SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 9 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, about 333,830 new cases of prostate cancer will be diagnosed in 2026 and 36,320 men will die of the disease.
Androgen Receptor (AR) signaling remains the central driver of metastatic Hormone-Sensitive Prostate Cancer (mHSPC). However, prostate cancer is biologically heterogeneous, and genomic alterations can provide tumor cells with additional mechanisms to sustain proliferation and survival despite effective androgen deprivation and AR pathway inhibition.
The Rationale for Dual AR and AKT Pathway Blockade
AKT is a central downstream effector of PhosphoInositide 3-Kinase (PI3K) signaling and exists in three major isoforms—AKT1, AKT2, and AKT3. Activation of AKT regulates multiple processes that are essential for tumor growth, including cell-cycle progression, resistance to apoptosis, cellular metabolism, and survival signaling.
One of the most clinically important alterations involves loss of the tumor suppressor Phosphatase and Tensin homolog (PTEN). PTEN normally restrains signaling through the PI3K/protein kinase B (AKT) pathway. When PTEN function is lost, PI3K/AKT signaling becomes constitutively activated, promoting cell proliferation, survival, metabolism, and tumor progression.
Across the prostate cancer disease continuum, PTEN deficiency has been associated with more aggressive disease, earlier recurrence, shorter time to progression, and poorer outcomes with conventional treatment approaches. Although the prognostic significance of PTEN loss has been particularly well described in localized prostate cancer and metastatic Castration-Resistant Prostate Cancer (mCRPC), emerging clinical data support the view that PTEN deficiency also identifies a biologically aggressive subgroup within mHSPC.
Capivasertib (TRUQAP®) is a potent, selective inhibitor of all three AKT isoforms. By inhibiting AKT signaling and downstream phosphorylation events, Capivasertib is designed to suppress the proliferative and survival signals generated through pathway activation.
Preclinical models of PTEN-deficient prostate cancer demonstrated greater tumor growth inhibition when AKT inhibition was combined with androgen signaling blockade, than with AR pathway inhibition alone. These findings provided the biological foundation for CAPItello-281, a Phase III trial designed to test whether targeting both pathways could improve outcomes in patients with PTEN-deficient mHSPC.
CAPItello-281: A Biomarker-Selected Phase III Study
CAPItello-281 was a global, randomized, double-blind, placebo-controlled Phase III trial evaluating Capivasertib in combination with Abiraterone (ZYTIGA®) in patients with PTEN-deficient mHSPC.
A total of 1012 eligible patients were randomized 1:1 to receive to receive Capivasertib (400 mg twice daily; 4 days on, 3 days off) plus Abiraterone and Prednisone (N=507) or placebo plus Abiraterone and Prednisone (N=505), with both arms receiving Androgen Deprivation Therapy (ADT). Treatment was continued until disease progression, or unacceptable toxicity.
Randomization was stratified according to metastatic disease burden and the presence or absence of visceral metastases, as well as geographic region. High-volume disease was defined according to CHAARTED criteria as visceral metastasis and/or at least four bone metastases with at least one lesion beyond the vertebral bodies or pelvis. Importantly, the trial used prospective central ImmunoHistoChemistry (IHC) testing to identify patients with substantial PTEN protein loss. The prespecified definition of PTEN deficiency was loss of PTEN staining in at least 90% of viable malignant cells.
The choice of Abiraterone as the ARPI partner was driven in part by pharmacokinetic considerations. Enzalutamide and Apalutamide are strong CYP3A4 inducers and can reduce Capivasertib exposure, potentially compromising AKT inhibition. Darolutamide, which has weaker enzyme-inducing properties, was not approved for mHSPC when CAPItello-281 was initiated. Therefore, Abiraterone was selected to avoid the clinically important drug–drug interaction associated with strong CYP3A4 induction.
The Primary endpoint was investigator-assessed radiographic Progression-Free Survival (rPFS), while Overall Survival (OS) was a key Secondary endpoint.
A Significant Improvement in Radiographic Disease Control
CAPItello-281 met its Primary endpoint.
After a median follow-up of 18.4 months, among patients with PTEN-deficient mHSPC, median rPFS was:
- 33.2 months with Capivasertib plus Abiraterone
- 25.7 months with placebo plus Abiraterone
This corresponded to a statistically significant reduction in the risk of radiographic disease progression or death (HR, 0.81; 95% CI, 0.66–0.98; P=0.034). The absolute improvement in median rPFS was 7.5 months. The combination reduced the risk of radiographic progression or death by 19%.
The benefit was observed across prespecified subgroups, including patients with both high- and low-volume metastatic disease. This is clinically relevant because metastatic burden is an important determinant of treatment selection and prognosis in mHSPC.
Greater Relative Benefit with Increasing PTEN Loss
A notable exploratory finding from CAPItello-281 was the relationship between the degree of PTEN deficiency and treatment effect. A consistent pattern emerged. The efficacy of Capivasertib plus Abiraterone remained relatively stable across the increasingly stringent PTEN-loss thresholds, whereas outcomes with Abiraterone alone progressively worsened.
Median rPFS in the control arm decreased from 25.7 months in the population with at least 90% PTEN loss to 22.1 months among patients with complete PTEN loss. At the same time, the relative treatment effect numerically increased, with an exploratory rPFS Hazard Ratio of 0.68 in the 100% PTEN-loss subgroup.
At the interim analysis, OS data were not mature. Additional secondary efficacy outcomes, including measures related to progression to castration resistance, PSA progression, and skeletal complications, provided further support for the clinical activity of the combination.
The most common adverse events (AEs) for Capivasertib plus Abiraterone were diarrhea, (52%), hyperglycemia (38.0%) and rash (35.4%).
PTEN Testing: IHC versus Genomic Approaches
A key practical issue is how PTEN deficiency should be identified. PTEN status can be assessed using several approaches, including:
- IHC
- Next-generation sequencing
- Fluorescence In Situ Hybridization (FISH)
- Other genomic or molecular methods
Each approach has advantages and limitations. Genomic testing may fail to capture all mechanisms of PTEN loss, particularly when protein loss is caused by mechanisms such as epigenetic regulation, microRNA activity, subclonal alterations, or other non-genomic processes. IHC, in contrast, directly assesses PTEN protein expression and can identify the extent of protein loss within the tumor. It may also offer practical advantages, including lower test failure rates, faster turnaround, and lower cost compared with some genomic approaches. However, IHC results can be influenced by tissue quality, antibody performance, protein preservation, and scoring criteria.
Clinical Implications: Moving Toward Biomarker-Driven Intensification
Treatment intensification has become a central component of modern mHSPC management. However, treatment selection has traditionally been driven primarily by clinical factors such as metastatic volume, disease distribution, symptoms, comorbidities, performance status, and chemotherapy fitness.
The findings suggest that PTEN deficiency identifies patients with a poorer prognosis on AR-directed therapy alone and, at the same time, a population that may benefit from targeted AKT inhibition.
Practical Considerations for Treatment Selection
For patients with PTEN-deficient mHSPC, the CAPItello-281 data support consideration of dual AR and AKT pathway inhibition as a targeted treatment strategy.
The findings may be particularly relevant when:
- The tumor demonstrates substantial PTEN protein loss
- A targeted, non-chemotherapy intensification strategy is clinically preferred
- The patient is not an ideal candidate for Docetaxel-based therapy
- The clinician is seeking to address a defined molecular mechanism of disease progression
However, treatment decisions should remain individualized. The final OS analysis is awaited, and there are no direct randomized comparisons between Capivasertib-based therapy and chemotherapy-containing triplet regimens in PTEN-deficient disease.
Conclusion:
CAPItello-281 establishes a clinically important proof of concept for biomarker-directed pathway inhibition in mHSPC. In patients with PTEN-deficient tumors, targeting both the AR and PI3K/AKT axes may provide a more effective strategy than suppressing androgen signaling alone.
Capivasertib plus abiraterone in PTEN-deficient metastatic hormone-sensitive prostate cancer: CAPItello-281 phase III study. Fizazi K, Clarke NW, De Santis M. et al. for the CAPItello-281 Study Group. Annals of Oncology 2025;37:53-68.
