rPFS Improves With Capivasertib Combo in Metastatic HSPC Trial

Among patients with PTEN-deficient hormone-sensitive prostate cancer (mHSPC), combining capivasertib (Truqap) with abiraterone acetate (Zytiga) significantly improved radiographic progression-free survival (rPFS) without negatively impacting quality of life, according to findings from the phase 3 CAPItello-281 trial (NCT04493853) presented at the 2026 ASCO Genitourinary Cancers Symposium.

In a presentation of the data, Daniel James George, MD, also reported early declines in physical well-being, though they appeared transient and largely related to on-target toxicities associated with AKT inhibition.

CAPItello-281 met its primary end point, demonstrating a statistically significant improvement in rPFS with capivasertib plus abiraterone (n = 507) vs placebo plus abiraterone (n = 505). Patients treated with capivasertib plus abiraterone achieved a median rPFS of 33.2 months (95% CI, 25.8-44.2) compared with 25.7 months (95% CI, 22.0-29.9) in those treated with placebo plus abiraterone (HR, 0.81; 95% CI, 0.66-0.98; P = .032).

“Capivasertib in combination with abiraterone represents a potential first-in-class targeted treatment for patients with PTEN-deficient mHSPC,” George, director of Genitourinary (GU) Oncology at Duke Cancer Institute and professor of medicine and surgery at Duke University School of Medicine, explained.

How the CAPItello-281 trial was designed

CAPItello-281 is a large, global, randomized study enrolling patients with mHSPC whose tumors demonstrated PTEN loss in at least 90% of cells by immunohistochemistry. In total, 1,012 patients were randomized 1:1 to receive capivasertib plus abiraterone and prednisone or placebo plus abiraterone and prednisone, all on a backbone of androgen deprivation therapy (ADT).

Capivasertib or placebo was administered at 400 mg twice daily on an intermittent schedule of 4 days on and 3 days off, along with 1000 mg once a day plus ADT. According to George, this dosing strategy was selected to “maintain efficacy, but to allow for mitigation of the cumulative side effects that this regimen could cause.”

The primary end point was investigator-assessed rPFS, with overall survival (OS) as a key secondary end point. Patient-reported outcomes (PROs) and tolerability were prespecified exploratory analyses.

Enrollment for the trial occurred from July 13, 2020, through February 5, 2024. The current analysis took place on October 7, 2024, with a median rPFS follow-up of approximately 18 months. The final OS data cutoff was planned at 522 deaths, corresponding to 52.2% maturity.

George emphasized the biological rationale for targeting this population, noting that “PTEN is a parallel driver of disease, proliferation, and survival,” and that “PTEN deficiency has been shown to be a poor prognostic factor throughout the continuum of prostate cancer, including this metastatic hormone-sensitive disease setting.” Capivasertib is a potent and selective inhibitor of AKT1, AKT2, and AKT3, and prior studies in metastatic castration-resistant prostate cancer demonstrated benefit when AKT inhibition was combined with androgen receptor (AR) pathway inhibition.

Additional findings from CAPItello-281

Additional analyses examined outcomes across higher thresholds of PTEN loss (95%, 99%, and 100%). In the capivasertib arm, rPFS was consistent regardless of the degree of PTEN loss. However, in the control arm, higher levels of PTEN loss were associated with worse outcomes.

“When we look at 95%, 99%, and 100% cutoffs, we see a worse prognosis and a shorter median rPFS,” George explained. “Consequently, we see a greater difference in median rPFS between that and the capivasertib arm.” A similar pattern was observed for OS, suggesting that increasing degrees of PTEN loss may be associated with greater relative benefit from AKT inhibition.

Among patients with at least 95% PTEN loss, treatment with capivasertib plus abiraterone (n = 404) resulted in a median rPFS of 33.2 months compared with 22.7 months for those treated with placebo plus abiraterone (n = 410; HR, 0.75; 95% CI, 0.60-0.94). In patients with at least 99% PTEN loss, the median rPFS was 34.1 months with capivasertib plus abiraterone (n = 205) vs 22.4 months with placebo plus abiraterone (n = 196; HR, 0.71; 95% CI, 0.52-0.97).

Among patients with complete PTEN loss, capivasertib plus abiraterone (n = 169) achieved a median rPFS of 34.1 months compared with 22.1 months for placebo plus abiraterone (n = 162; HR, 0.68; 95% CI, 0.48-0.96).

George went on to highlight the discordance between prostate-specific antigen (PSA) changes and radiographic progression in this population. “The majority of patients develop radiographic progression without a PSA rise,” he said, suggesting that “we may be seeing a different biology emerging from this biomarker-selected population.”

Exploring the patient-reported outcomes

PROs were assessed using the Functional Assessment of Cancer Therapy–Prostate (FACT-P) questionnaire, which includes domains for physical well-being, functional well-being, emotional well-being, social/family well-being, and prostate cancer–specific symptoms. Compliance exceeded 80%.

Findings showed that for FACT–P physical well-being (including outcomes such as side effects, energy, nausea, and pain), the mean change from baseline across all time points was −1.7 (adjusted mean [SE], 0.20) with capivasertib plus abiraterone (n = 309) vs −1.3 (SE, 0.20) with placebo plus abiraterone (n = 317), which led to an LS mean difference of −0.4 (95% CI, −0.89-0.14), which did not meet the prespecified threshold for a clinically meaningful three-point change.

Regarding time to clinically meaningful deterioration in FACT–P physical well-being, events occurred in 175 patients in the capivasertib arm and 152 patients in the placebo arm, with median times of 7.2 months (95% CI, 4.5-10.0) and 14.6 months (95% CI, 8.1-not calculable), respectively (HR, 1.43; 95% CI, 1.15-1.78).

“[These] suggest that the initial decline is driven by the addition of capivasertib to the regimen,” he continued, “but from that point on, the subsequent declines are really driven by the backbone of ADT and abiraterone in both arms.”

For FACT–P functional well-being (including physical, functional, and emotional well-being, as well as prostate cancer symptoms), the mean change from baseline across all time points was −1.0 (adjusted mean [SE], 0.26) with capivasertib plus abiraterone (n = 309) vs −0.7 (SE, 0.27) with placebo plus abiraterone (n = 317), resulting in an LS mean difference of −0.3 (95% CI, −1.01-0.37), which did not meet the prespecified three-point threshold for clinical meaningfulness.

Regarding time to clinically meaningful deterioration in functional well-being, events occurred in 33.7% of patients in the capivasertib arm and 34.7% of those in the placebo arm, with median times of 6.3 months (95% CI, 4.4-10.9) and 8.1 months (95% CI, 5.4-14.6), respectively (HR, 1.06; 95% CI, 0.86-1.32).

Functional well-being, which reflects daily activities, work, sleep, and enjoyment of life, did not differ meaningfully between treatment arms. Even in the early treatment period, no separation of curves was observed. “We’re not seeing any functional well-being decline associated with this,” George said.

Similarly, total FACT-P scores were comparable between groups. These findings indicate that overall quality of life was maintained despite higher toxicity rates in the experimental arm.

What was observed regarding safety and tolerability?

Overall adverse event (AE) rates, grade 3 or higher AEs, and serious AEs were higher in the capivasertib arm (98.8%; 67.0%; and 42.5%) compared with the placebo arm (92.0%; 40.4%; 26.0%). Discontinuation due to AEs occurred in approximately 18% of patients receiving capivasertib compared with 4.8% of patients receiving placebo.

“That drop-off is happening early,” George said, “in that same time frame that we’re seeing this decline in physical well-being.”

The most common AEs were consistent with AKT inhibition and included diarrhea (51.9%), hyperglycemia (38%), and rash (35.4%). Median time to onset was approximately 12 to 13 days for rash and diarrhea and within 2 months for hyperglycemia.

“If you start this drug, you’re going to find out pretty quickly if the patient’s going to have this complication,” George explained.

Management strategies relied largely on supportive care. Rash was treated with antihistamines and topical steroids, diarrhea with loperamide, and hyperglycemia primarily with metformin rather than insulin. Dose interruptions and reductions were more common for rash, while permanent discontinuation was uncommon for diarrhea or hyperglycemia.

“The common AEs are AKT inhibition–related on-target effects that occur early and are manageable,” George concluded. “Despite this, our patient-reported outcomes suggest that the functional aspects and the overall quality of life are not affected.”

Reference

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. J Clin Onc. 2026;44(suppl 7):14. doi: 10. 10.1200/JCO.2026.44.7_suppl.14.