What Is the Akt Inhibitor Capivasertib?

Capivasertib is a targeted cancer drug that blocks a protein called AKT, which helps tumor cells grow and survive. Approved by the FDA in November 2023 under the brand name Truqap, it is used alongside the hormone therapy fulvestrant to treat a specific subset of advanced breast cancers that have certain genetic alterations. The drug represents the first AKT inhibitor to reach the market, filling a gap in a signaling pathway that oncologists have been trying to drug for decades.

How Capivasertib Works

Your cells rely on a chain of molecular signals called the PI3K/AKT/mTOR pathway to regulate basic functions like growth, survival, and energy use.¹ In healthy tissue, this pathway is kept in check by built-in brakes. But in many cancers, mutations knock out those brakes or jam the accelerator, causing cells to multiply out of control. This pathway is one of the most frequently altered in breast cancer.²

Capivasertib sits right in the middle of this chain. It is a selective inhibitor of all three forms of the AKT protein (AKT1, AKT2, and AKT3), working by competing with ATP, the energy molecule AKT needs to function.³ By blocking AKT, capivasertib disrupts the downstream signals that tell cancer cells to keep dividing and to resist death. The drug doesn’t just target one form of AKT, which matters because different cancers may rely on different versions of the protein.

Who Is Eligible for Treatment

Capivasertib’s FDA approval is specifically for people with hormone receptor-positive, HER2-negative advanced breast cancer whose disease has progressed on or after prior hormone-based treatment. Within that group, the strongest benefit has been seen in patients whose tumors harbor alterations in one or more of three genes: PIK3CA, AKT1, and PTEN. These alterations are now considered actionable biomarkers, meaning they can guide treatment decisions.⁴

The label covers patients regardless of whether their tumors carry these mutations, but the benefit differs. In the pivotal trial, patients with pathway alterations saw a larger improvement in how long they lived without their cancer worsening. Even patients with rare variants of these pathway genes appeared to derive meaningful benefit from the drug.⁵ This makes genetic testing of the tumor an important step before starting treatment, though the drug can still be prescribed in the overall population.

The Trial That Led to Approval

The approval was built on a large phase 3 study called CAPItello-291, which enrolled over 700 patients with hormone receptor-positive, HER2-negative advanced breast cancer whose disease had gotten worse during or after aromatase inhibitor treatment.⁶ Patients were randomly assigned to receive either capivasertib plus fulvestrant or a placebo plus fulvestrant.

In the overall study population, adding capivasertib roughly doubled the time before the cancer progressed: a median of about 7.2 months compared with 3.6 months for fulvestrant alone.⁷ Among patients whose tumors carried alterations in PIK3CA, AKT1, or PTEN (roughly two-fifths of the trial population), the benefit was even more pronounced: median progression-free survival was about 7.3 months versus 3.1 months.⁸ In the biomarker-negative group, the difference was smaller and did not reach statistical significance in the exploratory analysis.

These numbers, while meaningful in advanced cancer, represent time without disease progression rather than a cure. Overall survival data from the trial have been eagerly awaited and continue to mature. The progression-free survival improvement alone, however, was enough for the FDA to grant approval.

Side Effects and How They Are Managed

The most common side effects of capivasertib fall into three categories: diarrhea, rash, and elevated blood sugar. In CAPItello-291, roughly seven in ten patients on capivasertib experienced diarrhea, about four in ten developed a rash, and about a third reported nausea. Severe (grade 3 or higher) events were less common: rash affected about one in eight patients, diarrhea about one in eleven, and high blood sugar about one in forty.⁹ These side effects tend to appear early, typically within the first two weeks of starting treatment, and are managed with supportive medications, dose adjustments, or temporary treatment pauses.¹⁰

The hyperglycemia side effect deserves special attention. Because AKT is a key part of how insulin signals your body to absorb sugar from the bloodstream, blocking it can cause insulin resistance. In most cases, blood sugar rises modestly and can be watched with routine monitoring. In rare instances, however, patients have developed diabetic ketoacidosis, a serious condition in which the body can’t use sugar for fuel and starts breaking down fat at a dangerous rate. Case reports have documented this happening even in patients with no prior history of diabetes.¹¹ The blood sugar problems can emerge at any point during treatment and don’t necessarily correlate with how well-controlled a patient’s sugar was beforehand. When the drug is stopped, the insulin resistance typically reverses.¹²

Early experience has pointed toward using insulin-sensitizing drugs like metformin and pioglitazone to preemptively manage the blood sugar issue, rather than drugs that push the pancreas to make more insulin. This approach aligns with the underlying mechanism: the problem is that cells can’t respond to insulin, not that the body isn’t making enough. Some oncology teams now start metformin at the same time as capivasertib to get ahead of the problem.

The Dosing Schedule and Why It Matters

Capivasertib is taken as a pill, 400 mg twice daily, on a four-days-on, three-days-off schedule. This intermittent dosing isn’t arbitrary. Exposure-safety analyses have shown that the four-on/three-off pattern results in fewer serious adverse events, fewer dose discontinuations, and less rash and diarrhea compared with a continuous daily dosing approach.¹³ The three days off give the body a window to recover from the metabolic effects of AKT blockade, particularly the insulin resistance, while still maintaining enough drug exposure to keep the cancer in check.

Pharmacokinetic studies in healthy volunteers show that capivasertib reaches its peak blood concentration in under two hours after swallowing and has a half-life of about 13 hours. The body clears it roughly equally through the kidneys and the gut. Most of the drug is converted into an inactive metabolite before being excreted.¹⁴

Quality of Life During Treatment

One of the persistent concerns with adding a new drug to an existing therapy is whether the extra side effects cancel out whatever disease benefit you gain. Patient-reported data from CAPItello-291 paint a mostly reassuring picture. Overall quality-of-life scores stayed stable from baseline and were similar between the two treatment groups throughout the study. In fact, the time before patients reported a meaningful worsening of their overall quality of life was longer in the capivasertib group: about 25 months compared with 12 months for placebo.¹⁵ This likely reflects the fact that keeping the cancer from progressing has its own quality-of-life benefit that offsets the side effects of treatment.

The exception, predictably, was diarrhea. Patients on capivasertib were substantially more likely to report worsening diarrhea, particularly in the first treatment cycle. By subsequent cycles, the gap narrowed. Other side effects like rash, mouth sores, itching, and tingling in the hands or feet were reported as absent or mild by most patients in both groups.

How Capivasertib Compares to Alpelisib

Before capivasertib, the main targeted option for patients with PI3K pathway-altered breast cancer was alpelisib (Piqray), a drug that blocks PI3K, the protein one step upstream of AKT. The two drugs have never been tested head-to-head, so comparisons rely on indirect methods. One such analysis estimated that capivasertib-fulvestrant had an 87% probability of being more effective than alpelisib-fulvestrant in slowing disease progression in patients with PIK3CA-altered tumors.¹⁶

The safety profiles differ in ways that matter for individual patients. A systematic review found that both drugs cause gastrointestinal side effects like nausea and loss of appetite. However, capivasertib tends to cause more rash and hypertension, while alpelisib is associated with more hyperglycemia, hair loss, and mouth sores.¹⁷ These differences guide real-world prescribing. A patient with pre-existing diabetes may be better suited to capivasertib (which causes less hyperglycemia than alpelisib), while a patient prone to skin issues might lean the other way. Without a head-to-head trial, the choice often comes down to comorbidities and patient preference. Capivasertib also has a broader label because it covers AKT1 and PTEN alterations in addition to PIK3CA mutations, while alpelisib is approved only for PIK3CA-mutated disease.

Testing for the Right Biomarkers

Identifying which patients carry PIK3CA, AKT1, or PTEN alterations requires genomic testing, and there are two main approaches: testing the tumor tissue itself (from a biopsy) or testing circulating tumor DNA shed into the bloodstream (a “liquid biopsy”). Both approaches have strengths and trade-offs.

A retrospective comparison of tissue-based and blood-based sequencing found that when the amount of tumor DNA in the blood was at least 1%, the two methods agreed over 90% of the time for the relevant mutations.¹⁸ But when circulating tumor DNA levels were very low (below 1%), agreement dropped to about a third.¹⁹ This means a liquid biopsy can be a convenient, minimally invasive option for many patients, but a negative liquid biopsy doesn’t definitively rule out a treatable alteration. When clinical suspicion is high, tissue testing may still be needed. Certain types of alterations, like PTEN deletions and some copy number changes, were also harder to detect with liquid biopsies, even at higher circulating tumor DNA levels.

Beyond Hormone Receptor-Positive Breast Cancer

Researchers have been exploring capivasertib in other cancer settings. The results so far are mixed.

In triple-negative breast cancer, a smaller early trial (PAKT) combining capivasertib with paclitaxel chemotherapy showed a promising survival signal: median overall survival was about 19 months with capivasertib versus about 13 months without it.²⁰ However, a much larger follow-up trial (CAPItello-290) did not confirm this. Median overall survival was essentially the same in both groups, at about 18 months, regardless of biomarker status. There was a modest progression-free survival benefit, but the overall survival results were disappointing.²¹ This outcome is a reminder that early trial signals don’t always hold up in larger studies.

In prostate cancer, a phase 2 trial (ProCAID) combined capivasertib with docetaxel chemotherapy in men with metastatic castration-resistant disease. The primary endpoint of composite progression-free survival was not met, but there was an intriguing overall survival signal, with a median of about 31 months in the capivasertib group versus about 20 months in the placebo group.²² A later update with more events showed the trend persisting but no longer reaching statistical significance.²³ A separate phase 2 trial (RE-AKT) tested capivasertib with enzalutamide, a different prostate cancer drug, and found no benefit at all.²⁴ For now, capivasertib’s role in prostate cancer remains uncertain and is not an approved indication.

Why Cancers Eventually Stop Responding

Even when capivasertib works initially, most cancers eventually find a way around the blockade. Researchers are starting to map out how this happens. One common escape route involves tumors reactivating mTORC1, a signaling hub downstream of AKT. Even while AKT stays blocked, cancer cells can rewire their internal signaling to bypass the blockade and turn mTORC1 back on through alternative pathways. Lab studies of resistant tumors have found dramatic increases in PDK1 and mTORC2 activity, both of which can feed into mTORC1 without going through AKT.²⁵

Clinical data from patients enrolled in a combination trial (CAPItello-292) showed that by the end of treatment, new genetic alterations had accumulated. Mutations in the RAS pathway, a growth-signaling route largely independent of AKT, were found in a quarter of patients at end of treatment versus fewer at baseline. Loss-of-function mutations in TSC1, a gene that normally holds mTORC1 in check, also became more common. CRISPR screening in the lab confirmed that loss of TSC1 and its partner TSC2 were among the changes most capable of blunting the drug’s effectiveness.²⁶

Separate research has found that even among patients selected for known pathway alterations, variability in response to capivasertib may be driven by differences in downstream mTORC1 activity and protein translation. Tumors that were already pumping out proteins at a high rate via mTORC1 before treatment started seemed to get less benefit from AKT inhibition alone.²⁷ Understanding these resistance mechanisms is critical for figuring out what should come after capivasertib fails and for designing smarter combination regimens.

The Cost Question

Targeted cancer drugs are expensive, and capivasertib is no exception. Independent economic analyses have produced different estimates depending on the assumptions used, but neither paints a favorable picture at the drug’s current list price. One analysis found that adding capivasertib to fulvestrant cost roughly $280,000 per quality-adjusted life year gained, well above the typical willingness-to-pay threshold used in U.S. health economics. That analysis suggested the drug’s price would need to drop by nearly 70% to cross the cost-effectiveness threshold.²⁸ A second analysis, using a different model, arrived at a somewhat more favorable (but still high) figure of about $128,000 per quality-adjusted life year, right at the borderline of cost-effectiveness at a higher willingness-to-pay threshold.²⁹

These figures represent list-price calculations before insurance negotiations, patient assistance programs, or manufacturer discounts. Real out-of-pocket costs vary enormously depending on coverage. Still, the gap between the drug’s price and its assessed value is wide enough that payers and patients alike face difficult decisions, particularly when the benefit in the biomarker-negative subgroup is smaller and less certain. This tension between clinical promise and economic burden is a familiar one in oncology, and it shapes not just who gets the drug but how aggressively clinicians push for biomarker testing to identify the patients most likely to benefit.

PTEN Loss and Prior Treatment Failures

One intriguing niche for capivasertib involves tumors that have lost the tumor-suppressor gene PTEN. PTEN normally acts as a brake on the PI3K/AKT pathway, so when it is inactivated, AKT signaling runs unchecked. PTEN loss has been linked to resistance against other standard treatments, including CDK4/6 inhibitors and the PI3K-alpha inhibitor alpelisib. A phase 1 expansion study tested capivasertib with fulvestrant specifically in patients whose tumors harbored PTEN mutations. Even in this heavily pretreated group (a median of seven prior therapies), the combination showed meaningful antitumor activity, with about a fifth of patients having measurable tumor shrinkage and about two-fifths achieving clinical benefit for at least 24 weeks.³⁰ For patients who have exhausted other options and whose cancers are driven by PTEN loss, capivasertib represents a biologically rational approach that other drugs in the same pathway space have struggled to address.