TRUQAP

1 INDICATIONS AND USAGE TRUQAP is a kinase inhibitor indicated: HR positive, HER2 negative locally advanced or metastatic breast cancer • in combination with fulvestrant 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 -alterations 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. ( 1.1 ) PTEN-deficient metastatic androgen pathway modulation-naïve or -sensitive (mAPMN/S) prostate cancer • in combination with abiraterone and prednisone for the 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. ( 1.2 ) 1.1 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. 1.2 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.

2 DOSAGE AND ADMINISTRATION • 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 . ( 2.1 ) • Select patients for the treatment of mAPMN/S prostate cancer with TRUQAP based on PTEN deficiency in tumor tissue. ( 2.1 ) • Recommended Dosage: 400 mg orally twice daily, with or without food, for 4 days followed by 3 days off. ( 2.3 ) 2.1 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 [see Clinical Studies (14) ] . 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 [see Clinical Studies (14) ] . 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 2.2 Recommended Evaluation Before Initiating TRUQAP 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) ] . 2.3 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. Continue TRUQAP until disease progression or unacceptable toxicity. 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. 2.4 Administration 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. 2.5 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 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 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. 2.6 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 [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.

4 CONTRAINDICATIONS TRUQAP is contraindicated in patients with severe hypersensitivity to TRUQAP or any of its components. Severe hypersensitivity to TRUQAP or any of its components. (4)

5 WARNINGS AND PRECAUTIONS • Hyperglycemia: TRUQAP can cause severe hyperglycemia, including diabetic ketoacidosis and fatal outcomes. Evaluate blood glucose levels and hemoglobin A1C prior to starting and at regular intervals during treatment. Withhold, reduce dose, or permanently discontinue TRUQAP based on severity. ( 2.2 , 2.5 , 5.1 ) • Diarrhea: TRUQAP caused diarrhea in most patients. Advise patients to increase oral fluids, start antidiarrheal treatment, and consult with a healthcare provider if diarrhea occurs while taking TRUQAP. Withhold, reduce dose, or permanently discontinue TRUQAP based on severity. ( 2.5 , 5.2 ) • Cutaneous Adverse Reactions: Monitor for signs and symptoms of cutaneous adverse reactions. Withhold, reduce dose, or permanently discontinue TRUQAP based on severity. ( 2.5 , 5.3 ) • Embryo-Fetal Toxicity: TRUQAP can cause fetal harm. Advise patients of potential risk to a fetus and to use effective contraception. Refer to the Full Prescribing Information of fulvestrant for pregnancy and contraception information. ( 5.4 , 8.1 , 8.3 ) 5.1 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 1, 2, 4, 6 and 8; 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 [see Clinical Studies ( 14.1 , 14.2 )] . Based on the severity of the hyperglycemia, withhold, reduce dose, or permanently discontinue TRUQAP [see Dosage and Administration (2.5) ]. CAPItello 291 Increased fasting glucose from baseline occurred in 37% of patients treated with TRUQAP, including 11% of patients with Grade 2 (FG > 160 to 250 mg/dL), 2% with Grade 3 (FG > 250 to 500 mg/dL), and 1.1% with Grade 4 (FG > 500 mg/dL) events. 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%. In CAPItello-291, 12% (43/355) of patients who received TRUQAP had an anti-hyperglycemic medication regimen either initiated or changed during the study, including treatment with insulin in 4.8% (17/355) of patients. CAPItello 281 Increased fasting glucose from baseline occurred in 69% of patients treated with TRUQAP, including 25% of patients with Grade 2 (FG > 160 to 250 mg/dL), 12% with Grade 3 (FG > 250 to 500 mg/dL), and 1.2% of patients with Grade 4 (FG > 500 mg/dL) events. 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. In CAPItello 281, 41% (204/503) of patients who received TRUQAP had an anti-hyperglycemic medication regimen either initiated or changed during the study, including treatment with insulin in 16% (81/503) of patients. 5.2 Diarrhea TRUQAP can cause severe diarrhea associated with dehydration. 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 (2.5) ] . 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. 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). CAPItello 281 In CAPItello 281, diarrhea of any grade occurred in 264 (52%) patients, Grade 3 occurred in 31 (6%) patients and Grade 4 occurred in 1 (0.2%) patient. The median time to first occurrence was 12 days (range: 3 to 48). In the study, dose reductions were required in 26 (5%) patients and 6 (1.2%) patients discontinued TRUQAP due to diarrhea. In the 264 patients with diarrhea, anti-diarrheal medication was required in 64% (170/264) of patients to manage diarrhea symptoms. 5.3 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. Withhold, reduce dose, or permanently discontinue TRUQAP based on severity [see Dosage and Administration (2.5) ] . 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. 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). CAPItello 281 Cutaneous adverse reactions occurred in 53% of patients. Grade 3 cutaneous adverse reactions occurred in 84 (17%) patients and Grade 4 occurred in 1 (0.2%) patient. In the study, dose reduction was required in 58 (12%) patients and 38 (8%) patients discontinued TRUQAP due to rash. The median time to onset of rash was 13 days (range: 11 to 63 days). Among the 265 patients with cutaneous adverse reactions, 80% (212/265) required treatment and 91% (242/265) recovered in the study. Of these, 54% (115/212) were treated with topical corticosteroids and 25% (54/212) with systemic corticosteroids. 5.4 Embryo-Fetal Toxicity 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 or abiraterone. Refer to the Full Prescribing Information of fulvestrant or abiraterone for pregnancy and contraception information.

7 DRUG INTERACTIONS • Strong CYP3A Inhibitors: Avoid concomitant use. If concomitant use cannot be avoided, reduce TRUQAP dose. ( 2.6 , 7.1 ) • Moderate CYP3A Inhibitors: Reduce TRUQAP dose. ( 2.6 , 7.1 ) • Strong and Moderate CYP3A Inducers: Avoid concomitant use. ( 7.1 ) 7.1 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 [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.

6 ADVERSE REACTIONS The following adverse reactions are also discussed in greater details in other sections of the labeling: • Hyperglycemia [see Warnings and Precautions (5.1) ] • Diarrhea [see Warnings and Precautions (5.2) ] • Cutaneous Adverse Reactions [see Warnings and Precautions (5.3) ] Most common adverse reactions (incidence ≥20%), including laboratory abnormalities, in patients with: • HR-positive, HER2-negative breast cancer were diarrhea, cutaneous adverse reactions, increased random glucose, decreased lymphocytes, decreased hemoglobin, increased fasting glucose, nausea, fatigue, decreased leukocytes, increased triglycerides, decreased neutrophils, increased creatinine, vomiting and stomatitis. ( 6.1 ) • PTEN-deficient mAPMN/S prostate cancer were increased fasting glucose, decreased hemoglobin, decreased lymphocytes, cutaneous adverse reactions, diarrhea, decreased potassium, increased creatinine, increased non-fasting glucose, increased alanine aminotransferase, increased triglycerides, increased aspartate aminotransferase, decreased sodium, and fatigue. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca at 1-800-236-9933 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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. Among the 355 patients who received TRUQAP in combination with fulvestrant, 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%). 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 [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 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 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 [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 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 [see Clinical Studies (14) ] . Among the 503 patients who received TRUQAP, 74% were exposed for 6 months or longer, 58% were exposed for 12 months or longer, and 35% were exposed for more than 2 years. Serious adverse reactions occurred in 47% of patients who received TRUQAP with abiraterone and prednisone. The most common serious adverse reactions (≥ 2%) were pneumonia (7%), cutaneous adverse reactions (5%), hyperglycemia (5%), hemorrhage (3.4%), urinary tract infection (3.2%), ischemic cerebro /cardiovascular events (3.2%), acute kidney injury (2.2%), and hypokalemia (2.2%). Fatal adverse reactions occurred in 8% of patients who received TRUQAP with abiraterone and prednisone, including sepsis (1.2%), ischemic cerebro-/cardiovascular events (1%), hemorrhage (0.6%), pneumonia (0.4%), and diabetic ketoacidosis (0.2%). Dosage interruptions of TRUQAP due to an adverse reaction occurred in 65% of patients. Adverse reactions leading to dosage interruption in ≥ 2% of patients included cutaneous adverse reactions (22%), hyperglycemia (15%), diarrhea (13%), pneumonia (4%), hypokalemia (3.4%), fatigue (3.2%), pyrexia (3.2%), vomiting (2.6%), urinary tract infection (2.4%), nausea (2%) and anemia (2%). Permanent TRUQAP discontinuation due to an adverse reaction occurred in 20% of patients. The most common adverse reactions (≥ 2%) leading to treatment discontinuation were cutaneous adverse reactions (8%) and hyperglycemia (2.4%). Dose reductions of TRUQAP due to adverse reactions occurred in 32% patients. Adverse reactions leading to TRUQAP dose reductions in ≥ 2% of patients were cutaneous adverse reactions (12%), hyperglycemia (9%), diarrhea (5%), and fatigue (2%). The most common (≥ 20%) adverse reactions including laboratory abnormalities were increased fasting glucose, decreased hemoglobin, decreased lymphocytes, cutaneous adverse reactions, diarrhea, decreased potassium, increased creatinine, increased non-fasting glucose, increased alanine aminotransferase, increased triglycerides, increased aspartate aminotransferase, decreased sodium, and fatigue. 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 [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 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 Clinically relevant adverse reactions occurring in < 10% of patients treated with TRUQAP included vomiting, stomatitis, decreased weight, dyspepsia, dysgeusia, hypersensitivity, and diabetic ketoacidosis. 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. 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

8.1 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 [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.