcome measures were overall survival (OS), investigator assessed objective response rate (ORR) and duration of response (DoR). Eastern Cooperative Oncology Group (ECOG) performance status was were premenopausal or perimenopausal. Seventy-six percent of patients had an alteration in PIK3CA, 13% had an alteration in AKT1, and 17% had an alteration in PTEN.

All patients received prior endocrine-based therapy (100% AI based treatment and 44% received tamoxifen). Seventy-one percent of patients were previously treated with a CDK4/6 inhibitor and 18% received prior chemotherapy for locally advanced (inoperable) or metastatic disease. A statistically significant difference in PFS was observed in the overall population and the population of patients whose tumors have PIK3CA/AKT1/PTEN -alteration.

An exploratory analysis of PFS in the 313 (44%) patients whose tumors did not have a PIK3CA/AKT1/PTEN -alteration showed a HR of indicating that the difference in the overall population was primarily attributed to the results seen in the population of patients whose tumors have PIK3CA/AKT1/PTEN -alteration. Efficacy results for PIK3CA/AKT1/PTEN -altered subgroup are presented in Table 9 and Figure 1. Results from the blinded independent review committee (BICR) assessment were consistent with the investigator assessed PFS results.

Overall survival results were immature at the time of the PFS analysis (30% of the patients died). Table 9: Efficacy Results for CAPItello-291 (Patients with PIK3CA/AKT1/PTEN-Altered Tumors) 8.6 Figure 1: Kaplan-Meier Plot of Progression-Free Survival in CAPItello-291 (Investigator Assessment, Patients with PIK3CA/AKT1/PTEN -Altered Tumors) figure_1

PTEN-Deficient Metastatic Androgen Pathway Modulation-Naïve or -Sensitive (mAPMN/S) Prostate Cancer The efficacy of TRUQAP with abiraterone was evaluated in CAPItello-281 (NCT04305496), a randomized, double-blind, placebo-controlled, multicenter trial that enrolled 1012 adult patients with newly diagnosed, PTEN-deficient mAPMN/S prostate cancer (previously referred to as metastatic hormone-sensitive prostate cancer or mHSPC). Tumor PTEN deficiency status (≥ 90% of viable malignant cells with no specific cytoplasmic staining) was prospectively determined using central testing with the immunohistochemistry based VENTANA PTEN (SP218) RxDx Assay. The only allowable prior systemic therapy was up to 93 days of androgen deprivation therapy (ADT) and/or abiraterone.

Patients were randomized (1:1) to receive capivasertib 400 mg orally twice daily for 4 days followed by 3 days off treatment each week, in combination with abiraterone 1000 mg orally daily (N=507) compared with placebo plus abiraterone (N=505) until disease progression, death, withdrawal of consent, or unacceptable toxicity. Patients were required to receive either prednisone or prednisolone 5 mg daily, and a gonadotropin-releasing hormone (GnRH) analog or prior orchiectomy. Randomization was stratified by combination of volume of disease and visceral metastases (high-volume disease with visceral metastases vs. high-volume disease without visceral metastases vs. low-volume disease), and geographical region (Western Europe, Australia, North America, Latin America, Eastern Europe, Asia).

The major efficacy outcome was investigator-assessed radiographic progression-free survival (rPFS). Overall survival (OS) was an additional efficacy outcome measure. Seventy-four percent of patients had high volume disease including 19% with visceral metastases and 55% without visceral metastases.

Type 2 diabetes mellitus was reported in 14% of patients. Ninety-nine percent of patients received previous hormonal therapy including 98% with ADT and 11% with abiraterone. The study demonstrated a statistically significant reduction in the risk of investigator-assessed radiographic progression (rPFS) for patients receiving TRUQAP in combination with abiraterone compared to patients receiving placebo in combination with abiraterone.

Efficacy results are presented in Table 10 and Figure 2. Overall survival results were immature at the time of the rPFS analysis (26% of the patients died).

Table 9: Efficacy Results for CAPItello-291 (Patients with PIK3CA/AKT1/PTEN-Altered Tumors)
	TRUQAP with fulvestrant N=155	Placebo with fulvestrant N=134
Investigator-Assessed Progression-Free Survival (PFS)
Number of events (%)	121 (78%)	115 (86%)
Median, months (95%CI)	7.3 (5.5, 9.0)	3.1 (2.0, 3.7)
Hazard ratio (95% CI) Stratified Cox proportional hazards model stratified by presence of liver metastases (yes vs no), and prior use of CDK4/6 inhibitors (yes vs no).	0.50 (0.38, 0.65)
p-value Stratified log-rank test stratified by presence of liver metastases (yes vs no), and prior use of CDK4/6 inhibitors (yes vs no).	<0.0001
Investigator-Assessed Confirmed Objective Response Rate (ORR)
Patients with measurable disease	132	124
ORR (95% CI)	26% (19, 34)	8% (4, 14)
Complete response rate	2.3%	0
Partial response rate	23%	8%
Median DoR, months (95%CI)	10.2 (7.7, NC NC = not calculable )	8.6 (3.8, 9.2)

Table 10: Efficacy Results in CAPItello 281
	TRUQAP plus Abiraterone (N=507)	Placebo plus Abiraterone (N=505)
Investigator‑Assessed Radiographic Progression-Free Survival (rPFS)
Number of events (%)	183 (36)	215 (43)
Median, months (95% CI)	33.2 (25.8, 44.2)	25.7 (22.0, 29.9)
Hazard ratio (95% CI) Stratified Cox proportional hazards model stratified by volume of disease/visceral metastases, geographic location	0.81 (0.66, 0.98)
p-value Two-sided p-value based on a stratified log-rank test stratified by volume of disease/visceral metastases, geographic location	0.034

Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.

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