TRUQAP (capivasertib) is a kinase inhibitor. The molecular formula for capivasertib is C 21 H 25 ClN 6 O 2 and the molecular weight is 428.92 g/mol. The chemical name of capivasertib is 4-amino- N -[(1S)-1-(4-chlorophenyl)-3-hydroxypropyl]-1-(7 H -pyrrolo[2,3- d ]pyrimidin-4-yl)-4-piperidinecarboxamide. Capivasertib is a white to off-white powder with pH-dependent solubility. It is freely soluble in water at pH values below 1.2 and practically insoluble at pH values above 6.8. Capivasertib has the following structural formula: TRUQAP film-coated tablets are supplied for oral administration with 160 mg or 200 mg capivasertib. The tablets also contain croscarmellose sodium, dibasic calcium phosphate, magnesium stearate, and microcrystalline cellulose. The film coat contains the following inactive ingredients: copovidone, hypromellose, iron oxide black, iron oxide red, iron oxide yellow, medium chain triglycerides, polydextrose, polyethylene glycol 3350, and titanium dioxide. chemical structure

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-approved 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. TRUQAP is a kinase inhibitor indicated, 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-approved 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.

Tablets: • 160 mg: beige film-coated, round, biconvex tablets debossed with ‘CAV’ above ‘160’ on one side and plain on the reverse. • 200 mg: beige film-coated, capsule-shaped, biconvex tablets debossed with ‘CAV 200’ on one side and plain on the reverse. Tablets: 160 mg and 200 mg

• 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 . • Recommended Dosage: 400 mg orally twice daily, with or without food, for 4 days followed by 3 days off

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 . Information on FDA-approved tests for the detection of PIK3CA, AKT1 , and PTEN alterations is 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 and Administration 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

Dosage Modifications 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) refer to section Warnings and Precautions. (Fasting Glucose [FG]) 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 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 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 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

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.

• Hyperglycemia: TRUQAP can cause hyperglycemia. Evaluate blood glucose levels prior to starting and at regular intervals during treatment. Withhold, reduce dose, or permanently discontinue TRUQAP based on severity. ( 2.2 , 2.4 , 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. • Cutaneous Adverse Reactions: Monitor for signs and symptoms of cutaneous adverse reactions. Withhold, reduce dose, or permanently discontinue TRUQAP based on severity. • 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 Severe hyperglycemia, including diabetic ketoacidosis and fatal outcomes, can occur in patients treated with TRUQAP. 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 ketoacidosis occurred in 0.3% of patients and diabetic metabolic decompensation in 0.6% of patients. 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. 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. 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. Patients with a history of well-controlled Type 2 diabetes mellitus may require intensified anti-hyperglycemic treatment and 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. Based on the severity of the hyperglycemia, withhold, reduce dose, or permanently discontinue TRUQAP

Diarrhea 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

Cutaneous Adverse Reactions 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

Embryo-Fetal Toxicity Based on findings from animals and mechanism of action, TRUQAP can cause fetal harm when administered to a pregnant woman . 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. Refer to the Full Prescribing Information of fulvestrant for pregnancy and contraception information.

• Strong CYP3A Inhibitors : Avoid concomitant use. If concomitant use cannot be avoided, reduce TRUQAP dose. • Moderate CYP3A Inhibitors: Reduce TRUQAP dose. • Strong and Moderate CYP3A Inducers: Avoid concomitant use

Effects of Other Drugs on TRUQAP 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 , 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. Moderate CYP3A inhibitors increase capivasertib exposure , 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 . 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.