Capivasertib Plus Abiraterone: The First Targeted Therapy in PTEN-Deficient Metastatic Prostate Cancer

KEY FINDINGS

• FDA approval: On 12 June 2026 the FDA approved capivasertib plus abiraterone and prednisone for PTEN-deficient mHSPC/mAPMN/S - the first FDA-approved molecularly targeted therapy in this indication.
• Efficacy: Phase 3 CAPItello-281 trial: median rPFS 33.2 months (capivasertib arm) versus 25.7 months (placebo arm) - a meaningful 7.5-month gain.
• Risk reduction: A 19% reduction in the risk of progression or death (HR 0.81; 95% CI 0.66-0.98; P = 0.034).
• Subgroup: PTEN deficiency is an aggressive subtype seen in approximately one in four patients with mHSPC.
• Diagnostics: The companion diagnostic VENTANA PTEN (SP218) RxDx Assay was approved simultaneously.

Study Design and Background

PTEN (Phosphatase and Tensin Homolog) is a tumour suppressor frequently altered in prostate cancer. Loss of PTEN activates the PI3K/AKT/mTOR pathway, creating a tumour growth mechanism independent of the androgen receptor (AR) pathway. Approximately 25% of patients diagnosed with metastatic hormone-sensitive prostate cancer (mHSPC) have PTEN deficiency, and this subgroup is characterised by faster progression and a worse prognosis compared with PTEN-intact patients.

Capivasertib is an agent of the AKT inhibitor class and targets the PI3K/AKT pathway whose activation follows PTEN loss. The phase 3 CAPItello-281 trial (NCT04493853) was designed to compare capivasertib plus abiraterone plus androgen deprivation therapy (ADT) with placebo plus abiraterone plus ADT.

"Patients with PTEN-deficient mHSPC experience faster progression and a worse prognosis than PTEN-intact patients. In these patients, extending remission and disease-free life as far as possible is the highest priority."
- Daniel J. George, MD, Duke Cancer Institute, Director of Genitourinary Oncology

Study population: 1,012 patients with PTEN-deficient mAPMN/S (mHSPC) were randomized 1:1. Capivasertib arm (n=507), placebo arm (n=505). Baseline characteristics were balanced between the two arms. PTEN deficiency was determined immunohistochemically (IHC) with the FDA-approved companion diagnostic VENTANA PTEN (SP218) RxDx Assay.

Key Results

The primary endpoint of the trial, radiographic progression-free survival (rPFS), improved to a statistically significant degree.

The rPFS advantage was observed in the great majority of prespecified subgroups, independent of disease risk and metastatic volume.

Safety Profile

Grade 3 or higher adverse events were reported in 67% of patients in the capivasertib arm.

Deaths related to adverse events occurred in 7.2% of the capivasertib arm and 5.2% of the placebo arm. The safety profile was broadly consistent with the known profile of both agents.

Dosing Information

Capivasertib: 400 mg orally twice daily (approximately 12 hours apart), with or without food; administered cyclically as 4 days on treatment / 3 days off. Continued until disease progression or unacceptable toxicity.

Abiraterone acetate: 1,000 mg once daily plus prednisone 5 mg once daily. Concurrent GnRH analogue therapy must be continued or the patient must have undergone bilateral orchiectomy.

Implications for Clinical Practice

1. Biomarker testing has become mandatory

For the capivasertib indication, confirmation of PTEN deficiency with the FDA-approved VENTANA PTEN (SP218) RxDx Assay is required. It may become necessary to incorporate PTEN IHC testing of biopsy material into the routine assessment at mHSPC diagnosis.

2. A new patient subgroup has been defined

Approximately 25% of mHSPC patients are PTEN-deficient. This subgroup is being considered under the new terminology mAPMN/S (metastatic androgen pathway modulation-naive or sensitive).

3. Combined AKT and AR pathway inhibition

The combination of capivasertib (an AKT inhibitor) and abiraterone (a CYP17A1 inhibitor) simultaneously suppresses AR-dependent and AR-independent growth pathways. This mechanism may help overcome resistance to AR pathway monotherapy.

4. Toxicity management is critical

Diarrhoea (51.9%) and hyperglycaemia (38%) are the most frequent adverse effects. Close monitoring of these patients for diabetes/glucose control and diarrhoea management is recommended.

5. OS data awaited

Overall survival data are not yet mature; the trial continues for OS assessment. Long-term results will be decisive for treatment decisions.

Conclusion

FDA approval of capivasertib plus abiraterone and prednisone represents a paradigm shift in the treatment of PTEN-deficient mHSPC/mAPMN/S. For the first time in metastatic hormone-sensitive prostate cancer, a targeted treatment option has become available for a specific patient subgroup defined by molecular profile.

This development will accelerate the integration of biomarker-based patient selection and personalised therapy into prostate cancer management in clinical practice. Determining PTEN status at the time of diagnosis in mHSPC patients will become a critical step in treatment planning.

Overall survival data and completion of long-term follow-up will more clearly define the lasting place of this treatment in the prostate cancer treatment algorithm.

References

• Clarke H. FDA approves capivasertib plus abiraterone and prednisone for PTEN-deficient mHSPC. Urology Times. 12 June 2026. - urologytimes.com
• The ASCO Post Staff. FDA Approves Capivasertib Plus Abiraterone and Prednisone for Metastatic Prostate Cancer. The ASCO Post. 12 June 2026. - ascopost.com
• FDA. FDA approves capivasertib with abiraterone and prednisone for PTEN-deficient androgen pathway modulation-naive or sensitive prostate cancer. 12 June 2026. - fda.gov
• Fizazi K, Clarke NW, Santis MD, et al. Capivasertib plus abiraterone in PTEN-deficient metastatic hormone-sensitive prostate cancer: CAPItello-281 phase III study. Ann Oncol. 2026;37(1):53-68. doi:10.1016/j.annonc.2025.10.004
• AstraZeneca. TRUQAP (capivasertib) combination approved in the US as first and only targeted treatment for PTEN-deficient metastatic hormone-sensitive prostate cancer. 12 June 2026. - astrazeneca.com