AKT inhibition with capivasertib shows benefit in PTEN-deficient prostate cancer

The phase 3 CAPItello-281 trial (NCT04493853) showed that adding capivasertib (Truqap) to abiraterone acetate (Zytiga) and androgen deprivation therapy (ADT) significantly improved radiographic progression-free survival (rPFS) in patients with PTEN-deficient metastatic hormone-sensitive prostate cancer, supporting AKT inhibition as a new targeted treatment strategy.¹

The analysis, presented at the 2026 American Society of Clinical Oncology Genitourinary Cancers Symposium in San Francisco, California, also found that the regimen’s effects on functional well-being and overall quality of life were similar to that of placebo, although treatment with capiversatib was associated with an initial decline in physical well-being.

“In patients with PTEN-intact or -proficient prostate cancer, androgen receptor is the key driver of disease proliferation.² However, in patients that have PTEN-deficient prostate cancer, there’s an additional pathway. There’s activation of this PI3 kinase AKT pathway, which is sort of a parallel driver of disease proliferation and survival.³ And it’s because of this that PTEN deficiency has been shown to be a poor prognostic factor throughout the continuum of prostate cancer, including this APMN disease setting,”^3-5 explained presenter Daniel J. George, MD, Eleanor Easley Distinguished Professor in the School of Medicine, Medicine, Medical Oncology, professor of medicine, and professor of surgery at Duke University in Durham, North Carolina. Further, George said previous phase 2 and phase 3 data have indicated benefit with the AKT inhibitor ipatasertib in combination with abiraterone with PTEN-deficient mCRPC.^3,4

Turning to CAPItello-281, George outlined the study’s structure. Patients were eligible if they had PTEN-deficient de novo metastatic hormone-sensitive prostate cancer. Out of approximately 6200 patients who submitted tumor tissue, 97% had a valid immunohistochemistry result and 25% were PTEN deficient. Ultimately, 1012 patients were randomly assigned to either capivasertib 400 mg twice daily at 4 days on, 3 days off, along with abiraterone/prednisone 1000 mg/5 mg once daily plus androgen deprivation therapy (ADT), or to placebo plus abiraterone/prednisone 1000 mg/5 mg once daily plus ADT. The primary end point was investigator-assessed rPFS, and key secondary end points included overall survival (OS), time to first subsequent therapy, symptomatic skeletal-event free survival, and time to pain progression. Patient-reported outcome/tolerability end points included FACT-P (including Physical Well-being [PWB] and Functional Well-being [FWB]), adverse event (AE) assessment, and PGI-S.

Enrollment took place from July 13, 2020 until February 5, 2024. Primary rPFS data cut-off occurred on October 7, 2024, and final OS data cut-off is planned at 522 deaths (52.2% maturity).

As was previously reported at the 2025 European Society for Medical Oncology Congress in Berlin, Germany, the trial met its primary end point, with a median rPFS of 33.2 months (95% CI, 25.8-44.2) in the capivasertib arm vs 25.7 months (95% CI, 22.0-29.9) in the placebo arm (HR: 0.81; 95% CI, 0.66-0.98; P = 0.034).⁶

George also reported results from a post hoc analysis looking at PTEN subgroups; specifically, PTEN cut-offs of 95% or higher, 99% or higher, and 100%. “Essentially, they’re all overlapping. We see the same rPFS regardless of the level of PTEN deficiency. However, when we look at our control arm…as we look at 95%, 99%, and 100% cut-off, we see a worse prognosis. We see a shorter median rPFS associated with this higher threshold of PTEN loss and consequently a greater difference in the median rPFS between that and the capivasertib arm,” George said.

George turned to results from the FACT-P questionnaire. Regarding PWB, a higher degree of clinically meaningful decline was observed in the capivasertib arm (adjusted mean –1.7) vs the placebo arm (adjusted mean –1.3).

“If we dive a little deeper into this time to clinically meaningful decrease in this physical well-being, you see that even with the very first assessment at 6 weeks, there’s already a decline in the capivasertib arm, and that’s maintained at 3 months, about a 10% difference. But from that point on, the curves are parallel, which suggests to me that the initial decline is driven by the addition of capivasertib to this regimen. But from that point on, the subsequent declines are really driven by the backbone of ADT and abiraterone in both arms,” George explained.

For FWB, George said there was “essentially no difference” between the 2 arms. The median time to clinically meaningful decrease was 6.3 months (95% CI, 4.4-10.9) in the capivasertib arm vs 8.1 months (95% CI, 5.4-14.6) in the placebo arm (HR: 1.06; 95% CI, 0.86-1.32).

When FACT-P total score was evaluated, the median time to clinically meaningful decrease was 9.0 months (95% CI, 6.3-20.1) in the capivasertib arm vs 12.7 months (95% CI, 8.1-21.9) in the placebo arm (HR: 1.10; 95% CI, 0.89-1.37).

The number of any AEs was 497 (98.8%) in the capivasertib arm vs 463 (92.0%) in the placebo arm, and the number of any grade 3 or higher AEs was 337 (67.0%) in the capivasertib arm vs 203 (40.4%) in the placebo arm. There were a total of 92 (18.3%) AEs leading to discontinuation of capivasertib and 24 (4.8%) AEs leading to discontinuation of placebo. In the capivasertib arm, there were 48 (9.5%) AEs leading to discontinuation of abiraterone vs. 27 (5.4%) in the placebo arm. The AEs with the highest incidence were diarrhea, hyperglycemia, and rash. George noted that all of these are “AKT inhibition driven.”

“In summary, capivasertib in combination with abiraterone represents a potential first-in-class targeted treatment for patients with this now PTEN-defined metastatic APMN,” George said.

REFERENCES

1. 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): CAPItello-281. Presented at: 2026 American Society of Clinical Oncology Genitourinary Cancers Symposium. February 26-28, 2026. San Francisco, California. Abstract 14. https://meetings.asco.org/meetings/2026-asco-genitourinary-cancers-symposium/334/16912?presentation=257280

2. Quistini A, Chierigo F, Fallara G, et al. Androgen receptor signalling in prostate cancer: Mechanisms of resistance to endocrine therapies. Res Rep Urol. 2025;17:211–223. doi:10.2147/RRU.S388265

3. de Bono JS, De Giorgi U, Rodrigues DN, et al. Randomized phase II study evaluating Akt blockade with ipatasertib, in combination with abiraterone, in patients with metastatic prostate cancer with and without PTEN loss. Clin Cancer Res. 2019;25(3):928-936. doi:10.1158/1078-0432.CCR-18-0981

4. Sweeney C, Bracarda S, Sternberg CN, et al. Ipatasertib plus abiraterone and prednisolone in metastatic castration-resistant prostate cancer (IPATential150): a multicentre, randomised, double-blind, phase 3 trial. Lancet. 2021;10;398(10295):131-142. doi:10.1016/S0140-6736(21)00580-8

5. Rathkopf D, Zhao D, Kovacevic L, et al. Real-world patient (pt) characteristics, treatment patterns, and overall survival (OS) in metastatic hormone-sensitive prostate cancer (mHSPC): Insights by PTEN status. J Clin Oncol. 2025;43(suppl _16):5096. doi:10.1200/JCO.2025.43.16_suppl.5096

6. Fizazi K, Clarke NW, De Santis M, et al. A phase III study of capivasertib (capi) + abiraterone (abi) vs placebo (pbo) + abi in patients (pts) with PTEN deficient de novo metastatic hormone-sensitive prostate cancer (mHSPC): CAPItello-281. Presented at: 2025 ESMO Congress; October 17-21, 2025; Berlin, Germany. Abstract 2383O.