Capivasertib Brings Biomarker-Driven Strategy to Hormone-Sensitive Prostate Cancer | ASCO GU

Capivasertib (Truqap; AstraZeneca Pharmaceuticals LP) in combination with abiraterone (Zytiga; Janssen Biotech, Inc) met its primary end point of radiographic progression-free survival (rPFS) in the phase 3 CAPItello-281 trial (NCT04493853), which evaluated patients with PTEN-deficient de novo metastatic hormone-sensitive prostate cancer (mHSPC). Findings from the global study were presented at the 2026 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, which took place February 26 to 28.^1,2

Prostate Cancer and the Role of PTEN

Prostate cancer is the most commonly diagnosed cancer and the second leading cause of cancer-related death among men in the United States. Although outcomes are generally favorable for patients with localized disease, survival remains poor for those who present with distant metastatic disease at diagnosis—an estimated 10% of patients—or who later develop recurrent metastases.³

Metastatic hormone-sensitive prostate cancer (mHSPC), increasingly referred to as androgen-pathway–dependent metastatic disease, is characterized by disease that has spread beyond the prostate but remains responsive to therapies that suppress or block androgen signaling. This stage represents a biologically aggressive form of prostate cancer with a high risk of progression despite initial sensitivity to hormonal treatment.^2,3

The current standard of care for mHSPC typically includes androgen deprivation therapy (ADT) in combination with an androgen receptor pathway inhibitor, with or without the addition of docetaxel chemotherapy and/or radiation. While treatment intensification has improved outcomes for many patients, responses remain heterogeneous, underscoring an unmet need for biologically targeted approaches that address key drivers of disease progression.^2,3

One such target is PTEN, a critical tumor suppressor gene that plays a central role in regulating cell growth and survival by inhibiting the PI3K/AKT signaling pathway. Alterations in PTEN become more common as prostate cancer advances, occurring in approximately 30% to 40% of patients with mHSPC, and are consistently associated with poorer prognosis across disease settings.⁴

“In patients with PTEN-intact prostate cancer, androgen receptor signaling is the dominant driver of disease,” said Daniel J. George, MD, FASCO, from Duke Cancer Institute in Durham, North Carolina. “However, in PTEN-deficient tumors, activation of the PI3K/AKT pathway serves as an additional, parallel driver of tumor growth and survival.”²

Capivasertib is an oral, pan-AKT inhibitor that targets all 3 AKT isoforms—AKT1, AKT2, and AKT3—thereby blocking downstream signaling activated by PTEN loss. The agent is currently approved for use in breast cancer, and its investigation in prostate cancer reflects growing interest in incorporating pathway-directed therapies earlier in the disease course.⁵

CAPItello-281 Trial Design

CAPItello-281 is a randomized, double-blind trial assessing the efficacy and safety of capivasertib plus abiraterone compared with placebo plus abiraterone in patients with de novo mHSPC characterized by PTEN deficiency, defined as loss of PTEN expression in at least 90% of viable tumor cells by immunohistochemistry.^2,6

A total of 1012 patients were randomly assigned 1:1 to receive capivasertib (400 mg twice daily, administered on an intermittent schedule of 4 days on and 3 days off) plus abiraterone, prednisone or prednisolone, and ADT, or placebo plus abiraterone, prednisone or prednisolone, and ADT.^2,6

The primary end point was investigator-assessed rPFS, with key secondary end points including overall survival, patient-reported outcomes, and safety.^2,6

Efficacy Outcomes

At the primary analysis, data showed that capivasertib plus abiraterone demonstrated a statistically and clinically meaningful improvement in rPFS. Median rPFS was 33.2 months in the capivasertib arm compared with 25.7 months in the control arm, representing an absolute improvement of 7.5 months. The HR for disease progression or death was 0.81 (95% CI, 0.66-0.98; P = .034).^2,6

Data from post hoc analyses showed that the rPFS benefit with capivasertib was consistent across varying degrees of PTEN loss. In contrast, outcomes in the control arm worsened as PTEN loss increased, suggesting that greater PTEN deficiency defines a higher-risk population in which AKT inhibition may provide greater relative benefit.^2,6

Patient-Reported Outcomes

Health-related quality of life was assessed using the Functional Assessment of Cancer Therapy–Prostate (FACT-P) questionnaire, with adherence exceeding 80% throughout the study. No clinically meaningful differences were observed between treatment arms in overall FACT-P scores or functional well-being.^2,6

Physical well-being declined more rapidly in the capivasertib arm, with a higher proportion of patients experiencing a clinically meaningful decline early in treatment. This effect was most pronounced within the first 6 to 12 weeks and largely resolved by approximately 3 months, after which trajectories paralleled those of the control arm. Investigators attributed this early dip primarily to capivasertib-related toxicity rather than ongoing hormonal therapy.^2,6

Safety and Tolerability

Higher rates of adverse events (AEs) were observed in the capivasertib arm, including grade 3 or higher events, serious adverse events, and treatment discontinuations. Approximately 18% of patients discontinued capivasertib, most within the first 3 months of therapy, compared with 4.8% in the placebo arm.^2,6

The most common on-target AEs associated with AKT inhibition were diarrhea, hyperglycemia, and rash, occurring in approximately 52%, 38%, and 35% of patients, respectively. These toxicities typically emerged early, within weeks to 2 months of treatment initiation, and were generally manageable with supportive care, dose interruptions, or dose reductions.^2,6

“What we’re doing instead is supportive care,” explained George. “Most of these patients are being managed for these toxicities with these supportive care measures. About 25% to 33% [are receiving] antihistamines and topical steroids for rash. For diarrhea, that’s ammonium. And for hyperglycemia, that’s metformin—not necessarily insulin.”²

Clinical Implications

CAPItello-281 addresses a significant unmet need for targeted therapies in PTEN-deficient mHSPC. The addition of capivasertib to abiraterone and ADT resulted in a meaningful improvement in rPFS, with preserved overall quality of life and a manageable safety profile in most patients. Although early toxicity led to treatment discontinuation in a subset of patients, those who remained on therapy maintained functional well-being and overall health-related quality of life.

“So in conclusion,” said George, “CAPItello-281 met its primary end point of statistically significant improvement in [rPFS], in what I would consider to be now a relatively new unmet need population of this PTEN-deficient, poor prognostic population.”²

REFERENCES

1. Capivasertib+abiraterone as treatment for patients with metastatic hormone-sensitive prostate cancer and PTEN deficiency (CAPItello-281). ClinicalTrials.gov. Updated January 20, 2026. Accessed February 26, 2026. https://clinicaltrials.gov/study/NCT04493853

2. Dorff T, Ong M, Sweeney C. Treatment selection, response assessment, and monitoring across the spectrum of advanced prostate cancer. Panel presented at: 2026 ASCO GU Cancers Symposium; February 26-28, 2026; San Francisco, CA.

3. Tsung I, Yentz SE, Reichert ZR. Controversies in metastatic hormone-sensitive prostate cancer. Cancer. 2025;131(16):e70030. doi:10.1002/cncr.70030

4. Garcia de Herreros M, Jiménez N, Padrosa J, et al. Clinical and transcriptomic characterization of metastatic hormone-sensitive prostate cancer patients with low PTEN expression. Int J Mol Sci. 2025;26(13):6244. doi:10.3390/ijms26136244

5. Yenamandra A. Same pathway, different profiles: clinical considerations for alpelisib, capivasertib, and inavolisib. Pharmacy Times. October 16, 2025. Accessed February 26, 2026. https://www.pharmacytimes.com/view/same-pathway-different-profiles-clinical-considerations-for-alpelisib-capivasertib-and-inavolisib

6. George DJ, Clarke NW, De Santis M, et al. Patient reported outcomes (PRO) and tolerability of capivasertib (capi) plus abiraterone (abi) versus placebo (pbo) plus abi in patients (pts) with PTEN deficient metastatic hormone-sensitive prostate cancer (mHSPC): CAPltello-281. J Clin Oncol. 2026;44(suppl 7; abstr 14). doi:10.1200/JCO.2026.44.7_suppl.14