Capivasertib

Capivasertib (Truqap) is an oral targeted therapy used for certain HR-positive, HER2-negative, locally advanced or metastatic breast cancers when used with fulvestrant, and it is also used for specific PTEN-deficient metastatic prostate cancer when used with abiraterone and prednisone.

Capivasertib is a kinase inhibitor that works by blocking a protein called AKT, which signals cancer cells to grow and survive. By blocking AKT, capivasertib helps slow the growth and spread of the cancer. It is used in cancers with specific gene mutations in PIK3CA, AKT1, or PTEN. Capivasertib is not chemotherapy.

Capivasertib tablets are taken twice a day on a 4-days-on, 3-days-off schedule.

Capivasertib brand name is Truqap.

Capivasertib is FDA approved for two cancer types, each confirmed with an FDA-authorized companion diagnostic test:

• HR-positive, HER2-negative breast cancer (approved November 16, 2023): with fulvestrant, in adults with hormone receptor (HR)-positive, HER2-negative locally advanced or metastatic breast cancer bearing one or more PIK3CA, AKT1, or PTEN alterations, following progression on at least one endocrine-based regimen in the metastatic setting or recurrence on or within 12 months of completing adjuvant therapy. Eligibility is confirmed with the FoundationOne CDx assay.
• PTEN-deficient prostate cancer (approved June 12, 2026): with abiraterone and prednisone, in adults with metastatic androgen pathway modulation-naive or -sensitive (mAPMN/S) prostate cancer that is PTEN-deficient. PTEN deficiency is confirmed with the VENTANA PTEN (SP218) RxDx Assay.

Patient selection is based on the presence of the relevant genetic alteration (breast) or PTEN deficiency (prostate) in tumor tissue. Premenopausal and perimenopausal women, and men in the breast cancer setting, should receive an LHRH agonist per current practice; prostate cancer patients should receive a GnRH analog concurrently or have undergone bilateral orchiectomy.

• High blood sugar levels (hyperglycemia): Hyperglycemia is common with this medicine and may be severe. Untreated severe hyperglycemia can lead to a condition called diabetic ketoacidosis that can happen in people treated with capivasertib. Diabetic ketoacidosis is a serious condition that requires treatment in a hospital and can lead to death. If you have a fever, chills, infection, serious injury, or a new illness, tell your healthcare provider before taking your next dose, as a suspected serious infection or acute illness can increase the risk of severe hyperglycemia or ketoacidosis. Your healthcare provider will monitor your blood sugar levels before you start and during treatment with TRUQAP. It is not known if TRUQAP is safe in people with type 1 diabetes or people who use insulin to treat their diabetes. Your healthcare provider will monitor your blood sugar levels more often if you have a history of diabetes. Tell your healthcare provider right away if you develop symptoms of hyperglycemia, including
• Diarrhea: occurred in the majority of patients and can be severe with dehydration. Advise increased oral fluids and early antidiarrheal treatment; withhold, reduce, or discontinue by severity.
• Cutaneous adverse reactions: can be severe, including erythema multiforme, palmar-plantar erythrodysesthesia, and drug reaction with eosinophilia and systemic symptoms (DRESS). Early dermatology consultation is recommended.
• Embryo-fetal toxicity: can cause fetal harm. Verify pregnancy status before initiation; advise effective contraception during treatment and for 1 month (females) or 4 months (males with female partners of reproductive potential) after the last dose. Advise women not to breastfeed during treatment. Refer to fulvestrant or abiraterone labeling for combination-specific guidance.
• Severe allergic reactions: Do not take capivasertib if you have had a severe allergic reaction to it or any of its ingredients.

Do not take capivasertib if you have had a severe allergic reaction to capivasertib or to any of the inactive ingredients in the tablets.

Tell your healthcare provider about all of your medical conditions before you start treatment, including if you:

• have high blood sugar (hyperglycemia) or diabetes, or have had either in the past
• have had a rash or another skin condition
• have liver problems
• currently have an infection
• are pregnant, planning a pregnancy, or breastfeeding

Pregnancy

Capivasertib can harm an unborn baby. Let your healthcare provider know if you are pregnant or planning to become pregnant before you start treatment.

If you can become pregnant, your healthcare provider will do a pregnancy test before your first dose. Use effective birth control while you are taking capivasertib and for 1 month after your final dose, and ask your healthcare provider which contraception options are suitable for you. Contact your healthcare provider straight away if you become pregnant or think you may be pregnant during treatment.

Males with a female partner who can become pregnant should use effective birth control during treatment and for 4 months after the last dose. Tell your healthcare provider straight away if your partner becomes pregnant.

Breastfeeding

Do not breastfeed while taking capivasertib. Talk to your healthcare provider about how best to feed your baby during treatment and about when breastfeeding can safely resume.

The most common side effects of capivasertib are diarrhea, high blood sugar, skin reactions, nausea, fatigue, and changes in blood test results. The specific profile depends on the medicine it is combined with.

Serious side effects

Capivasertib can cause serious side effects. The most important are severe high blood sugar (hyperglycemia), which can lead to a dangerous condition called diabetic ketoacidosis; severe diarrhea, which can cause dehydration; and severe skin reactions. It can also cause harm to an unborn baby. Patients should contact their healthcare provider right away if they develop symptoms such as excessive thirst, frequent urination, severe or persistent diarrhea, or a new or worsening rash. See Warnings and monitoring for details on how these are monitored and managed.

Common side effects

In clinical trials, the side effects reported in 20% or more of patients (including laboratory abnormalities) were:

• Breast cancer (with fulvestrant): diarrhea, skin reactions, high blood sugar (increased random and fasting glucose), low white blood cell counts (decreased lymphocytes, leukocytes, and neutrophils), low red blood cell count (decreased hemoglobin), nausea, fatigue, raised triglycerides, raised creatinine, vomiting, and mouth inflammation (stomatitis).
• Prostate cancer (with abiraterone): high blood sugar (increased fasting and non-fasting glucose), low red blood cell count (decreased hemoglobin), low lymphocyte count, skin reactions, diarrhea, low potassium, raised creatinine, raised liver enzymes (ALT and AST), raised triglycerides, low sodium, and fatigue.

These are not all the possible side effects of this medicine. Contact your healthcare provider for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

CAPItello-291 clinical trial results (breast cancer)

CAPItello-291 was a randomized, double-blind, placebo-controlled, multicenter trial of capivasertib plus fulvestrant versus placebo plus fulvestrant in HR-positive, HER2-negative advanced breast cancer.

• Enrolment: 708 adults, of whom 289 had tumors with eligible PIK3CA, AKT1, or PTEN alterations.
• Eligibility: progression on an aromatase inhibitor-based regimen in the metastatic setting, or recurrence on or within 12 months of completing adjuvant AI therapy. Up to two prior lines of endocrine therapy and one line of chemotherapy for advanced disease were allowed.
• Treatment: randomized 1:1 to capivasertib 400 mg twice daily (4 days on / 3 days off) or placebo, each with fulvestrant.
• Primary endpoint: investigator-assessed progression-free survival (PFS), in the overall population and in the altered subgroup.

In the altered subgroup, capivasertib plus fulvestrant more than doubled median progression-free survival, from 3.1 to 7.3 months (HR 0.50, 95% CI 0.38 to 0.65; p<0.0001), and roughly tripled the objective response rate, from 8% to 26%. The benefit was concentrated in biomarker-altered tumors: an exploratory analysis in patients without an alteration showed a hazard ratio of 0.79 (95% CI 0.61 to 1.02). Overall survival was immature at the time of the PFS analysis, with 30% of patients having died.

Population: patients with PIK3CA/AKT1/PTEN-altered tumors. Objective response rate assessed in patients with measurable disease.

CAPItello-281 clinical trial results (prostate cancer)

CAPItello-281 was a randomized, double-blind, placebo-controlled, multicenter trial of capivasertib plus abiraterone versus placebo plus abiraterone in PTEN-deficient metastatic prostate cancer.

• Enrolment: 1,012 adults with newly diagnosed, PTEN-deficient mAPMN/S prostate cancer, with PTEN deficiency determined centrally by immunohistochemistry.
• Eligibility: only permitted prior systemic therapy was up to 93 days of androgen deprivation therapy and/or abiraterone.
• Treatment: randomized 1:1 to capivasertib 400 mg twice daily (4 days on / 3 days off) or placebo, each with abiraterone 1,000 mg daily plus prednisone or prednisolone 5 mg daily, alongside a GnRH analog or prior orchiectomy.
• Primary endpoint: investigator-assessed radiographic progression-free survival (rPFS).

Capivasertib plus abiraterone significantly extended median radiographic progression-free survival, from 25.7 to 33.2 months (HR 0.81, 95% CI 0.66 to 0.98; p=0.034), a reduction in the risk of radiographic progression. Blinded independent review was consistent with the investigator assessment. Overall survival was immature at the time of the rPFS analysis, with 26% of patients having died.

Population: patients with PTEN-deficient mAPMN/S prostate cancer.

Capivasertib works by inhibiting the kinase AKT, blocking all three of its forms (AKT1, AKT2, and AKT3). AKT has a central role in the PI3K/AKT/PTEN signaling pathway, which drives tumor cell growth and survival and commonly becomes overactive through activating mutations in PIK3CA or AKT1 or loss of PTEN function. By suppressing AKT signaling, capivasertib stops the overactive pathway from sending growth and survival signals to the cancer cells.

In preclinical models, capivasertib reduced growth of breast cancer cell lines bearing PIK3CA or AKT1 mutations or PTEN alterations, and of androgen receptor-positive, PTEN-deficient prostate cancer cell lines. In animal studies, antitumor activity was greater when capivasertib was combined with fulvestrant in models of estrogen receptor-positive breast cancer and with abiraterone in models of PTEN-deficient prostate cancer, supporting the approved combination regimens.

• Absorption: Tmax approximately 1 to 2 hours; absolute bioavailability 29%. No clinically meaningful food effect.
• Distribution: steady-state volume of distribution about 1,847 L; plasma protein binding 78%; plasma-to-blood ratio 0.71.
• Metabolism: primarily by CYP3A4 and UGT2B7.
• Elimination: half-life approximately 8.3 hours; steady-state oral clearance about 50 L/h. Recovery approximately 45% in urine and 50% in feces after a single radiolabeled dose.

Steady-state concentrations are reached on the third and fourth dosing days of each week from week 2, and off-dosing-day concentrations fall to roughly 0.2% to 5.1% of steady-state Cmax.

Recommended dosage: 400 mg orally twice daily (approximately 12 hours apart), with or without food, for 4 consecutive days followed by 3 days off each week. Continue until disease progression or unacceptable toxicity. Tablets are swallowed whole and are not chewed, crushed, or split.

Available strengths: 160 mg and 200 mg film-coated tablets. The 400 mg dose is taken as two 200 mg tablets per dose.

Missed or vomited dose: a missed dose may be taken within 4 hours of the usual time; beyond 4 hours, skip it and resume at the next scheduled dose. If a dose is vomited, do not replace it; resume at the next scheduled dose.

Storage: Store at room temperature in the original packaging. If the tablets are not kept in their original packaging, throw them away after 45 days. Keep out of the reach of children.

Dose reductions for adverse reactions

Two sequential reductions are permitted before discontinuation:

Permanently discontinue if the patient cannot tolerate the second reduction. Withhold, reduce, or discontinue based on the severity of hyperglycemia, diarrhea, cutaneous reactions, or other adverse reactions per the prescribing information.

CYP3A dose modification: with a strong or moderate CYP3A inhibitor that cannot be avoided, reduce to 320 mg twice daily (4 days on / 3 days off). Resume the prior dose 3 to 5 inhibitor half-lives after the inhibitor is stopped.

• Strong CYP3A inhibitors: avoid; if unavoidable, reduce the capivasertib dose (itraconazole is predicted to raise AUC up to 1.7-fold).
• Moderate CYP3A inhibitors: reduce the capivasertib dose (predicted AUC increase up to 1.5-fold).
• Strong or moderate CYP3A inducers: avoid (rifampicin predicted to reduce AUC by 70%; efavirenz by 60%).
• Grapefruit: avoid grapefruit and grapefruit products during treatment.

This list does not include all possible interactions. Other medicines may interact with capivasertib, including prescription and over-the-counter drugs, vitamins, and herbal products. Tell your doctor and pharmacist about all the medicines you take before starting capivasertib.

• Pregnancy: capivasertib can cause fetal harm based on findings in animals and its mechanism of action. There are no data on use in pregnant women. Verify pregnancy status before initiation, and advise pregnant women and females of reproductive potential of the potential risk to a fetus. Females should use effective contraception during treatment and for 1 month after the last dose; males with female partners of reproductive potential should do so during treatment and for 4 months after the last dose. Refer to the fulvestrant or abiraterone labeling for combination-specific pregnancy and contraception guidance.
• Renal impairment: no dosage adjustment for mild to moderate impairment (CLcr 30 to 89 mL/min). Not studied in severe renal impairment.
• Hepatic impairment: no dosage adjustment for mild impairment. Monitor patients with moderate impairment for adverse reactions due to potentially increased exposure. Not studied in severe hepatic impairment.
• Lactation: advise against breastfeeding during treatment.
• Pediatric use: safety and effectiveness in pediatric patients have not been established.