New analyses from the multicenter phase III CAPItello-281 trial of the AKT1/2/3 inhibitor capivasertib plus the CYP17-inhibitor abiraterone in PTEN-deficient metastatic hormone-sensitive prostate cancer—now sometimes described as androgen pathway modulation–resistant (APMR) (or modulation-sensitive [APMS]) disease—offer insight into how patients experience the regimen during treatment. Presented by Daniel J. George, MD, FASCO, of Duke Cancer Institute, Durham, North Carolina, at the 2026 ASCO Genitourinary (GU) Cancers Symposium, the findings evaluated patient-reported outcomes and adverse events associated with the combination.1
In the present updated tolerability analysis, diarrhea, hyperglycemia, and rash remained the most common adverse events with capivasertib plus abiraterone. “[They] are AKT inhibition–related on-target effects that occur early and are manageable,” Dr. George said.
Although adverse events were more often seen with the experimental regimen, “the addition of capivasertib [to abiraterone] did not affect other functional aspects of patient life and overall health-related quality of life…,” Dr. George said, allowing approximately 80% of patients to continue treatment.
About CAPItello-281
PTEN deficiency activates the PI3K/AKT pathway, providing what Dr. George described as a “parallel driver of disease proliferation” alongside androgen receptor signaling. He noted that this biology contributes to the poorer prognosis associated with PTEN-deficient disease. Prior evidence with ipatasertib plus abiraterone showed clinical benefit, he noted, supporting the strategy of dual AKT and androgen receptor inhibition in this context.
In this double-blind trial, patients with PTEN-deficient (defined as loss in ≥ 90% of viable malignant cells by immunohistochemistry) de novo metastatic hormone-sensitive prostate cancer were enrolled. A total of 1,012 were randomly assigned in a 1:1 ratio to receive capivasertib plus abiraterone/prednisone or placebo plus abiraterone/prednisone (the standard of care at the time of the study), both on a backbone of androgen-deprivation therapy. Capivasertib and placebo were administered at 400 mg twice daily on an intermittent schedule (4 days on, 3 days off), which Dr. George said was “selected specifically to maintain efficacy but allow for mitigation of the cumulative side effects that [the capivasertib-containing] regimen could cause.”
Despite more adverse events [with the experimental regimen], the addition of capivasertib [to abiraterone] did not affect other functional aspects of patient life and overall health-related quality of life….— DANIEL J. GEORGE, MD, FASCO
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The trial previously met its primary endpoint of investigator-assessed radiographic progression–free survival, findings that Dr. George briefly reviewed.2 The median was 25.7 months with placebo, which he described as “significantly lower than what we typically see in this population.” The addition of capivasertib to the prevailing standard of care extended the median to 33.2 months, representing a 7.5-month improvement (hazard ratio [HR] = 0.81; P = .034).
A post hoc analysis explored radiographic progression–free survival across higher thresholds of PTEN deficiency. In the capivasertib arm, outcomes were found to be similar across the overall population and subgroups with at least 95%, 99%, and 100% PTEN deficiency.
In the control arm, however, increasing levels of PTEN loss appeared to be associated with shorter median radiographic progression–free survival, resulting in “a greater difference between that and the capivasertib arm,” Dr. George explained. A similar pattern was observed in the overall survival data, “looking like there is a relative nature to the PTEN loss.”
The safety profile of capivasertib plus abiraterone was previously described as consistent with the known profiles of the individual agents; patient-reported outcomes had not been reported.
Patient-Reported Outcomes
The present analysis included patient-reported outcomes assessed with the Functional Assessment of Cancer Therapy–Prostate (FACT-P) questionnaire, which includes five subscales: physical well-being, functional well-being, emotional well-being, social/family well-being, and prostate cancer–specific symptoms. Dr. George focused on the physical and functional well-being domains as well as the overall FACT-P score. Compliance with FACT-P reporting was described as “good,” with compliance rates of greater than 80%.
For physical well-being, which includes measures such as side effects, energy, nausea, and pain, the adjusted mean change from baseline was −1.7 with capivasertib plus abiraterone vs −1.3 with placebo plus abiraterone (least-squares [LS] mean difference = −0.4; clinically meaningful change defined as ≥ 3 points). Dr. George noted that in the first two assessments there is “a dip [in the curve with capivasertib, but] it comes back up close to the placebo arm” over about 3 months, after which the curves remained relatively similar.
Time to clinically meaningful decrease in physical well-being was shorter with capivasertib than with placebo (HR = 1.43). A decline was observed in the capivasertib arm at the first assessment at 6 weeks and was maintained at 3 months, after which the curves were parallel. As Dr. George stated, “this suggests that the initial decline is driven by the addition of capivasertib to this regimen, but from that point on, the subsequent decline is driven by the backbone of androgen-deprivation therapy and abiraterone in both arms.”
Likewise, for functional well-being, which includes outcomes such as ability to work, sleep quality, and ability to enjoy life, no clinically meaningful difference was observed between arms (adjusted mean change from baseline, −1.0 vs −0.7; LS mean difference = −0.3). Dr. George described the results as “essentially overlapping data,” with similar time to deterioration between arms (HR = 1.06), including during the first 6 to 12 weeks of treatment.
The FACT-P total score showed adjusted mean changes from baseline of −4.1 with capivasertib plus abiraterone vs −4.5 with placebo plus abiraterone (LS mean difference = 0.4; clinically meaningful change defined as ≥ 10 points). Time to deterioration was also found to be comparable between arms (HR = 1.10). The curve suggested that declines were more related to hormonal therapy than to the addition of capivasertib, Dr. George said.
Updated Tolerability Data
“As you’d expect from any study where we are adding on a therapeutic agent vs placebo, we are going to see more adverse events in the experimental arm, and we do,” Dr. George stated. The overall adverse event, grade 3 or greater adverse event, and serious adverse event rates were higher with capivasertib. Adverse events leading to treatment discontinuation were reported in 18.3% of patients treated with capivasertib compared with 4.8% of those who received placebo.
Dr. George highlighted that “what is interesting is [discontinuations are] happening early,” with 63% of capivasertib discontinuations occurring within the first 3 months, corresponding with the early decline in physical well-being observed in the patient-reported outcomes analysis. After that point, he reported that the curves were relatively parallel, “suggesting a less specific reason for discontinuation.”
The most common adverse events associated with capivasertib were diarrhea, hyperglycemia, and rash, which Dr. George described as on-target effects of AKT inhibition. These events occurred at “high” rates of 51.9%, 38.0%, and 35.4%, respectively. The median time to onset for rash and diarrhea was within approximately 2 weeks of starting capivasertib, whereas the median for hyperglycemia was within about 2 months—all occurring “relatively early on.”
Management appeared to vary by toxicity. Rash more often required modification of capivasertib treatment, including interruptions (16.9%), dose reductions (8.5%), and discontinuations (4.8%). For diarrhea and hyperglycemia, Dr. George noted “a little bit different of a picture,” highlighting that about 11% to 12% of patients required interruption and 1% discontinued treatment. Most events were instead managed with supportive care, he added; approximately 25% to 33% received such interventions.
Taken together with the previously reported efficacy findings, these new data suggest that “capivasertib in combination with abiraterone represents a potential first-in-class targeted treatment for patients with PTEN-deficient metastatic hormone-sensitive prostate cancer,” Dr. George concluded.
DISCLOSURE: The study was funded by AstraZeneca. Dr. George has held a leadership role with Capio Biosciences; has stock and other ownership interests in Bristol Myers Squibb and Pfizer; has received honoraria from Astellas Pharma, AstraZeneca, Axess Oncology, Bayer, Candel Therapeutics, Eisai, IDEOlogy Health, Janssen Oncology, Merck, Millennium Medical Publishing, Novartis, OncLive, Pfizer, Sumitomo, and UroToday; has served as a consultant or advisor for Astellas Pharma, AstraZeneca, Bayer, Candel Therapeutics, Janssen, Merck Sharp & Dohme, Michael J. Hennessy Associates, Novartis, Pfizer, and Physicians’ Education Resource; has received institutional research funding from Astellas Pharma, AstraZeneca, Bristol Myers Squibb, Convergent Therapeutics, Corvus Pharmaceuticals, Exelixis, Janssen Oncology, Merck, Novartis, and Pfizer; has given expert testimony for Exelixis; and has received reimbursement for travel-related expenses from Bayer, Exelixis, Merck, Novartis, and Pfizer.
REFERENCES
1. George DJ, Clarke NW, De Santis M, et al: Patient reported outcomes and tolerability of capivasertib plus abiraterone (abi) versus placebo plus abi in patients with PTEN-deficient metastatic hormone-sensitive prostate cancer: CAPItello-281. 2026 ASCO GU Cancers Symposium. Abstract 14. Presented February 26, 2026.
2. Fizazi K, Clarke NW, De Santis M, et al: Capivasertib plus abiraterone in PTEN-deficient metastatic hormone-sensitive prostate cancer: CAPItello-281 phase III study. Ann Oncol 37:53-68, 2026.
